- July 19, 2022
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Background
Metastatic breast cancer, which is also known as stage IV breast cancer, has metastasized, meaning it has extended to other areas of the body, primarily the skeletal system, pulmonary organs, cerebral region, or hepatic organ.
The phenomenon of cancer dissemination is referred to as metastasis. Metastasis occurs when cancerous cells detach from the primary tumor in the breast and migrate to different regions within the body. These malignant cells travel either through the circulatory or lymphatic systems (the intricate network of lymph nodes and vessels responsible for eliminating bacteria, viruses, and cellular debris).
The exact causes of breast cancer and its metastasis are not fully understood, but certain risk factors have been identified. These include age (the risk increases with age), family history of breast cancer, particular genetic mutations (e.g., BRCA1 and BRCA2), hormonal factors (such as early menstruation or late menopause), exposure to estrogen, obesity, and a previous history of breast cancer.
Metastatic breast cancer is typically diagnosed through imaging tests such as CT scans, PET scans, bone scans, and MRIs, which can identify the presence and extent of metastasis. Biopsies may also be performed to confirm the presence of cancer cells in the affected sites.
Epidemiology
Breast cancer is indeed a significant health concern in the United States. It is the most common cancer among women, excluding skin cancer, and ranks as the second leading cause of cancer-related deaths in women. The statistics highlight the impact of breast cancer in terms of diagnosis and prevalence.
According to the estimated numbers, around 300,590 people are expected to be diagnosed with invasive breast cancer in the American states in 2023. It’s worth noting that breast cancer can also affect men, although it is less common. The incidence rate and prevalence are higher among women. Globally, breast cancer is the commonly diagnosed cancer, accounting for 1 in 8 cancer diagnoses globally. In 2020, there were nearly 2.3 million new breast cancer cases worldwide, and about 685,000 deaths occurred due to this disease. The burden of breast cancer is expected to increase, with estimates suggesting that by 2040, there will be over 3 million new breast cancer cases and over 1 million deaths yearly.
Metastatic breast cancer is responsible for the most of deaths from breast cancer. In 2023, there will be 43,700 deaths from breast cancer in the United States, with metastatic breast cancer being the leading cause of these deaths. Worldwide, breast cancer is the fifth leading cause of death among women.
Anatomy
Pathophysiology
Metastatic breast cancer, where cancer cells from the breast have spread to other areas of the body. The primary origin of cancer remains the breast, and even when it spreads to other parts of the body, it is still considered breast cancer. Metastasis commonly occurs in the bones, brain, liver, and lungs.
Metastatic breast cancer can occur in different situations. Some individuals may be initially diagnosed with metastatic breast cancer, known as de novo metastatic breast cancer. In most cases, metastatic breast cancer is diagnosed after the initial treatment for early-stage breast cancer, referred to as distant recurrence. Distant recurrence can happen even years after the initial diagnosis and treatment.
Different types of factors can contribute to the risk of developing metastatic breast cancer. These include tumor characteristics (type of cancer cells), the stage of the initial diagnosis, and the treatments received. However, it is essential to note that fewer than 1 in 3 women diagnosed with early-stage breast cancer later develop metastatic breast cancer.
The exact cause of metastatic breast cancer is not fully understood. Metastasis occurs when cancer cells invade nearby lymph nodes or blood vessels and travel to different body parts through the lymphatic or blood circulatory system. It is believed that metastatic cancer can happen when the initial treatment fails to eliminate all cancer cells and a few remain dormant or undetectable. The reasons for this have yet to be fully discovered.
Symptoms of metastatic breast cancer may vary based on the organs involved. Common sites of metastasis include the bones, lungs, liver, and, in some cases, the brain. Symptoms may include back or neck pain, pain in the bones, fatigue, cough, shortness of breath, headache, seizures, vision changes, and other symptoms specific to the affected organs.
Etiology
The etiology, or the cause, of metastatic breast cancer is multifactorial and involves a combination of genetic, environmental, and lifestyle factors. Here are some critical factors associated with the development of metastatic breast cancer:
Genetics
Prognostic Factors
Prognostic factors are important indicators that help predict the likely course and outcome of the disease. Here are some prognostic factors for metastatic breast cancer:
Clinical History
The clinical presentation of metastatic breast cancer can vary depending on several factors, including age group, associated comorbidity or activity, and acuity of presentation.
Physical Examination
In the physical examination for metastatic breast cancer, the following components are typically included:
History: A thorough clinical history is obtained to assess risk factors and gather information about the patient’s symptoms and medical background. This helps in understanding the patient’s overall health and aids in the diagnosis and treatment planning for metastatic breast cancer.
Inspection: The breasts are visually examined for any abnormalities or asymmetry. The following aspects are observed during the inspection:
Palpation: Palpation involves using the hands to examine the breasts and surrounding areas. It is vital to perform palpation without gloves to better appreciate any lesions or abnormalities, especially the smaller ones. The examination is generally performed with the patient sitting upright and the examiner standing behind. Palpation helps to identify any lumps, masses, or areas of tenderness.
Lymph node examination: The regional lymph nodes, including the axillary, supraclavicular, and infraclavicular lymph nodes, are examined for any enlargement or tenderness. Lymph node involvement is an important aspect to consider in staging metastatic breast cancer.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Metastatic breast cancer generally refers to breast cancer that has spread beyond the breast and ipsilateral lymph nodes to other parts of the body. When considering the differential diagnosis of metastatic breast cancer, evaluating other conditions that may present with similar symptoms or findings is essential. Here are some potential differential diagnoses for metastatic breast cancer:
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
The treatment paradigm for metastatic breast cancer depends on various factors, including the subtype of breast cancer, the extent and location of metastasis, the patient’s overall health, and individual preferences.
Systemic Therapy: Systemic therapy involves the use of medications that circulate throughout the body, targeting cancer cells wherever they may be. It includes:
Surgery: Surgery may be considered for select cases of metastatic breast cancer. It is typically performed to alleviate symptoms or complications caused by metastases, such as removing a tumor that is causing pain or obstruction in vital organs.
Radiation Therapy: Radiation therapy can be used to relieve pain and other symptoms associated with metastases in specific areas, such as bone metastases. It uses high-energy beams to target and destroy cancer cells in the treated area.
Palliative Care: Palliative care focuses on improving the quality of life for patients with advanced or metastatic cancer. It addresses pain management, symptom control, psychological support, and assistance with treatment side effects.
by Stage
by Modality
Chemotherapy
Radiation Therapy
Surgical Interventions
Hormone Therapy
Immunotherapy
Hyperthermia
Photodynamic Therapy
Stem Cell Transplant
Targeted Therapy
Palliative Care
Use of the Non-pharmacological therapy for modifying the environment
Non-pharmacological therapy options for metastatic breast cancer include supportive counseling for emotional and psychological support, mind-body techniques like meditation and yoga to diminish stress and promote well-being, regular exercise and physical therapy to manage fatigue and improve physical strength, nutritional support through a well-balanced diet, palliative care and hospice services to address symptoms and enhance quality of life, and complementary therapies such as acupuncture or massage therapy for symptom relief. These therapies aim to provide physical, emotional, and psychological support, alongside conventional medical treatments, to improve the overall well-being and also quality of life for individuals with metastatic breast cancer.
Modifying the environment in metastatic breast cancer is a complex topic that involves understanding the tumor microenvironment (TME) and its role in breast cancer progression and metastasis. The TME consists of various components such as fibroblasts, immune cells, blood and lymphatic vessels, and extracellular matrix, all interacting with cancer cells and influencing tumor behavior. The modifications in the TME during metastasis play a crucial role in the spread of breast cancer to distant sites.
Use of aromatase inhibitor with CDK 4/6 inhibitors as preferred first-line therapy
The use of aromatase inhibitors (AIs) in combination with CDK 4/6 inhibitors has become the preferred first-line therapy for postmenopausal women with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. This treatment approach has demonstrated improved progression-free survival and overall response rates compared to AIs alone.
Aromatase inhibitors work by reducing the production of estrogen in postmenopausal women, as estrogen promotes the growth of hormone receptor-positive breast cancer cells. CDK 4/6 inhibitors, on the other hand, target proteins that promote cell division and proliferation, specifically cyclin-dependent kinase 4 and 6. By combining these two classes of drugs, the treatment can achieve a more comprehensive and effective approach to blocking estrogen-driven cancer cell growth.
The most commonly used CDK 4/6 inhibitors in combination with AIs are:
palbociclib:
It was the first CDK 4/6 inhibitor approved by the FDA for the treatment of metastatic HR+, HER2-negative breast cancer. Clinical trials have shown that the combination of palbociclib with an AI, such as letrozole or anastrozole, significantly improves progression-free survival compared to AI alone.
ribociclib:
Similar to palbociclib, ribociclib is also used in combination with an AI for the treatment of metastatic HR+ breast cancer. Clinical studies have demonstrated improved outcomes in terms of progression-free survival when ribociclib is added to an AI, such as letrozole or exemestane.
abemaciclib:
abemaciclib can be used in combination with an AI, such as anastrozole or letrozole, as a first-line treatment for HR+, HER2-negative metastatic breast cancer. It has shown efficacy in improving progression-free survival and is also approved for use as monotherapy in patients who have progressed after endocrine therapy.
The combination of an AI and a CDK 4/6 inhibitor has become the standard of care as the preferred first-line therapy for postmenopausal women with HR+, HER2-negative metastatic breast cancer.
fulvestrant monotherapy as Alternative front-line option
fulvestrant monotherapy is an alternative front-line treatment option for hormone receptor-positive (HR+) metastatic breast cancer. fulvestrant is a selective estrogen receptor degrader (SERD) that works by blocking the estrogen receptor and degrading it, thereby inhibiting the growth-promoting effects of estrogen on breast cancer cells.
fulvestrant has demonstrated efficacy as a monotherapy in several clinical trials, and it is approved by regulatory authorities for the treatment of HR+ metastatic breast cancer. However, compared to the combination of AIs and CDK 4/6 inhibitors, fulvestrant monotherapy has shown inferior efficacy in terms of progression-free survival and overall response rates.
Clinical studies, such as the PALOMA-3 trial, have established the superiority of combining CDK 4/6 inhibitors with AIs compared to fulvestrant alone. The addition of CDK 4/6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, to AIs has consistently demonstrated improved outcomes, including prolonged progression-free survival and increased overall response rates.
Therefore, the upfront use of AIs in combination with CDK 4/6 inhibitors has become the preferred first-line treatment option for most postmenopausal women with HR+, HER2-negative metastatic breast cancer. fulvestrant monotherapy may be considered as an alternative in situations where patients are unable to tolerate or have contraindications to AIs or CDK 4/6 inhibitors. It may also be used as a subsequent therapy after progression on AIs and CDK 4/6 inhibitors.
