Systemic Therapy Options for Treating HR+/HER2– Metastatic Breast Cancer

An estimated 276,480 women in the United States will be diagnosed with invasive breast cancer in 2020. Approximately 42,170 women are expected to die from breast cancer in 2020. The average 5-year survival rate for patients with breast cancer is 90%, regardless of stage. However, the 5-year survival rate for patients with metastatic breast cancer is only 28%. The median age at the time of initial breast cancer diagnosis is 62 years. Following initial breast cancer diagnosis by mammography, MRI, or ultrasound, treatment is largely based upon the histologic subtype and staging of the tumor(s).¹

Identification of the histologic subtype involves pathological evaluation of a biopsy specimen. There are 4 main histologic subtypes of breast cancer: hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HR-negative/HER2-negative (triple negative breast cancer), HR-positive/HER2-positive (triple-positive breast cancer), and HR-negative/HER2-positive. Hormone receptor (ie, estrogen receptor and progesterone receptor) status as well as HER2 status are usually confirmed via immunohistochemistry staining. Fluorescence in-situ hybridization testing may also be used to identify HER2 status. The HR+/HER2— subtype is the most common subtype and occurs in 68% of women with breast cancer.²

Breast cancer is staged from stage 0 to stage IV using the American Joint Committee on Cancer 8th Edition cancer staging manual’s guidelines (TNM system). These stages are further categorized depending on the size of the primary tumor (T), whether the cancer has spread to lymph nodes (N), and whether the cancer has spread to other parts of the body (M). Stage 0, also called carcinoma in situ, is the earliest breast cancer stage and is considered noninvasive. Stages I, II, III, and IV comprise invasive breast cancer. Stage IV, also known as metastatic breast cancer, occurs when the cancer has spread beyond the lymph nodes to other parts of the body. Patients suspected of having metastatic breast cancer may be evaluated with CT scans or positron emission tomography scans to identify focal sites of metastases. The most common sites of metastatic spread of breast cancer include the bones, liver, lungs, and brain.^3,4

The initial treatment of HR+/HER2— metastatic breast cancer is dictated by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Breast Cancer (version 4.2020). When considering selection of an appropriate treatment regimen in this scenario, the oncologist must take into account whether or not the patient is having a visceral crisis, such as symptomatic tumor burden involving an organ system; whether or not the patient has had prior endocrine therapy within the previous year; and whether or not the patient was premenopausal or postmenopausal at the time of diagnosis.⁵

For patients with HR+/HER2— metastatic breast cancer presenting with an initial visceral crisis, the NCCN guidelines recommend initial systemic therapy with cytotoxic chemotherapy. Generally, single-agent chemotherapy is recommended with agents such as anthracyclines (ie, doxorubicin, liposomal doxorubicin), taxanes (ie, paclitaxel), antimetabolites (ie, capecitabine), or microtubule inhibitors (ie, vinorelbine, eribulin). In select circumstances of patients with rapidly progressing disease in the setting of a visceral crisis, combination chemotherapy may be considered, with such regimens as doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/fluorouracil.⁵

For patients with HR+/HER2— metastatic breast cancer who present without a visceral crisis and who have not received endocrine therapy within the prior year, treatment options vary dependent upon menopausal status at the time of initial breast cancer diagnosis. For premenopausal patients, systemic endocrine-based therapy in combination with ovarian ablation/suppression (either via oophorectomy, ovarian radiation, or luteinizing hormone releasing hormone agonist therapy) or selective estrogen receptor modulator therapy alone are recommended as first-line treatment. For postmenopausal patients, systemic endocrine-based therapy without ovarian ablation/ suppression is recommended as first-line treatment. For patients with HR+/HER2– metastatic breast cancer who present without a visceral crisis and who have received endocrine therapy within the prior year, the recommended treatment options for premenopausal and postmenopausal patients are very similar.⁵

Preferred first-line systemic endocrine-based therapy options, which are category 1 recommendations (based on phase 3 clinical trial evidence) per NCCN guidelines, include an aromatase inhibitor (ie, anastrozole, exemestane, or letrozole) in combination with a CDK4/6 inhibitor (ie, palbociclib, ribociclib, or abemaciclib); fulvestrant with or without a nonsteroidal aromatase inhibitor (ie, anastrozole or letrozole); or fulvestrant in combination with a CDK4/6 inhibitor. Other preferred first-line systemic endocrine-based therapy options include nonsteroidal aromatase inhibitor monotherapy; selective estrogen receptor modulator (ie, tamoxifen or toremifene) monotherapy; or steroidal aromatase inhibitor (ie, exemestane) monotherapy.⁵

Given that patients with HR+/HER2— metastatic breast cancer will ultimately progress following first-line therapy, second-line systemic endocrine-based therapy options must be considered. Preferred second-line systemic endocrine-based therapy options, which are Category 1 recommendations per NCCN guidelines, include fulvestrant in combination with a CDK4/6 inhibitor (if a CDK4/6 inhibitor was not utilized in the first-line setting) or fulvestrant in combination with alpelisib (only in patients with PIK3CA mutations). Other preferred second-line systemic endocrine-based therapy options include everolimus in combination with exemestane, tamoxifen, or fulvestrant; fulvestrant monotherapy; nonsteroidal aromatase inhibitor monotherapy; or selective estrogen receptor modulator monotherapy.⁵