Use of ESR1 wild-type in PIK3CA wild-type following AI plus CDK 4/6 inhibitor
In patients with PIK3CA and ESR1 wild-type tumors who have progressed on an aromatase inhibitor (AI) plus cyclin-dependent kinase (CDK) 4/6 inhibitor, the use of the selective estrogen receptor degrader (SERD) fulvestrant with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus can be considered as a treatment option.
Fulvestrant is a SERD that works by blocking and degrading the estrogen receptor, thereby inhibiting estrogen signaling in hormone receptor-positive breast cancer. It has shown efficacy as a monotherapy in patients who have progressed on AIs, and it can be continued as a single agent in subsequent lines of treatment.
Everolimus is an mTOR inhibitor that targets the mTOR signaling pathway, which is often dysregulated in breast cancer. It can be combined with fulvestrant to enhance its efficacy. The combination of fulvestrant and everolimus has been studied in clinical trials, such as the BOLERO-2 trial, which demonstrated improved progression-free survival in patients with advanced hormone receptor-positive, HER2-negative breast cancer who had progressed on AIs.
The decision to use fulvestrant with or without everolimus in this specific patient population should take into account individual patient factors, including their overall health, tolerability, and preferences.
Use of PIK3CA mutated following AI plus CDK 4/6 inhibitor
The phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling cascade performs a vital function in facilitating cellular proliferation, viability, and the development of blood vessels.
fulvestrant with alpelisib: For individuals harboring PIK3CA mutations in their tumors, whose cancer has advanced following treatment with an AI, we recommend considering the combined administration of alpelisib, an inhibitor specific to the alpha isoform of PI3K, and fulvestrant.
Use of AI with CDK 4/6 inhibitors for those earlier treated on tamoxifen
In individuals who have previously received tamoxifen as part of their adjuvant treatment and later develop metastatic breast cancer, the preferred initial therapy is typically the combination of an aromatase inhibitor (AI) with CDK 4/6 inhibition.
Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as adjuvant therapy for hormone receptor-positive breast cancer. However, in the metastatic setting, AIs in combination with CDK 4/6 inhibitors have shown superior efficacy compared to tamoxifen.
Aromatase inhibitors (such as letrozole, anastrozole, or exemestane) block the production of estrogen in postmenopausal women by inhibiting the enzyme aromatase. CDK 4/6 inhibitors (such as palbociclib, ribociclib, or abemaciclib) target proteins that promote cell division and proliferation.
Clinical trials, such as PALOMA-2 and MONALEESA-2, have demonstrated that the combination of an AI with a CDK 4/6 inhibitor as first-line therapy for metastatic hormone receptor-positive, HER2-negative breast cancer significantly improves progression-free survival, overall response rates, and quality of life compared to AI monotherapy.
The specific choice of AI and CDK 4/6 inhibitor may depend on factors such as the patient’s overall health, tolerability, and individual characteristics.
Use of Chemotherapy, antibody drug-conjugates as later-line therapy
sacituzumab govitecan:
sacituzumab govitecan, also known as an anti-Trop-2 antibody-drug conjugate, is prescribed to individuals diagnosed with hormone receptor-positive, HER2-negative cancers who have undergone previous treatments such as endocrine therapy (ET), a cyclin-dependent kinase (CDK) 4/6 inhibitor, and at least two rounds of chemotherapy (including a taxane) for advanced breast cancer, whether in the neoadjuvant/adjuvant or advanced disease stage.
fam-trastuzumab deruxtecan:
Fam-trastuzumab deruxtecan is a suitable choice for patients with tumors exhibiting HER2 immunohistochemistry 1+ or 2+ status and negative in situ hybridization. These patients should have undergone at least one round of chemotherapy for metastatic disease. In cases where the tumor is hormone receptor-positive and unresponsive to endocrine therapy (ET), fam-trastuzumab deruxtecan presents itself as a viable treatment option.
tamoxifen and abemaciclib:
In cases where patients have yet to receive prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor, the combination of tamoxifen and abemaciclib has demonstrated effectiveness and tolerability. This combination therapy has exhibited enhanced outcomes compared to using abemaciclib alone.
While tamoxifen is not our preferred choice for initial endocrine therapy (ET) lines, it can be considered an option in later-line settings. It’s important to note that response rates to tamoxifen in such cases tend to be low.
abemaciclib monotherapy
abemaciclib monotherapy demonstrates single-agent activity, meaning it can effectively be a standalone treatment option. While cyclin-dependent kinase (CDK) 4/6 inhibitors are commonly combined with endocrine therapy (ET), they also possess independent efficacy when used alone.
Use of Hormonal therapy as later-line therapy
Hormonal therapies can still be considered as later-line therapy for metastatic hormone receptor-positive breast cancer. Hormonal therapies work by either blocking the effects of estrogen (anti-estrogens) or reducing the production of estrogen in the body.
The choice of hormonal therapy in later lines of treatment may include:
Selective Estrogen Receptor Modulators (SERMs):
SERMs like tamoxifen or toremifene can still be used in later lines of therapy for metastatic breast cancer. They work by blocking the estrogen receptor and inhibiting estrogen’s growth-promoting effects on cancer cells.
Selective Estrogen Receptor Degraders (SERDs):
fulvestrant, a SERD, is an option for later-line therapy. It works by binding to and degrading the estrogen receptor, thereby inhibiting estrogen signaling.
Progestins:
Progestins, such as megestrol acetate, have some activity against hormone receptor-positive breast cancer and can be considered as later-line hormonal therapy. However, as you mentioned, progestins are associated with an increased risk of thromboembolic events, and their use should be avoided in patients with a history of thromboembolic disorders or those with other risk factors for thromboembolic disease.
Medication
6
mg/m^2
Intravenous (IV)
with other anti-cancer agents
0.3 - 0.4
mg/kg
Intravenous (IV)
one time only
1 - 4
weeks
adjuvant treatment: 175 mg/m2 IV over 3hrs 3 weeks for four courses administered sequentially to doxorubicin containing chemotherapy :
175
mg
Intravenous (IV)
over 3 hr
3
weeks
Initial dose:
3.7
mg/m^2
Intravenous (IV)
usual dose: 5.5-7.4 mg per m2 IV once every 7 days <>br
Max: 18.5 mg per m2 once every seven days.
The patient should not take a high dose if the white cell count reduces to 3000 cells per mm3.
Single drug-treatment:
60 - 75
mg/m^2
Intravenous (IV)
over 3 to 10 minutes once in 21 days for 4 cycles.
Combination drug-treatment: 30 to 60 mg/m2 IV once every 21 to 28 days in combination with cyclophosphamide, fluorouracil, and docetaxel.
10
mg
Orally
once a day
the total duration of therapy is continued until disease progression or no toxicity occurs
Note:
Do not combine the brands of Afinitor tablets and Afinitor Disperz to reach the desired dose
Only use any one of them
For postmenopausal patients:
1
mg
Orally
once a day
until tumor progression
300
mg
Orally
once a day
;Treatment continued until the disease progression, or unacceptable toxicity occurs
The dose recommended for fulvestrant is 500 mg given orally on days 1, 15, and 29, and once monthly thereafter
Note:
Alpelisib with fulvestrant combination used for the treatment of PIK3CAmutated, postmenopausal women, and men, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer and recommended by FDA
5 years of duration of therapy for postmenopausal females:
60
mg
Orally
once a day
The duration can be modified for use longer than 5 years depending on the disease progression and symptoms
Limitations of raloxifene therapy:
No specific recommendation is available for the effectiveness of raloxifene in breast cancer associated with BRCA1 and BRCA2
Not indicated for the reduction of the risk of recurrence of breast cancer
Not recommended for reduction in risk of non-invasive breast cancer
Dose Adjustments
Use with caution if creatinine clearance is <50 ml/minute
No significant data available for dose adjustment for hepatic impairment
150
mg
Orally
twice a day
; when used with tamoxifen or an aromatase inhibitor
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Monotherapy :
200
mg
Orally
twice a day
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
When used in combination therapy with an aromatase inhibitor
150 mg orally taken twice a day PLUS an aromatase inhibitor
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Note:
This combination is helpful for initial endocrine-based therapy for postmenopausal women and men with HR-positive, HER2-negative advanced or metastatic breast cancer
When used in combination therapy with fulvestrant
150 mg orally taken twice a day PLUS Fulvestrant 500 mg given IM as on days 1, 15, and 29, and continue this course once monthly after that
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Note:
This combination is helpful with fulvestrant for adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy
840
mg
Intravenous (IV)
was given on days 1 and 15, followed by protein-bound paclitaxel and 100 mg per m2 IV on Days 1, 8, and 15 for each 28-day course cycle
Continue the course until disease progression, or unacceptable toxicity occurs
Note:
the first infusion administered for over 60 minutes if well-tolerated, and subsequent infusions administered for around 30 minutes
First-line adjuvant therapy:
25
mg
Orally
once a day
for 5 years
Postmenopausal patients: 25 mg orally once a day for 5 years of endocrine therapy, following 2 to 3 years of tamoxifen therapy
Advanced Breast cancer:
25 mg orally once a day in combination with everolimus
Risk reduction treatment for Breast cancer:
Premenopausal for women > 35 years: 25 mg orally once a day for 5 years
Dose Adjustments
Decreased mineral density of bone: manage bone density with suitable supplements as clinically indicated
Vitamine D deficiency: administer the supplement as clinically indicated
Postmenopausal:
60
mg
Orally
once a day
, continue until disease progression or severe health side effects
1
mg
Capsule
Orally
once a day
Continue the therapy until disease progression or unacceptable toxicity occurs
Dose Adjustments
Renal Dose Adjustments: Mild: No adjustment recommended Moderate (CrCl 30-59 ml/min): 0.75 mg orally once a day Severe (CrCl 15-29 ml/min): 0.5 mg orally once a day Liver Dose Adjustments: No adjustment recommended
3.6
mg
Subcutaneous (SC)
28
days
which is placed in the upper abdominal wall
Long term treatment intended for unless clinically inappropriate
Initial dose: 4 mg/kg IV over 90 mins
Maintenance dose: 2 mg/kg IV over 30 min every 3 Weeks during the first 12 weeks of chemotherapy, 6 mg/kg IV infused over 30 to 90 minutes every 3 Weeks for 52 weeks 1 week after chemotherapy completed
Adjuvant treatment with concurrent docetaxel/carboplatin:
Initial dose: 4 mg/kg IV over 90 mins
Maintenance dose: 2 mg/kg IV over 30 min every Week during the first 18 weeks of chemotherapy, 6 mg/kg IV infused over 30 to 90 minutes q3Weeks for 52 weeks 1 week after chemotherapy completed
Adjuvant treatment with anthracycline-based chemotherapy:
Initial dose: 8 mg/kg IV over 90 mins
Maintenance dose: 6 mg/kg IV infused over 30 to 90 minutes every 3 Weeks for 52 weeks 1 week after chemotherapy completed
500 or 600 mg/m² intravenously on 1st and 8th day of every 28 days cycle for 6 cycles, as a part of multi drug regimen, based on cyclophosphamide
Indicated combined with paclitaxel for 1st line treatment of metastatic breast cancer that occurs after the anthracycline-containing adjuvant chemotherapy failure 1250 mg/m² intravenously for 30 minutes on 1st and 8th day of every 21-days cycle It can also be given with 175 mg/m² paclitaxel on 1st day as a 3 hourly infusion prior to gemcitabine
Metastatic Breast Cancer i.e., HER2-overexpressing
1250 mg per day should be given orally from 1st to 21st day along with capecitabine on 1st to 14th day, repeatedly in a 21-day cycle
HER2-positive advanced breast cancer:
1500 mg orally each day in combination with 2.5 mg lapatinib orally each day
Dose modifications:
Diarrhea
In case of Grade 3 diarrhea interrupt the dosing
Other toxicities
In case of Grade 2 or more toxicity interrupt the dosing
300 mg orally twice daily. Continue for a year or until unacceptable toxicity, disease recurrence, or whichever occurs first
Early-stage breast cancer
In the adults diagnosed with early-stage breast cancer, 240 mg of the drug in the form of tablets is administered orally each day for one year
In a cycle of 21 days
1-21 days- 240 mg orally each day, including
1-14 days- 750 mg/m2 capecitabine orally twice daily
Continue until unacceptable toxicities or disease progression
Dose Adjustments
In case of general toxicities and adverse reactions:
Monotherapy
1st dose reduction is 200 mg/day
2nd dose reduction is 160 mg/day
3rd dose reduction is 120 mg/day
When combined with capecitabine
1st dose reduction is 160 mg/day
2nd dose reduction is 120 mg/day
Renal impairment
No significant changes required
Hepatic impairment
Reduce the loading dose to 80 mg
ribociclib is indicated in women with (HR)-positive hormone receptor (HER2) human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
A dose of 600 mg is administered each day orally for the initial 21 days of every 28-day cycle
The medication is continued until the disease is reduced to acceptable toxicity
Dose Adjustments
In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 400 mg daily
Second dose reduction: 200 mg daily
In case the patient is unable to tolerate 200 mg daily, discontinue the treatment
Hepatic impairment
In the case of mild Child-Pugh A, there is no dose adjustment required
In case of moderate-to-severe Child-Pugh B or C: Reduce the starting dose to 400 mg/day
Renal impairment
In the case of mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment is necessary
In case of severe (CrCl 15-30 mL/min): reduce the starting dose to 200 mg/day
palbociclib is indicated in patients for the treatment of patients with breast cancer
Patients with positive hormone receptors and negative human epidermal growth factor receptors 2 are treated with palbociclib
palbociclib and aromatase inhibitor in combination are administered in post-menopausal women and men with breast cancer
Combination therapy
125 mg tablet in combination with an aromatase inhibitor or fulvestrant is given orally, four times daily from the 1st to the 21st day, in a 28-day cycle
In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 100 mg/day
Second dose reduction: 75 mg/day
In case of more reduction of dose, discontinue the treatment
Dose Adjustments
In case of adverse reactions
1st dose reduction- reduce the dose to 100 mg per day
2nd dose reduction- reduce the dose to 75 mg per day
Discontinue the treatment if further dose reduction is required
In case of hepatic impairment
Mild or moderate hepatic impairment, no dose adjustment required
Severe hepatic impairment required a reduced dose to 75 mg/day for the initial 21 days of each 28-day cycle
Renal impairment
No dose adjustment is required in case of mild to moderate to severe renal impairment (CrCl >15 mL/min)
No studies have been performed in the case of hemodialysis
recommended in conjunction with chemotherapy for patients with metastatic HER2-positive (HER2+) breast cancer who have had two or more anti-HER2 regimens, at least one for treating metastatic disease.
every three weeks, 15 mg/kg intravenous
Continue until the condition worsens or the toxicity becomes intolerable
Dose Adjustments
Dosage Modifications
Dysfunction of left ventricle
Delay dosage for about four weeks.
Left ventricular ejection fraction (LVEF) decreased by 16% in absolute terms from baseline.
LVEF below normal institutional limits (or 50% if there are no restrictions) and a 10% absolute decline from pretreatment values in LVEF
LVEF must rebound to normal ranges, and the absolute drop from baseline must be 15% within eight weeks before treatment may continue.
Immediately stop using
LVEF decrease lasts longer than eight weeks, or
Dosing stopped more than three times due to LVEF deterioration
Reactions associated with infusion
Reduce infusion rate if it's mild or moderate
Indicated for Fibrocystic Breast Cancer
100-400 mg/day orally divided twice daily
The therapy is maintained for 3-6 months
In approximately half of the patients, the symptoms will reoccur within 1 year
Hence restart the treatment if required
In females as palliative adjunctive therapy, 10-40 mg/day orally divided for 3 months or more
Off-label
It can be used in prophylaxis of angioneurotic edema and post-partum breast engorgement
It is indicated for management of metastatic breast cancer in females
50-100 mg intramuscularly as a deep injection, once every week
testosterone enanthate is indicated for non-surgical breast cancer in women
200-400 mg intramuscularly every 2-4 weeks
It is used as an adjunctive therapy in the treatment of disseminated or advanced breast carcinoma. The condition prevails in women after menopause, who are given hormonal therapy and whose ovarian function is terminated subsequently
250 mg orally every 6 hours for at least 3 months
Indicated for reducing the pain and symptoms due to advanced breast carcinoma
40 mg orally every 6 hours daily for 2 months
It shouldn’t be used as a substitute of radiotherapy, chemotherapy, or surgery
40
mg/m²
Intravenous (IV)
over 3 hr
3
week
Do not exceed 88 mg daily
Triple negative breast carcinoma
10 mg/kg intravenously on the 1st and 8th day of 21 days cycle
HR-positive, HER2-negative breast carcinoma
10 mg/kg intravenously on the 1st and 8th day of 21 days cycle
Indicated for locally advanced/metastatic breast cancer that HER2-positive unresectable
The drug is pending FDA approval
Indicated as combined with paclitaxel for 1st line treatment for HER2-overexpressing metastatic breast cancer
600 mg trastuzumab with 1000 units of hyaluronidase subcutaneously every 3 weeks
It can be used singly or as a combination with docetaxel & carboplatin
or
in combination with cyclophosphamide, doxorubicin, and docetaxel/paclitaxel
Continue until the disease is progressed
Indicated as combined with paclitaxel for 1st line treatment for HER2-overexpressing metastatic breast cancer
600 mg trastuzumab with 1000 units of hyaluronidase subcutaneously every 3 weeks
Continue until the disease is progressed
Dose Modifications
In cardiomyopathy, withhold the dose for more than 4 weeks if-
there is more than 16% decrease in the LVEF (left ventricular ejection fraction from the baseline
Permanently discontinue, if the LVEF decline persists for more than 8 weeks
HER2-Positive Breast Cancer
Indicated for metastatic breast cancer (HER2-positive) who have taken a prior regimen based on anti-HER2
5.4 mg/kg intravenously every 3 weeks as a 21-day cycle
Continue until the disease is progressed
HER2-Low Breast Cancer
Indicated for metastatic breast cancer (HER2 low) in patients who have taken a prior chemotherapy
5.4 mg/kg intravenously every 3 weeks as a 21-day cycle
Continue until the disease is progressed
Indicated for breast cancer:
Early breast cancer
Indicated as adjuvant therapy of positive for HER2 early breast cancer (EBC) patients with remaining invasive disease following taxane and trastuzumab-based treatment
3.6mg/kg intravenously every 3 weeks
Dosages more than 3.6 mg/kg should not be given.
Unless disease progression or intolerable toxicity occurs, therapy should be continued for 14 cycles.
Metastatic breast cancer
Indicated for the treatment of metastatic breast cancer (MBC) and HER2-positive, in patients who have received trastuzumab and a taxane, separately or in combination
3.6mg/kg intravenously every 3 weeks
Dosages more than 3.6 mg/kg should not be given.
Continue until illness recurrence or intolerable toxicity.
Dose Adjustments
Adverse reactions for dosage reduction
First dosage reduction: 3 mg/kg
Second dosage reduction: 2.4 mg/kg
Need for additional dosage reduction: Treatment should be discontinued.
Hepatotoxicity
MBC
AST/ALT >2.5 to ≤5x ULN in Grade 2: keep the dosage level constant
AST/ALT >5 to ≤20x ULN in Grade 3: Delay administration until AST/ALT returns to Grade ≤2, then lower one dosage level.
Grade 4 (AST/ALT >20x ULN): Immediately stop using
EBC
Grade 2 (AST >3 to ≤5x ULN on the treatment day): Delay administration until AST recovers to Grade ≤1, then continue at the same dosage level.
Grade 2 or 3 (ALT >3 to ≤20x ULN) or Grade 3 (AST >5 to ≤20x ULN) on treatment day: When ALT/AST returns to Grade ≤1, wait and lower the dosage by one level.
AST/ALT >20x ULN at any moment in grade 4: Immediately stop using
Hyperbilirubinemia
MBC
Total bilirubin >1.5 to ≤ 10x ULN in Grade 2: Only provide when total bilirubin returns to ≤Grade 1, then maintain the same dosage level.
Total bilirubin >3 to ≤10x ULN in grade 3: Reduce 1 dosage level after waiting for total bilirubin to return to Grade ≤1 before administering.
Total bilirubin >10x ULN in grade 4: Immediately stop using
EBC
Total bilirubin >1 to ≤2x ULN on the day of treatment: Reduce 1 dosage level after delaying administration until total bilirubin is less than ≤1x ULN.
At any moment, total bilirubin >2x ULN: Immediately stop using
Left ventricular dysfunction
MBC
LVEF <40%: Do not provide medication; re-evaluate LVEF after 3 weeks; if LVEF <40% is verified, stop medication
LVEF 40% to ≤45% and a ≥10% point decline from baseline. Do not provide the medication; reassess the LVEF after three weeks; if the LVEF has not improved to within 10% of baseline, stop the medication.
LVEF 40% to ≤45% and a <10% point decline from baseline. Maintain drug use and LVEF testing within three weeks.
LVEF >45%: maintain drug
EBC
LVEF <45%: Do not provide medicine; repeat LVEF evaluation after 3 weeks, if <45% confirmed, cease treatment
LVEF 45% to <50% and reduction is ≥10% points from baseline: Do not provide medicine; repeat LVEF evaluation after 3 weeks; If LVEF stays below 50% and hasn't improved by at least 10% from baseline, treatment should be stopped.