Commercially available CDK4/6 inhibitors include abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali). As the name implies, these agents target the enzymes CDK4 and CDK6, which are involved in cell division. These inhibitors interrupt signals that stimulate the proliferation of malignant cells. While CDK4/6 proteins are found in both healthy cells and cancer cells, these proteins can become overactive in metastatic breast cancer patients and cause cancer cells to grow and proliferate. Additionally, antiestrogenic medications, such as aromatase inhibitors or fulvestrant, work synergistically to reduce tumor cell proliferation, which is driven by estrogen.⁶

Abemaciclib is indicated as initial endocrine-based therapy (in combination with an aromatase inhibitor) for the treatment of HR+/HER2— metastatic breast cancer in postmenopausal women; in combination with fulvestrant for the treatment of HR+/HER2– metastatic breast cancer in women with disease progressionfollowing endocrine therapy; and as monotherapy for the treatment of HR+/HER2– metastatic breast cancer in patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Abemaciclib is indicated as 150 mg or 200 mg orally (dependent upon indication for use) administered twice daily with or without food. Abemaciclib may require dose reductions for certain adverse events (AEs), certain drug interactions (abemaciclib is a major substrate of CYP3A4), and patients with severe hepatic impairment (Child-Pugh C). Abemaciclib is available as 50-mg, 100-mg, 150-mg, and 200-mg tablets. The most common AEs (incidence ≥20%) include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia. The prescribing information for abemaciclib contains warnings for diarrhea, neutropenia, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.⁷

Palbociclib is indicated for the treatment of adult patients with HR+/HER2— metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men, and in combination with fulvestrant in patients with disease progression following endocrine therapy. Palbociclib is indicated as 125 mg orally once daily for 21 days on followed by 7 days off. Palbociclib is presently available as 75-mg, 100-mg, and 125-mg capsules or tablets. Palbociclib capsules must be taken with food while palbociclib tablets may be taken with or without food. Pfizer, the brand manufacturer of Ibrance, will be discontinuing commercialization of the capsule formulation after August 2020.

Palbociclib may require dose reductions for certain AEs, certain drug interactions (palbociclib is a major substrate of CYP3A4), and patients with severe hepatic impairment. The most common AEs (incidence ≥10%) include neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and pyrexia. The prescribing information for palbociclib contains warnings for neutropenia, ILD/ pneumonitis, and embryo-fetal toxicity.⁸

Ribociclib is indicated in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with HR+/HER2— metastatic breast cancer. It is indicated in combination with fulvestrant for the treatment of postmenopausal women with HR+/HER2– metastatic breast cancer as initial endocrine-based therapy or following disease progression on endocrine therapy. Ribociclib is indicated as 600 mg orally once daily, with or without food, for 21 days on followed by 7 days off. Ribociclib is available as 200-mg tablets. Ribociclib may require dose reductions for certain AEs, certain drug interactions (ribociclib is a major CYP3A4 substrate), patients with moderate (Child-Pugh B) or severe hepatic impairments, and patients with severe renal impairment (creatinine clearance 15-30 mL/min). The most common AEs (incidence ≥20%) include neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough. The prescribing information for Kisqali contains warnings for ILD/pneumonitis, QT interval prolongation, increased QT prolongation with concomitant use of tamoxifen, hepatotoxicity, neutropenia, and embryo-fetal toxicity.⁹

Alpelisib (Piqray) is an inhibitor of PI3K, which causes abnormal cellular proliferation in PIK3CA-mutant breast cancer cells. Alpelisib in combination with fulvestrant has synergistic antitumor activity in PIK3CA-mutated, HR-positive cell lines. Alpelisib is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2—, PIK3CA-mutated metastatic breast cancer following progression on or after an endocrine-based regimen. PIK3CA mutations occur in approximately 40% of patients with HR+/HER2– metastatic breast cancer.

Alpelisib is indicated as 300 mg orally once daily with food, and it is available as 50-mg, 150-mg, and 200-mg tablets. Alpelisib may require dose reductions for certain AEs. The most common AEs including laboratory abnormalities (all grades, incidence ≥20%) include increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma-glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged partial thromboplastin time, and alopecia. The prescribing information for alpelisib contains warnings for severe hypersensitivity, severe cutaneous reactions, hyperglycemia, pneumonitis, diarrhea, and embryo-fetal toxicity.¹⁰

DAVID SCHOENBAECHLER, PHARMD, is senior pharmacy specialist, Onco360 Oncology Pharmacy of Louisville, Kentucky.JOSEPH BARONE, PHARMD, BCOP is senior director, Clinical Oncology Services, Onco360 Oncology Pharmacy of Louisville, Kentucky.

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• Verzenio. Prescribing information. Eli Lilly; 2019. Accessed July 8, 2020. https://uspl.lilly.com/verzenio/verzenio.html#pi
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