LVEF 45% to <50% and reduction is <10% from baseline: Continue medication and reassess LVEF within 3 weeks
LVEF >50%: Keep treating
Heart failure
MBC
Symptomatic heart failure: Stop the treatment
EBC
Symptomatic CHF, Grade 3-4 LVSD or Heart Failure, or Grade 2 Heart Failure with LVEF<45%: Stop using the medication.
Thrombocytopenia
MBC
Grade 3 (platelets 25,000/mm3 to ≤50,000/mm3): Do not provide until the platelet count returns to Grade ≤1 (e.g.,≥75,000/mm3), and then continue at the same dosage level.
Platelets <25,000/mm3 (Grade 4): Do not give until the platelet count has returned to Grade ≤1 (e.g., ≥75,000/mm3), and then lower the dosage by one level.
EBC
Grade 3 (platelets 25,000/mm3 to ≤75,000/mm3 on treatment day): Do not give until the platelet count returns to Grade ≤1 (i.e., ≥75,000/mm3), and then continue at the same dosage level; if the patient needs two delays, consider lowering the dose by one level.
Grade 4 (Platelets <25,000/mm3): Do not give until the platelet count has returned to Grade ≤1 (e.g., ≥75,000/mm3), and then lower the dosage by one level.
Pulmonary toxicity
Pneumonitis or interstitial lung disease: discontinue it permanently
Pneumonitis brought on by radiotherapy (EBC alone)
Grade 2: Stop if the condition does not improve with usual care.
Grade 3-4: Treatment should be discontinued
Renal impairment
Mild-to-moderate: No dosage change is required (CrCl ≥30 mL/min)
Severe (CrCl<30 mL/min): No dose change can be suggested for cases due to the lack of information.
Hepatic impairment
Mild to moderate: No dosage modification is necessary; patients with hepatic impairment should be continuously monitored due to the possibility of medication-associated hepatotoxicity.
Severe: Unstudied
Indicated for Breast cancer, early, adjuvant therapy as off-label
For Postmenopausal individuals:
1600 mg orally one time a day for 2-3 years
Hypercalcemia of malignancy
Initial dose: 300 mg intravenously for nearly 2 hr one time a day. Continue till the calcium level reaches normal (i.e., 2-5 days)
The therapy period should not exceed seven days
Maintenance dose: After calcium level reaches to normal, use intravenous bisphosphonate treatment
Oral dose: 1.6 gm-2.4 gm every day in divided one-two times
It should not exceed 3.2 gm in a day
Osteolytic bone metastases
Bonefos:
Initial dose: 1,600 mg orally every day; may be enhanced to a maximum of 3,200 mg every day
Clasteon:
1,600 mg-2,400 mg orally one time or two times a day
It should not exceed 3200 mg in a day
Administer dose of 25 to 50 mg/m2 intravenously as per body surface area (BSA) in every 3 to 4 weeks
Given as injection over 5 to 10 minutes into a rapidly flowing infusion of 5% glucose
Refer adult dosing
A minimum of 10 mg orally each day every 8 hours for 3 months
Future Trends
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Metastatic breast cancer, which is also known as stage IV breast cancer, has metastasized, meaning it has extended to other areas of the body, primarily the skeletal system, pulmonary organs, cerebral region, or hepatic organ.
The phenomenon of cancer dissemination is referred to as metastasis. Metastasis occurs when cancerous cells detach from the primary tumor in the breast and migrate to different regions within the body. These malignant cells travel either through the circulatory or lymphatic systems (the intricate network of lymph nodes and vessels responsible for eliminating bacteria, viruses, and cellular debris).
The exact causes of breast cancer and its metastasis are not fully understood, but certain risk factors have been identified. These include age (the risk increases with age), family history of breast cancer, particular genetic mutations (e.g., BRCA1 and BRCA2), hormonal factors (such as early menstruation or late menopause), exposure to estrogen, obesity, and a previous history of breast cancer.
Metastatic breast cancer is typically diagnosed through imaging tests such as CT scans, PET scans, bone scans, and MRIs, which can identify the presence and extent of metastasis. Biopsies may also be performed to confirm the presence of cancer cells in the affected sites.
Breast cancer is indeed a significant health concern in the United States. It is the most common cancer among women, excluding skin cancer, and ranks as the second leading cause of cancer-related deaths in women. The statistics highlight the impact of breast cancer in terms of diagnosis and prevalence.
According to the estimated numbers, around 300,590 people are expected to be diagnosed with invasive breast cancer in the American states in 2023. It’s worth noting that breast cancer can also affect men, although it is less common. The incidence rate and prevalence are higher among women. Globally, breast cancer is the commonly diagnosed cancer, accounting for 1 in 8 cancer diagnoses globally. In 2020, there were nearly 2.3 million new breast cancer cases worldwide, and about 685,000 deaths occurred due to this disease. The burden of breast cancer is expected to increase, with estimates suggesting that by 2040, there will be over 3 million new breast cancer cases and over 1 million deaths yearly.
Metastatic breast cancer is responsible for the most of deaths from breast cancer. In 2023, there will be 43,700 deaths from breast cancer in the United States, with metastatic breast cancer being the leading cause of these deaths. Worldwide, breast cancer is the fifth leading cause of death among women.
Metastatic breast cancer, where cancer cells from the breast have spread to other areas of the body. The primary origin of cancer remains the breast, and even when it spreads to other parts of the body, it is still considered breast cancer. Metastasis commonly occurs in the bones, brain, liver, and lungs.
Metastatic breast cancer can occur in different situations. Some individuals may be initially diagnosed with metastatic breast cancer, known as de novo metastatic breast cancer. In most cases, metastatic breast cancer is diagnosed after the initial treatment for early-stage breast cancer, referred to as distant recurrence. Distant recurrence can happen even years after the initial diagnosis and treatment.
Different types of factors can contribute to the risk of developing metastatic breast cancer. These include tumor characteristics (type of cancer cells), the stage of the initial diagnosis, and the treatments received. However, it is essential to note that fewer than 1 in 3 women diagnosed with early-stage breast cancer later develop metastatic breast cancer.
The exact cause of metastatic breast cancer is not fully understood. Metastasis occurs when cancer cells invade nearby lymph nodes or blood vessels and travel to different body parts through the lymphatic or blood circulatory system. It is believed that metastatic cancer can happen when the initial treatment fails to eliminate all cancer cells and a few remain dormant or undetectable. The reasons for this have yet to be fully discovered.
Symptoms of metastatic breast cancer may vary based on the organs involved. Common sites of metastasis include the bones, lungs, liver, and, in some cases, the brain. Symptoms may include back or neck pain, pain in the bones, fatigue, cough, shortness of breath, headache, seizures, vision changes, and other symptoms specific to the affected organs.
The etiology, or the cause, of metastatic breast cancer is multifactorial and involves a combination of genetic, environmental, and lifestyle factors. Here are some critical factors associated with the development of metastatic breast cancer:
Prognostic factors are important indicators that help predict the likely course and outcome of the disease. Here are some prognostic factors for metastatic breast cancer:
The clinical presentation of metastatic breast cancer can vary depending on several factors, including age group, associated comorbidity or activity, and acuity of presentation.
In the physical examination for metastatic breast cancer, the following components are typically included:
History: A thorough clinical history is obtained to assess risk factors and gather information about the patient’s symptoms and medical background. This helps in understanding the patient’s overall health and aids in the diagnosis and treatment planning for metastatic breast cancer.
Inspection: The breasts are visually examined for any abnormalities or asymmetry. The following aspects are observed during the inspection:
Palpation: Palpation involves using the hands to examine the breasts and surrounding areas. It is vital to perform palpation without gloves to better appreciate any lesions or abnormalities, especially the smaller ones. The examination is generally performed with the patient sitting upright and the examiner standing behind. Palpation helps to identify any lumps, masses, or areas of tenderness.
Lymph node examination: The regional lymph nodes, including the axillary, supraclavicular, and infraclavicular lymph nodes, are examined for any enlargement or tenderness. Lymph node involvement is an important aspect to consider in staging metastatic breast cancer.
Metastatic breast cancer generally refers to breast cancer that has spread beyond the breast and ipsilateral lymph nodes to other parts of the body. When considering the differential diagnosis of metastatic breast cancer, evaluating other conditions that may present with similar symptoms or findings is essential. Here are some potential differential diagnoses for metastatic breast cancer:
The treatment paradigm for metastatic breast cancer depends on various factors, including the subtype of breast cancer, the extent and location of metastasis, the patient’s overall health, and individual preferences.
Systemic Therapy: Systemic therapy involves the use of medications that circulate throughout the body, targeting cancer cells wherever they may be. It includes:
Surgery: Surgery may be considered for select cases of metastatic breast cancer. It is typically performed to alleviate symptoms or complications caused by metastases, such as removing a tumor that is causing pain or obstruction in vital organs.
Radiation Therapy: Radiation therapy can be used to relieve pain and other symptoms associated with metastases in specific areas, such as bone metastases. It uses high-energy beams to target and destroy cancer cells in the treated area.
Palliative Care: Palliative care focuses on improving the quality of life for patients with advanced or metastatic cancer. It addresses pain management, symptom control, psychological support, and assistance with treatment side effects.
Non-pharmacological therapy options for metastatic breast cancer include supportive counseling for emotional and psychological support, mind-body techniques like meditation and yoga to diminish stress and promote well-being, regular exercise and physical therapy to manage fatigue and improve physical strength, nutritional support through a well-balanced diet, palliative care and hospice services to address symptoms and enhance quality of life, and complementary therapies such as acupuncture or massage therapy for symptom relief. These therapies aim to provide physical, emotional, and psychological support, alongside conventional medical treatments, to improve the overall well-being and also quality of life for individuals with metastatic breast cancer.
Modifying the environment in metastatic breast cancer is a complex topic that involves understanding the tumor microenvironment (TME) and its role in breast cancer progression and metastasis. The TME consists of various components such as fibroblasts, immune cells, blood and lymphatic vessels, and extracellular matrix, all interacting with cancer cells and influencing tumor behavior. The modifications in the TME during metastasis play a crucial role in the spread of breast cancer to distant sites.
The use of aromatase inhibitors (AIs) in combination with CDK 4/6 inhibitors has become the preferred first-line therapy for postmenopausal women with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. This treatment approach has demonstrated improved progression-free survival and overall response rates compared to AIs alone.
Aromatase inhibitors work by reducing the production of estrogen in postmenopausal women, as estrogen promotes the growth of hormone receptor-positive breast cancer cells. CDK 4/6 inhibitors, on the other hand, target proteins that promote cell division and proliferation, specifically cyclin-dependent kinase 4 and 6. By combining these two classes of drugs, the treatment can achieve a more comprehensive and effective approach to blocking estrogen-driven cancer cell growth.
The most commonly used CDK 4/6 inhibitors in combination with AIs are:
palbociclib:
It was the first CDK 4/6 inhibitor approved by the FDA for the treatment of metastatic HR+, HER2-negative breast cancer. Clinical trials have shown that the combination of palbociclib with an AI, such as letrozole or anastrozole, significantly improves progression-free survival compared to AI alone.
ribociclib:
Similar to palbociclib, ribociclib is also used in combination with an AI for the treatment of metastatic HR+ breast cancer. Clinical studies have demonstrated improved outcomes in terms of progression-free survival when ribociclib is added to an AI, such as letrozole or exemestane.
abemaciclib:
abemaciclib can be used in combination with an AI, such as anastrozole or letrozole, as a first-line treatment for HR+, HER2-negative metastatic breast cancer. It has shown efficacy in improving progression-free survival and is also approved for use as monotherapy in patients who have progressed after endocrine therapy.
The combination of an AI and a CDK 4/6 inhibitor has become the standard of care as the preferred first-line therapy for postmenopausal women with HR+, HER2-negative metastatic breast cancer.
fulvestrant monotherapy is an alternative front-line treatment option for hormone receptor-positive (HR+) metastatic breast cancer. fulvestrant is a selective estrogen receptor degrader (SERD) that works by blocking the estrogen receptor and degrading it, thereby inhibiting the growth-promoting effects of estrogen on breast cancer cells.
fulvestrant has demonstrated efficacy as a monotherapy in several clinical trials, and it is approved by regulatory authorities for the treatment of HR+ metastatic breast cancer. However, compared to the combination of AIs and CDK 4/6 inhibitors, fulvestrant monotherapy has shown inferior efficacy in terms of progression-free survival and overall response rates.
Clinical studies, such as the PALOMA-3 trial, have established the superiority of combining CDK 4/6 inhibitors with AIs compared to fulvestrant alone. The addition of CDK 4/6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, to AIs has consistently demonstrated improved outcomes, including prolonged progression-free survival and increased overall response rates.
Therefore, the upfront use of AIs in combination with CDK 4/6 inhibitors has become the preferred first-line treatment option for most postmenopausal women with HR+, HER2-negative metastatic breast cancer. fulvestrant monotherapy may be considered as an alternative in situations where patients are unable to tolerate or have contraindications to AIs or CDK 4/6 inhibitors. It may also be used as a subsequent therapy after progression on AIs and CDK 4/6 inhibitors.
In patients with PIK3CA and ESR1 wild-type tumors who have progressed on an aromatase inhibitor (AI) plus cyclin-dependent kinase (CDK) 4/6 inhibitor, the use of the selective estrogen receptor degrader (SERD) fulvestrant with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus can be considered as a treatment option.
Fulvestrant is a SERD that works by blocking and degrading the estrogen receptor, thereby inhibiting estrogen signaling in hormone receptor-positive breast cancer. It has shown efficacy as a monotherapy in patients who have progressed on AIs, and it can be continued as a single agent in subsequent lines of treatment.
Everolimus is an mTOR inhibitor that targets the mTOR signaling pathway, which is often dysregulated in breast cancer. It can be combined with fulvestrant to enhance its efficacy. The combination of fulvestrant and everolimus has been studied in clinical trials, such as the BOLERO-2 trial, which demonstrated improved progression-free survival in patients with advanced hormone receptor-positive, HER2-negative breast cancer who had progressed on AIs.
The decision to use fulvestrant with or without everolimus in this specific patient population should take into account individual patient factors, including their overall health, tolerability, and preferences.
The phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling cascade performs a vital function in facilitating cellular proliferation, viability, and the development of blood vessels.
fulvestrant with alpelisib: For individuals harboring PIK3CA mutations in their tumors, whose cancer has advanced following treatment with an AI, we recommend considering the combined administration of alpelisib, an inhibitor specific to the alpha isoform of PI3K, and fulvestrant.
In individuals who have previously received tamoxifen as part of their adjuvant treatment and later develop metastatic breast cancer, the preferred initial therapy is typically the combination of an aromatase inhibitor (AI) with CDK 4/6 inhibition.
Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as adjuvant therapy for hormone receptor-positive breast cancer. However, in the metastatic setting, AIs in combination with CDK 4/6 inhibitors have shown superior efficacy compared to tamoxifen.
Aromatase inhibitors (such as letrozole, anastrozole, or exemestane) block the production of estrogen in postmenopausal women by inhibiting the enzyme aromatase. CDK 4/6 inhibitors (such as palbociclib, ribociclib, or abemaciclib) target proteins that promote cell division and proliferation.
Clinical trials, such as PALOMA-2 and MONALEESA-2, have demonstrated that the combination of an AI with a CDK 4/6 inhibitor as first-line therapy for metastatic hormone receptor-positive, HER2-negative breast cancer significantly improves progression-free survival, overall response rates, and quality of life compared to AI monotherapy.
The specific choice of AI and CDK 4/6 inhibitor may depend on factors such as the patient’s overall health, tolerability, and individual characteristics.
sacituzumab govitecan:
sacituzumab govitecan, also known as an anti-Trop-2 antibody-drug conjugate, is prescribed to individuals diagnosed with hormone receptor-positive, HER2-negative cancers who have undergone previous treatments such as endocrine therapy (ET), a cyclin-dependent kinase (CDK) 4/6 inhibitor, and at least two rounds of chemotherapy (including a taxane) for advanced breast cancer, whether in the neoadjuvant/adjuvant or advanced disease stage.
fam-trastuzumab deruxtecan:
Fam-trastuzumab deruxtecan is a suitable choice for patients with tumors exhibiting HER2 immunohistochemistry 1+ or 2+ status and negative in situ hybridization. These patients should have undergone at least one round of chemotherapy for metastatic disease. In cases where the tumor is hormone receptor-positive and unresponsive to endocrine therapy (ET), fam-trastuzumab deruxtecan presents itself as a viable treatment option.
tamoxifen and abemaciclib:
In cases where patients have yet to receive prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor, the combination of tamoxifen and abemaciclib has demonstrated effectiveness and tolerability. This combination therapy has exhibited enhanced outcomes compared to using abemaciclib alone.
While tamoxifen is not our preferred choice for initial endocrine therapy (ET) lines, it can be considered an option in later-line settings. It’s important to note that response rates to tamoxifen in such cases tend to be low.
abemaciclib monotherapy
abemaciclib monotherapy demonstrates single-agent activity, meaning it can effectively be a standalone treatment option. While cyclin-dependent kinase (CDK) 4/6 inhibitors are commonly combined with endocrine therapy (ET), they also possess independent efficacy when used alone.
Hormonal therapies can still be considered as later-line therapy for metastatic hormone receptor-positive breast cancer. Hormonal therapies work by either blocking the effects of estrogen (anti-estrogens) or reducing the production of estrogen in the body.
The choice of hormonal therapy in later lines of treatment may include:
Selective Estrogen Receptor Modulators (SERMs):
SERMs like tamoxifen or toremifene can still be used in later lines of therapy for metastatic breast cancer. They work by blocking the estrogen receptor and inhibiting estrogen’s growth-promoting effects on cancer cells.
Selective Estrogen Receptor Degraders (SERDs):
fulvestrant, a SERD, is an option for later-line therapy. It works by binding to and degrading the estrogen receptor, thereby inhibiting estrogen signaling.
Progestins:
Progestins, such as megestrol acetate, have some activity against hormone receptor-positive breast cancer and can be considered as later-line hormonal therapy. However, as you mentioned, progestins are associated with an increased risk of thromboembolic events, and their use should be avoided in patients with a history of thromboembolic disorders or those with other risk factors for thromboembolic disease.
6
mg/m^2
Intravenous (IV)
with other anti-cancer agents
0.3 - 0.4
mg/kg
Intravenous (IV)
one time only
1 - 4
weeks
adjuvant treatment: 175 mg/m2 IV over 3hrs 3 weeks for four courses administered sequentially to doxorubicin containing chemotherapy :
175
mg
Intravenous (IV)
over 3 hr
3
weeks
Initial dose:
3.7
mg/m^2
Intravenous (IV)
usual dose: 5.5-7.4 mg per m2 IV once every 7 days <>br
Max: 18.5 mg per m2 once every seven days.
The patient should not take a high dose if the white cell count reduces to 3000 cells per mm3.
Single drug-treatment:
60 - 75
mg/m^2
Intravenous (IV)
over 3 to 10 minutes once in 21 days for 4 cycles.
Combination drug-treatment: 30 to 60 mg/m2 IV once every 21 to 28 days in combination with cyclophosphamide, fluorouracil, and docetaxel.
10
mg
Orally
once a day
the total duration of therapy is continued until disease progression or no toxicity occurs
Note:
Do not combine the brands of Afinitor tablets and Afinitor Disperz to reach the desired dose
Only use any one of them
For postmenopausal patients:
1
mg
Orally
once a day
until tumor progression
300
mg
Orally
once a day
;Treatment continued until the disease progression, or unacceptable toxicity occurs
The dose recommended for fulvestrant is 500 mg given orally on days 1, 15, and 29, and once monthly thereafter
Note:
Alpelisib with fulvestrant combination used for the treatment of PIK3CAmutated, postmenopausal women, and men, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer and recommended by FDA
5 years of duration of therapy for postmenopausal females:
60
mg
Orally
once a day
The duration can be modified for use longer than 5 years depending on the disease progression and symptoms
Limitations of raloxifene therapy:
No specific recommendation is available for the effectiveness of raloxifene in breast cancer associated with BRCA1 and BRCA2
Not indicated for the reduction of the risk of recurrence of breast cancer
Not recommended for reduction in risk of non-invasive breast cancer
Dose Adjustments
Use with caution if creatinine clearance is <50 ml/minute
No significant data available for dose adjustment for hepatic impairment
150
mg
Orally
twice a day
; when used with tamoxifen or an aromatase inhibitor
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Monotherapy :
200
mg
Orally
twice a day
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
When used in combination therapy with an aromatase inhibitor
150 mg orally taken twice a day PLUS an aromatase inhibitor
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Note:
This combination is helpful for initial endocrine-based therapy for postmenopausal women and men with HR-positive, HER2-negative advanced or metastatic breast cancer
When used in combination therapy with fulvestrant
150 mg orally taken twice a day PLUS Fulvestrant 500 mg given IM as on days 1, 15, and 29, and continue this course once monthly after that
The treatment needs to be continued for two years until the disease progression or unacceptable toxicity occurs
Note:
This combination is helpful with fulvestrant for adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy
840
mg
Intravenous (IV)
was given on days 1 and 15, followed by protein-bound paclitaxel and 100 mg per m2 IV on Days 1, 8, and 15 for each 28-day course cycle
Continue the course until disease progression, or unacceptable toxicity occurs
Note:
the first infusion administered for over 60 minutes if well-tolerated, and subsequent infusions administered for around 30 minutes
First-line adjuvant therapy:
25
mg
Orally
once a day
for 5 years
Postmenopausal patients: 25 mg orally once a day for 5 years of endocrine therapy, following 2 to 3 years of tamoxifen therapy
Advanced Breast cancer:
25 mg orally once a day in combination with everolimus
Risk reduction treatment for Breast cancer:
Premenopausal for women > 35 years: 25 mg orally once a day for 5 years
Dose Adjustments
Decreased mineral density of bone: manage bone density with suitable supplements as clinically indicated
Vitamine D deficiency: administer the supplement as clinically indicated
Postmenopausal:
60
mg
Orally
once a day
, continue until disease progression or severe health side effects
1
mg
Capsule
Orally
once a day
Continue the therapy until disease progression or unacceptable toxicity occurs
Dose Adjustments
Renal Dose Adjustments: Mild: No adjustment recommended Moderate (CrCl 30-59 ml/min): 0.75 mg orally once a day Severe (CrCl 15-29 ml/min): 0.5 mg orally once a day Liver Dose Adjustments: No adjustment recommended
3.6
mg
Subcutaneous (SC)
28
days
which is placed in the upper abdominal wall
Long term treatment intended for unless clinically inappropriate
Initial dose: 4 mg/kg IV over 90 mins
Maintenance dose: 2 mg/kg IV over 30 min every 3 Weeks during the first 12 weeks of chemotherapy, 6 mg/kg IV infused over 30 to 90 minutes every 3 Weeks for 52 weeks 1 week after chemotherapy completed
Adjuvant treatment with concurrent docetaxel/carboplatin:
Initial dose: 4 mg/kg IV over 90 mins
Maintenance dose: 2 mg/kg IV over 30 min every Week during the first 18 weeks of chemotherapy, 6 mg/kg IV infused over 30 to 90 minutes q3Weeks for 52 weeks 1 week after chemotherapy completed
Adjuvant treatment with anthracycline-based chemotherapy:
Initial dose: 8 mg/kg IV over 90 mins
Maintenance dose: 6 mg/kg IV infused over 30 to 90 minutes every 3 Weeks for 52 weeks 1 week after chemotherapy completed
500 or 600 mg/m² intravenously on 1st and 8th day of every 28 days cycle for 6 cycles, as a part of multi drug regimen, based on cyclophosphamide
Indicated combined with paclitaxel for 1st line treatment of metastatic breast cancer that occurs after the anthracycline-containing adjuvant chemotherapy failure 1250 mg/m² intravenously for 30 minutes on 1st and 8th day of every 21-days cycle It can also be given with 175 mg/m² paclitaxel on 1st day as a 3 hourly infusion prior to gemcitabine
Metastatic Breast Cancer i.e., HER2-overexpressing
1250 mg per day should be given orally from 1st to 21st day along with capecitabine on 1st to 14th day, repeatedly in a 21-day cycle
HER2-positive advanced breast cancer:
1500 mg orally each day in combination with 2.5 mg lapatinib orally each day
Dose modifications:
Diarrhea
In case of Grade 3 diarrhea interrupt the dosing
Other toxicities
In case of Grade 2 or more toxicity interrupt the dosing
300 mg orally twice daily. Continue for a year or until unacceptable toxicity, disease recurrence, or whichever occurs first
Early-stage breast cancer
In the adults diagnosed with early-stage breast cancer, 240 mg of the drug in the form of tablets is administered orally each day for one year
In a cycle of 21 days
1-21 days- 240 mg orally each day, including
1-14 days- 750 mg/m2 capecitabine orally twice daily
Continue until unacceptable toxicities or disease progression
Dose Adjustments
In case of general toxicities and adverse reactions:
Monotherapy
1st dose reduction is 200 mg/day
2nd dose reduction is 160 mg/day
3rd dose reduction is 120 mg/day
When combined with capecitabine
1st dose reduction is 160 mg/day
2nd dose reduction is 120 mg/day
Renal impairment
No significant changes required
Hepatic impairment
Reduce the loading dose to 80 mg
ribociclib is indicated in women with (HR)-positive hormone receptor (HER2) human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
A dose of 600 mg is administered each day orally for the initial 21 days of every 28-day cycle
The medication is continued until the disease is reduced to acceptable toxicity
Dose Adjustments
In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 400 mg daily
Second dose reduction: 200 mg daily
In case the patient is unable to tolerate 200 mg daily, discontinue the treatment
Hepatic impairment
In the case of mild Child-Pugh A, there is no dose adjustment required
In case of moderate-to-severe Child-Pugh B or C: Reduce the starting dose to 400 mg/day
Renal impairment
In the case of mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment is necessary
In case of severe (CrCl 15-30 mL/min): reduce the starting dose to 200 mg/day
palbociclib is indicated in patients for the treatment of patients with breast cancer
Patients with positive hormone receptors and negative human epidermal growth factor receptors 2 are treated with palbociclib
palbociclib and aromatase inhibitor in combination are administered in post-menopausal women and men with breast cancer
Combination therapy
125 mg tablet in combination with an aromatase inhibitor or fulvestrant is given orally, four times daily from the 1st to the 21st day, in a 28-day cycle
In case of adverse reactions, the dose is modified or reduced
The pattern of dose reduction goes like this
First dose reduction: 100 mg/day
Second dose reduction: 75 mg/day
In case of more reduction of dose, discontinue the treatment
Dose Adjustments
In case of adverse reactions
1st dose reduction- reduce the dose to 100 mg per day
2nd dose reduction- reduce the dose to 75 mg per day
Discontinue the treatment if further dose reduction is required
In case of hepatic impairment
Mild or moderate hepatic impairment, no dose adjustment required
Severe hepatic impairment required a reduced dose to 75 mg/day for the initial 21 days of each 28-day cycle
Renal impairment
No dose adjustment is required in case of mild to moderate to severe renal impairment (CrCl >15 mL/min)
No studies have been performed in the case of hemodialysis
recommended in conjunction with chemotherapy for patients with metastatic HER2-positive (HER2+) breast cancer who have had two or more anti-HER2 regimens, at least one for treating metastatic disease.
every three weeks, 15 mg/kg intravenous
Continue until the condition worsens or the toxicity becomes intolerable
Dose Adjustments
Dosage Modifications
Dysfunction of left ventricle
Delay dosage for about four weeks.
Left ventricular ejection fraction (LVEF) decreased by 16% in absolute terms from baseline.
LVEF below normal institutional limits (or 50% if there are no restrictions) and a 10% absolute decline from pretreatment values in LVEF
LVEF must rebound to normal ranges, and the absolute drop from baseline must be 15% within eight weeks before treatment may continue.
Immediately stop using
LVEF decrease lasts longer than eight weeks, or
Dosing stopped more than three times due to LVEF deterioration
Reactions associated with infusion
Reduce infusion rate if it's mild or moderate
Indicated for Fibrocystic Breast Cancer
100-400 mg/day orally divided twice daily
The therapy is maintained for 3-6 months
In approximately half of the patients, the symptoms will reoccur within 1 year
Hence restart the treatment if required
In females as palliative adjunctive therapy, 10-40 mg/day orally divided for 3 months or more
Off-label
It can be used in prophylaxis of angioneurotic edema and post-partum breast engorgement
It is indicated for management of metastatic breast cancer in females
50-100 mg intramuscularly as a deep injection, once every week
testosterone enanthate is indicated for non-surgical breast cancer in women
200-400 mg intramuscularly every 2-4 weeks
It is used as an adjunctive therapy in the treatment of disseminated or advanced breast carcinoma. The condition prevails in women after menopause, who are given hormonal therapy and whose ovarian function is terminated subsequently
250 mg orally every 6 hours for at least 3 months
Indicated for reducing the pain and symptoms due to advanced breast carcinoma
40 mg orally every 6 hours daily for 2 months
It shouldn’t be used as a substitute of radiotherapy, chemotherapy, or surgery
40
mg/m²
Intravenous (IV)
over 3 hr
3
week
Do not exceed 88 mg daily
Triple negative breast carcinoma
10 mg/kg intravenously on the 1st and 8th day of 21 days cycle
HR-positive, HER2-negative breast carcinoma
10 mg/kg intravenously on the 1st and 8th day of 21 days cycle
Indicated for locally advanced/metastatic breast cancer that HER2-positive unresectable
The drug is pending FDA approval
Indicated as combined with paclitaxel for 1st line treatment for HER2-overexpressing metastatic breast cancer
600 mg trastuzumab with 1000 units of hyaluronidase subcutaneously every 3 weeks
It can be used singly or as a combination with docetaxel & carboplatin
or
in combination with cyclophosphamide, doxorubicin, and docetaxel/paclitaxel
Continue until the disease is progressed
Indicated as combined with paclitaxel for 1st line treatment for HER2-overexpressing metastatic breast cancer
600 mg trastuzumab with 1000 units of hyaluronidase subcutaneously every 3 weeks
Continue until the disease is progressed
Dose Modifications
In cardiomyopathy, withhold the dose for more than 4 weeks if-
there is more than 16% decrease in the LVEF (left ventricular ejection fraction from the baseline
Permanently discontinue, if the LVEF decline persists for more than 8 weeks
HER2-Positive Breast Cancer
Indicated for metastatic breast cancer (HER2-positive) who have taken a prior regimen based on anti-HER2
5.4 mg/kg intravenously every 3 weeks as a 21-day cycle
Continue until the disease is progressed
HER2-Low Breast Cancer
Indicated for metastatic breast cancer (HER2 low) in patients who have taken a prior chemotherapy
5.4 mg/kg intravenously every 3 weeks as a 21-day cycle
Continue until the disease is progressed
Indicated for breast cancer:
Early breast cancer
Indicated as adjuvant therapy of positive for HER2 early breast cancer (EBC) patients with remaining invasive disease following taxane and trastuzumab-based treatment
3.6mg/kg intravenously every 3 weeks
Dosages more than 3.6 mg/kg should not be given.
Unless disease progression or intolerable toxicity occurs, therapy should be continued for 14 cycles.
Metastatic breast cancer
Indicated for the treatment of metastatic breast cancer (MBC) and HER2-positive, in patients who have received trastuzumab and a taxane, separately or in combination
3.6mg/kg intravenously every 3 weeks
Dosages more than 3.6 mg/kg should not be given.
Continue until illness recurrence or intolerable toxicity.
Dose Adjustments
Adverse reactions for dosage reduction
First dosage reduction: 3 mg/kg
Second dosage reduction: 2.4 mg/kg
Need for additional dosage reduction: Treatment should be discontinued.
Hepatotoxicity
MBC
AST/ALT >2.5 to ≤5x ULN in Grade 2: keep the dosage level constant
AST/ALT >5 to ≤20x ULN in Grade 3: Delay administration until AST/ALT returns to Grade ≤2, then lower one dosage level.
Grade 4 (AST/ALT >20x ULN): Immediately stop using
EBC
Grade 2 (AST >3 to ≤5x ULN on the treatment day): Delay administration until AST recovers to Grade ≤1, then continue at the same dosage level.
Grade 2 or 3 (ALT >3 to ≤20x ULN) or Grade 3 (AST >5 to ≤20x ULN) on treatment day: When ALT/AST returns to Grade ≤1, wait and lower the dosage by one level.
AST/ALT >20x ULN at any moment in grade 4: Immediately stop using
Hyperbilirubinemia
MBC
Total bilirubin >1.5 to ≤ 10x ULN in Grade 2: Only provide when total bilirubin returns to ≤Grade 1, then maintain the same dosage level.
Total bilirubin >3 to ≤10x ULN in grade 3: Reduce 1 dosage level after waiting for total bilirubin to return to Grade ≤1 before administering.
Total bilirubin >10x ULN in grade 4: Immediately stop using
EBC
Total bilirubin >1 to ≤2x ULN on the day of treatment: Reduce 1 dosage level after delaying administration until total bilirubin is less than ≤1x ULN.
At any moment, total bilirubin >2x ULN: Immediately stop using
Left ventricular dysfunction
MBC
LVEF <40%: Do not provide medication; re-evaluate LVEF after 3 weeks; if LVEF <40% is verified, stop medication
LVEF 40% to ≤45% and a ≥10% point decline from baseline. Do not provide the medication; reassess the LVEF after three weeks; if the LVEF has not improved to within 10% of baseline, stop the medication.
LVEF 40% to ≤45% and a <10% point decline from baseline. Maintain drug use and LVEF testing within three weeks.
LVEF >45%: maintain drug
EBC
LVEF <45%: Do not provide medicine; repeat LVEF evaluation after 3 weeks, if <45% confirmed, cease treatment
LVEF 45% to <50% and reduction is ≥10% points from baseline: Do not provide medicine; repeat LVEF evaluation after 3 weeks; If LVEF stays below 50% and hasn't improved by at least 10% from baseline, treatment should be stopped.
LVEF 45% to <50% and reduction is <10% from baseline: Continue medication and reassess LVEF within 3 weeks
LVEF >50%: Keep treating
Heart failure
MBC
Symptomatic heart failure: Stop the treatment
EBC
Symptomatic CHF, Grade 3-4 LVSD or Heart Failure, or Grade 2 Heart Failure with LVEF<45%: Stop using the medication.
Thrombocytopenia
MBC
Grade 3 (platelets 25,000/mm3 to ≤50,000/mm3): Do not provide until the platelet count returns to Grade ≤1 (e.g.,≥75,000/mm3), and then continue at the same dosage level.
Platelets <25,000/mm3 (Grade 4): Do not give until the platelet count has returned to Grade ≤1 (e.g., ≥75,000/mm3), and then lower the dosage by one level.
EBC
Grade 3 (platelets 25,000/mm3 to ≤75,000/mm3 on treatment day): Do not give until the platelet count returns to Grade ≤1 (i.e., ≥75,000/mm3), and then continue at the same dosage level; if the patient needs two delays, consider lowering the dose by one level.
Grade 4 (Platelets <25,000/mm3): Do not give until the platelet count has returned to Grade ≤1 (e.g., ≥75,000/mm3), and then lower the dosage by one level.
Pulmonary toxicity
Pneumonitis or interstitial lung disease: discontinue it permanently
Pneumonitis brought on by radiotherapy (EBC alone)
Grade 2: Stop if the condition does not improve with usual care.
Grade 3-4: Treatment should be discontinued
Renal impairment
Mild-to-moderate: No dosage change is required (CrCl ≥30 mL/min)
Severe (CrCl<30 mL/min): No dose change can be suggested for cases due to the lack of information.
Hepatic impairment
Mild to moderate: No dosage modification is necessary; patients with hepatic impairment should be continuously monitored due to the possibility of medication-associated hepatotoxicity.
Severe: Unstudied
Indicated for Breast cancer, early, adjuvant therapy as off-label
For Postmenopausal individuals:
1600 mg orally one time a day for 2-3 years
Hypercalcemia of malignancy
Initial dose: 300 mg intravenously for nearly 2 hr one time a day. Continue till the calcium level reaches normal (i.e., 2-5 days)
The therapy period should not exceed seven days
Maintenance dose: After calcium level reaches to normal, use intravenous bisphosphonate treatment
Oral dose: 1.6 gm-2.4 gm every day in divided one-two times
It should not exceed 3.2 gm in a day
Osteolytic bone metastases
Bonefos:
Initial dose: 1,600 mg orally every day; may be enhanced to a maximum of 3,200 mg every day
Clasteon:
1,600 mg-2,400 mg orally one time or two times a day
It should not exceed 3200 mg in a day
Administer dose of 25 to 50 mg/m2 intravenously as per body surface area (BSA) in every 3 to 4 weeks
Given as injection over 5 to 10 minutes into a rapidly flowing infusion of 5% glucose
Safety and efficacy are not studied
Refer adult dosing
A minimum of 10 mg orally each day every 8 hours for 3 months
Metastatic breast cancer, which is also known as stage IV breast cancer, has metastasized, meaning it has extended to other areas of the body, primarily the skeletal system, pulmonary organs, cerebral region, or hepatic organ.
The phenomenon of cancer dissemination is referred to as metastasis. Metastasis occurs when cancerous cells detach from the primary tumor in the breast and migrate to different regions within the body. These malignant cells travel either through the circulatory or lymphatic systems (the intricate network of lymph nodes and vessels responsible for eliminating bacteria, viruses, and cellular debris).
The exact causes of breast cancer and its metastasis are not fully understood, but certain risk factors have been identified. These include age (the risk increases with age), family history of breast cancer, particular genetic mutations (e.g., BRCA1 and BRCA2), hormonal factors (such as early menstruation or late menopause), exposure to estrogen, obesity, and a previous history of breast cancer.
Metastatic breast cancer is typically diagnosed through imaging tests such as CT scans, PET scans, bone scans, and MRIs, which can identify the presence and extent of metastasis. Biopsies may also be performed to confirm the presence of cancer cells in the affected sites.
Breast cancer is indeed a significant health concern in the United States. It is the most common cancer among women, excluding skin cancer, and ranks as the second leading cause of cancer-related deaths in women. The statistics highlight the impact of breast cancer in terms of diagnosis and prevalence.
According to the estimated numbers, around 300,590 people are expected to be diagnosed with invasive breast cancer in the American states in 2023. It’s worth noting that breast cancer can also affect men, although it is less common. The incidence rate and prevalence are higher among women. Globally, breast cancer is the commonly diagnosed cancer, accounting for 1 in 8 cancer diagnoses globally. In 2020, there were nearly 2.3 million new breast cancer cases worldwide, and about 685,000 deaths occurred due to this disease. The burden of breast cancer is expected to increase, with estimates suggesting that by 2040, there will be over 3 million new breast cancer cases and over 1 million deaths yearly.
Metastatic breast cancer is responsible for the most of deaths from breast cancer. In 2023, there will be 43,700 deaths from breast cancer in the United States, with metastatic breast cancer being the leading cause of these deaths. Worldwide, breast cancer is the fifth leading cause of death among women.
Metastatic breast cancer, where cancer cells from the breast have spread to other areas of the body. The primary origin of cancer remains the breast, and even when it spreads to other parts of the body, it is still considered breast cancer. Metastasis commonly occurs in the bones, brain, liver, and lungs.
Metastatic breast cancer can occur in different situations. Some individuals may be initially diagnosed with metastatic breast cancer, known as de novo metastatic breast cancer. In most cases, metastatic breast cancer is diagnosed after the initial treatment for early-stage breast cancer, referred to as distant recurrence. Distant recurrence can happen even years after the initial diagnosis and treatment.
Different types of factors can contribute to the risk of developing metastatic breast cancer. These include tumor characteristics (type of cancer cells), the stage of the initial diagnosis, and the treatments received. However, it is essential to note that fewer than 1 in 3 women diagnosed with early-stage breast cancer later develop metastatic breast cancer.
The exact cause of metastatic breast cancer is not fully understood. Metastasis occurs when cancer cells invade nearby lymph nodes or blood vessels and travel to different body parts through the lymphatic or blood circulatory system. It is believed that metastatic cancer can happen when the initial treatment fails to eliminate all cancer cells and a few remain dormant or undetectable. The reasons for this have yet to be fully discovered.
Symptoms of metastatic breast cancer may vary based on the organs involved. Common sites of metastasis include the bones, lungs, liver, and, in some cases, the brain. Symptoms may include back or neck pain, pain in the bones, fatigue, cough, shortness of breath, headache, seizures, vision changes, and other symptoms specific to the affected organs.
The etiology, or the cause, of metastatic breast cancer is multifactorial and involves a combination of genetic, environmental, and lifestyle factors. Here are some critical factors associated with the development of metastatic breast cancer:
Prognostic factors are important indicators that help predict the likely course and outcome of the disease. Here are some prognostic factors for metastatic breast cancer:
The clinical presentation of metastatic breast cancer can vary depending on several factors, including age group, associated comorbidity or activity, and acuity of presentation.
In the physical examination for metastatic breast cancer, the following components are typically included:
History: A thorough clinical history is obtained to assess risk factors and gather information about the patient’s symptoms and medical background. This helps in understanding the patient’s overall health and aids in the diagnosis and treatment planning for metastatic breast cancer.
Inspection: The breasts are visually examined for any abnormalities or asymmetry. The following aspects are observed during the inspection:
Palpation: Palpation involves using the hands to examine the breasts and surrounding areas. It is vital to perform palpation without gloves to better appreciate any lesions or abnormalities, especially the smaller ones. The examination is generally performed with the patient sitting upright and the examiner standing behind. Palpation helps to identify any lumps, masses, or areas of tenderness.
Lymph node examination: The regional lymph nodes, including the axillary, supraclavicular, and infraclavicular lymph nodes, are examined for any enlargement or tenderness. Lymph node involvement is an important aspect to consider in staging metastatic breast cancer.
Metastatic breast cancer generally refers to breast cancer that has spread beyond the breast and ipsilateral lymph nodes to other parts of the body. When considering the differential diagnosis of metastatic breast cancer, evaluating other conditions that may present with similar symptoms or findings is essential. Here are some potential differential diagnoses for metastatic breast cancer:
The treatment paradigm for metastatic breast cancer depends on various factors, including the subtype of breast cancer, the extent and location of metastasis, the patient’s overall health, and individual preferences.
Systemic Therapy: Systemic therapy involves the use of medications that circulate throughout the body, targeting cancer cells wherever they may be. It includes:
Surgery: Surgery may be considered for select cases of metastatic breast cancer. It is typically performed to alleviate symptoms or complications caused by metastases, such as removing a tumor that is causing pain or obstruction in vital organs.
Radiation Therapy: Radiation therapy can be used to relieve pain and other symptoms associated with metastases in specific areas, such as bone metastases. It uses high-energy beams to target and destroy cancer cells in the treated area.
Palliative Care: Palliative care focuses on improving the quality of life for patients with advanced or metastatic cancer. It addresses pain management, symptom control, psychological support, and assistance with treatment side effects.
Oncology, Medical
Oncology, Other
Oncology, Radiation
Non-pharmacological therapy options for metastatic breast cancer include supportive counseling for emotional and psychological support, mind-body techniques like meditation and yoga to diminish stress and promote well-being, regular exercise and physical therapy to manage fatigue and improve physical strength, nutritional support through a well-balanced diet, palliative care and hospice services to address symptoms and enhance quality of life, and complementary therapies such as acupuncture or massage therapy for symptom relief. These therapies aim to provide physical, emotional, and psychological support, alongside conventional medical treatments, to improve the overall well-being and also quality of life for individuals with metastatic breast cancer.
Modifying the environment in metastatic breast cancer is a complex topic that involves understanding the tumor microenvironment (TME) and its role in breast cancer progression and metastasis. The TME consists of various components such as fibroblasts, immune cells, blood and lymphatic vessels, and extracellular matrix, all interacting with cancer cells and influencing tumor behavior. The modifications in the TME during metastasis play a crucial role in the spread of breast cancer to distant sites.
Oncology, Medical
Oncology, Other
Oncology, Radiation
The use of aromatase inhibitors (AIs) in combination with CDK 4/6 inhibitors has become the preferred first-line therapy for postmenopausal women with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. This treatment approach has demonstrated improved progression-free survival and overall response rates compared to AIs alone.
Aromatase inhibitors work by reducing the production of estrogen in postmenopausal women, as estrogen promotes the growth of hormone receptor-positive breast cancer cells. CDK 4/6 inhibitors, on the other hand, target proteins that promote cell division and proliferation, specifically cyclin-dependent kinase 4 and 6. By combining these two classes of drugs, the treatment can achieve a more comprehensive and effective approach to blocking estrogen-driven cancer cell growth.
The most commonly used CDK 4/6 inhibitors in combination with AIs are:
palbociclib:
It was the first CDK 4/6 inhibitor approved by the FDA for the treatment of metastatic HR+, HER2-negative breast cancer. Clinical trials have shown that the combination of palbociclib with an AI, such as letrozole or anastrozole, significantly improves progression-free survival compared to AI alone.
ribociclib:
Similar to palbociclib, ribociclib is also used in combination with an AI for the treatment of metastatic HR+ breast cancer. Clinical studies have demonstrated improved outcomes in terms of progression-free survival when ribociclib is added to an AI, such as letrozole or exemestane.
abemaciclib:
abemaciclib can be used in combination with an AI, such as anastrozole or letrozole, as a first-line treatment for HR+, HER2-negative metastatic breast cancer. It has shown efficacy in improving progression-free survival and is also approved for use as monotherapy in patients who have progressed after endocrine therapy.
The combination of an AI and a CDK 4/6 inhibitor has become the standard of care as the preferred first-line therapy for postmenopausal women with HR+, HER2-negative metastatic breast cancer.
Oncology, Medical
Oncology, Other
Oncology, Radiation
fulvestrant monotherapy is an alternative front-line treatment option for hormone receptor-positive (HR+) metastatic breast cancer. fulvestrant is a selective estrogen receptor degrader (SERD) that works by blocking the estrogen receptor and degrading it, thereby inhibiting the growth-promoting effects of estrogen on breast cancer cells.
fulvestrant has demonstrated efficacy as a monotherapy in several clinical trials, and it is approved by regulatory authorities for the treatment of HR+ metastatic breast cancer. However, compared to the combination of AIs and CDK 4/6 inhibitors, fulvestrant monotherapy has shown inferior efficacy in terms of progression-free survival and overall response rates.
Clinical studies, such as the PALOMA-3 trial, have established the superiority of combining CDK 4/6 inhibitors with AIs compared to fulvestrant alone. The addition of CDK 4/6 inhibitors, such as palbociclib, ribociclib, or abemaciclib, to AIs has consistently demonstrated improved outcomes, including prolonged progression-free survival and increased overall response rates.
Therefore, the upfront use of AIs in combination with CDK 4/6 inhibitors has become the preferred first-line treatment option for most postmenopausal women with HR+, HER2-negative metastatic breast cancer. fulvestrant monotherapy may be considered as an alternative in situations where patients are unable to tolerate or have contraindications to AIs or CDK 4/6 inhibitors. It may also be used as a subsequent therapy after progression on AIs and CDK 4/6 inhibitors.
Oncology, Medical
Oncology, Other
Oncology, Radiation
In patients with PIK3CA and ESR1 wild-type tumors who have progressed on an aromatase inhibitor (AI) plus cyclin-dependent kinase (CDK) 4/6 inhibitor, the use of the selective estrogen receptor degrader (SERD) fulvestrant with or without the mechanistic target of rapamycin (mTOR) inhibitor everolimus can be considered as a treatment option.
Fulvestrant is a SERD that works by blocking and degrading the estrogen receptor, thereby inhibiting estrogen signaling in hormone receptor-positive breast cancer. It has shown efficacy as a monotherapy in patients who have progressed on AIs, and it can be continued as a single agent in subsequent lines of treatment.
Everolimus is an mTOR inhibitor that targets the mTOR signaling pathway, which is often dysregulated in breast cancer. It can be combined with fulvestrant to enhance its efficacy. The combination of fulvestrant and everolimus has been studied in clinical trials, such as the BOLERO-2 trial, which demonstrated improved progression-free survival in patients with advanced hormone receptor-positive, HER2-negative breast cancer who had progressed on AIs.
The decision to use fulvestrant with or without everolimus in this specific patient population should take into account individual patient factors, including their overall health, tolerability, and preferences.
Oncology, Medical
Oncology, Other
Oncology, Radiation
The phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling cascade performs a vital function in facilitating cellular proliferation, viability, and the development of blood vessels.
fulvestrant with alpelisib: For individuals harboring PIK3CA mutations in their tumors, whose cancer has advanced following treatment with an AI, we recommend considering the combined administration of alpelisib, an inhibitor specific to the alpha isoform of PI3K, and fulvestrant.
Oncology, Medical
Oncology, Other
Oncology, Radiation
In individuals who have previously received tamoxifen as part of their adjuvant treatment and later develop metastatic breast cancer, the preferred initial therapy is typically the combination of an aromatase inhibitor (AI) with CDK 4/6 inhibition.
Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as adjuvant therapy for hormone receptor-positive breast cancer. However, in the metastatic setting, AIs in combination with CDK 4/6 inhibitors have shown superior efficacy compared to tamoxifen.
Aromatase inhibitors (such as letrozole, anastrozole, or exemestane) block the production of estrogen in postmenopausal women by inhibiting the enzyme aromatase. CDK 4/6 inhibitors (such as palbociclib, ribociclib, or abemaciclib) target proteins that promote cell division and proliferation.
Clinical trials, such as PALOMA-2 and MONALEESA-2, have demonstrated that the combination of an AI with a CDK 4/6 inhibitor as first-line therapy for metastatic hormone receptor-positive, HER2-negative breast cancer significantly improves progression-free survival, overall response rates, and quality of life compared to AI monotherapy.
The specific choice of AI and CDK 4/6 inhibitor may depend on factors such as the patient’s overall health, tolerability, and individual characteristics.
Oncology, Medical
Oncology, Other
Oncology, Radiation
sacituzumab govitecan:
sacituzumab govitecan, also known as an anti-Trop-2 antibody-drug conjugate, is prescribed to individuals diagnosed with hormone receptor-positive, HER2-negative cancers who have undergone previous treatments such as endocrine therapy (ET), a cyclin-dependent kinase (CDK) 4/6 inhibitor, and at least two rounds of chemotherapy (including a taxane) for advanced breast cancer, whether in the neoadjuvant/adjuvant or advanced disease stage.
fam-trastuzumab deruxtecan:
Fam-trastuzumab deruxtecan is a suitable choice for patients with tumors exhibiting HER2 immunohistochemistry 1+ or 2+ status and negative in situ hybridization. These patients should have undergone at least one round of chemotherapy for metastatic disease. In cases where the tumor is hormone receptor-positive and unresponsive to endocrine therapy (ET), fam-trastuzumab deruxtecan presents itself as a viable treatment option.
tamoxifen and abemaciclib:
In cases where patients have yet to receive prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor, the combination of tamoxifen and abemaciclib has demonstrated effectiveness and tolerability. This combination therapy has exhibited enhanced outcomes compared to using abemaciclib alone.
While tamoxifen is not our preferred choice for initial endocrine therapy (ET) lines, it can be considered an option in later-line settings. It’s important to note that response rates to tamoxifen in such cases tend to be low.
abemaciclib monotherapy
abemaciclib monotherapy demonstrates single-agent activity, meaning it can effectively be a standalone treatment option. While cyclin-dependent kinase (CDK) 4/6 inhibitors are commonly combined with endocrine therapy (ET), they also possess independent efficacy when used alone.
Oncology, Medical
Oncology, Other
Oncology, Radiation
Hormonal therapies can still be considered as later-line therapy for metastatic hormone receptor-positive breast cancer. Hormonal therapies work by either blocking the effects of estrogen (anti-estrogens) or reducing the production of estrogen in the body.
The choice of hormonal therapy in later lines of treatment may include:
Selective Estrogen Receptor Modulators (SERMs):
SERMs like tamoxifen or toremifene can still be used in later lines of therapy for metastatic breast cancer. They work by blocking the estrogen receptor and inhibiting estrogen’s growth-promoting effects on cancer cells.
Selective Estrogen Receptor Degraders (SERDs):
fulvestrant, a SERD, is an option for later-line therapy. It works by binding to and degrading the estrogen receptor, thereby inhibiting estrogen signaling.
Progestins:
Progestins, such as megestrol acetate, have some activity against hormone receptor-positive breast cancer and can be considered as later-line hormonal therapy. However, as you mentioned, progestins are associated with an increased risk of thromboembolic events, and their use should be avoided in patients with a history of thromboembolic disorders or those with other risk factors for thromboembolic disease.
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Founded in 2014, medtigo is committed to providing high-quality, friendly physicians, transparent pricing, and a focus on building relationships and a lifestyle brand for medical professionals nationwide.
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