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New Developments in Managing MBC
How I Apply New Clinical Developments to the Management of Metastatic Breast Cancer

Released: July 25, 2023

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Key Takeaways
  • Precision medicine has generated a wealth of novel therapeutic options for both early-stage and metastatic breast cancer patients based on the specific disease hormone profile and molecular biomarker status.
  • The growing number of therapeutic options for metastatic breast cancer has made the selection of optimal therapy more challenging for healthcare professionals.
  • Equity in metastatic breast cancer care remains an area of unmet need, with certain patient populations not having access to guideline-concordant care to manage their disease. Current nonprofit and patient advocacy groups aim to provide educational and financial resources for patients to facilitate access to clinical trials for those who can benefit most.

In this commentary, Komal Jhaveri, MD, FACP, shares insights on how she applies new clinical advances in the management of patients with metastatic breast cancer (MBC), tailoring therapy based on biomarker status and the most optimal sequencing in patients with disease relapse.

Breast Cancer Overview

Breast cancer is the most common cancer among women in the United States, with approximately 300,000 new cases and more than 40,000 deaths in 2023 alone. Most patients are diagnosed with localized disease (63%), but many cases are regional (28%) or metastatic (6%). Several factors—such as diagnostic stage, comorbidities, presence of distant metastases, noncompletion of therapy, and lack of access to high-quality follow-up care—often contribute to disparities in breast cancer deaths.

Evaluation of the estrogen receptor, progesterone receptor, and HER2 tumor status in patients with newly diagnosed MBC guides how this disease can be treated. Guidelines also recommend screening patients with any family history associated with an increased risk of mutations in BRCA1/2 genes, and patients who are triple negative (lack hormone receptors (HRs) and are negative for HER2 overexpression/amplification) are screened for PD-L1 immune proteins to determine eligibility for chemotherapy and immune checkpoint inhibitors. However, the growing number of treatment options for all three subtypes of breast cancer (HR+/HER2-, HER2+, TNBC) is making selection and sequencing of therapy more challenging for healthcare professionals.

Navigating the Treatment Landscape in MBC: How to Apply Novel Treatment Options

Based on HR status, patients with HR-positive/HER2-negative MBC may be treated with endocrine therapy (ET) with or without a CDK4/6 inhibitor, agents targeting the PI3K/AKT/mTOR pathway, antibody-drug conjugates, systemic chemotherapy, or a clinical trial (Table 1). Patients with early-stage or late-stage disease who are HER2 positive may receive frontline combination therapy with pertuzumab, trastuzumab, and taxane-based chemotherapy.

Deciding how to manage HR-positive/HER2-negative MBC after CDK4/6 inhibitors in the second-line setting is becoming more complex. You could choose either to switch CDK4/6 inhibitors or ET; do you pick elacestrant or alpelisib plus fulvestrant in a patient whose tumor harbors both ESR1-mutation and PIK3CA-mutation ? Capivasertib plus fulvestrant is under FDA review and may become an option regardless of the PIK3CA/AKT/PTEN mutation status. For endocrine refractory diseased, we now have antibody–drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) that we use in patients with HER2-low MBC (IHC 1+ or IHC 2+/ISH negative) and sacituzumab govitecan in patients with HER2 0 breast cancer or those who are heavily pretreated or in the 2nd line chemotherapy setting if they are not candidates for T-DXd.

Primary endocrine resistance used to be defined as progression on adjuvant therapy within 24 months, or 6 months in the metastatic setting. Current clinical guidelines in the United States and Europe define disease progression with a CDK4/6 inhibitor plus ET at least 12 months after completion of adjuvant ET. This 12-month cutoff also is supported by data from the phase III EMERALD trial, which showed that patients with an ESR1 mutation who progressed on ET and a CDK4/6 inhibitor >12 months had a better duration of response if treated with elacestrant compared with standard ET. 

Patients with triple-negative breast cancer often have fewer biomarkers, so selection of therapy is a little bit simpler. If the patients have PD-L1–positive or microsatellite instability‒high (MSI-H)/tumor mutational burden‒high (TMB-H) disease, they most likely will receive checkpoint inhibition with pembrolizumab with chemotherapy. If, on the other hand, the patients with triple-negative breast cancer have a germline BRCA1/2 mutation, they will receive a PARP inhibitor or platinum based chemotherapy. If the latter is true, then in the second line and beyond, patients could receive ADCs (T-DXd for HER2 low or sacituzumab govitecan) or could be tested for other biomarkers, such as NTRK or RET gene fusions or microsatellite instability‒high (MSI-H)/tumor mutational burden‒high (TMB-H), to determine eligibility for targeted therapies such as larotrectinib or entrectinib ( NTRK inhibitors) or selpercatinib (RET inhibitor), or pembrolizumab respectively. New advances and more options make it imperative for healthcare professionals to seek and learn from the latest clinical information and current guidelines to provide optimal therapy for their patients with MBC.

However, there is a difference between endocrine resistance and refractoriness. After patients are deemed refractory, we are not treating them with the combination therapy of ET plus CDK/4/6 or everolimus. Patients with germiline BRCA ½  mutations are treated with PARP inhibitors and then single agent sequential chemotherapy (taxane, capecitabine) is utilized for endocrine refractory disease. ADCs really come into play (after 1 line of chemotherapy) in the second-line setting and beyond, as previously mentioned. Other options include larotrectinib or entrectinib for NTRK fusions, selpercatinib for RET fusion, immunotherapy with pembrolizumab for (eg, in TMB-H or MSI-H/mismatch repair deficient [dMMR] disease), neratinib plus fulvestrant and trastuzumab for HER2 mutation (NCCN category 2b) , investigational agents such as HER3- or TROP2-targeted ADCs, among others (Table 2).

Enhancing Clinical Trial Participation

Clinical trials are vital for advancing cancer discoveries, yet less than 5% of patients with cancer participate in trials and there is underrepresentation of diversity.  Overcoming inequity in delivery of care for women with MBC takes a big-picture approach because inequity in cancer care can be multifactorial, and at times it can be challenging to execute cancer care homogeneously. However, if we continue addressing the issue as a community (eg, in academia, regulatory bodies, patient advocacy groups, and pharmaceutical companies) and stay consistent, it might work. In order to increase feasibility for patients to participate in clinical trials, pharmaceutical companies now allot budgets for travel, food and hotel stays for long days planned on a phase 1 trials. These measures can really make a difference in facilitating access. It is also important to actively collaborate and engage with institutions, centers, and programs that serve the underrepresented and socioeconomically disadvantaged patients because those are the populations we want to enrich for in our clinical trials. We need to involve patient advocacy groups to provide patient education on clinical trials to overcome the fear among racial and ethnic minority groups that being in a clinical trial means being a “guinea pig.” Patients need to hear from someone they trust and know “things will be all right.” We need to have outreach initiatives that help bring a trial to a patient rather than depend on a patient being able to access a trial. At Memorial Sloan Kettering, I am fortunate to have the Office of Health Equity that was established in 2020 to address disparities in cancer outcomes based on race, ethnicity, cultural differences, and socioeconomic status. US FDA requires pharmaceutical companies to submit a “Race and Ethnicity Diversity Plan” to the agency early in clinical development of a new medical product. Many such efforts and initiatives are endorsed by organizations such as the American Society of Clinical Oncology (ASCO) and the Association of Community Cancer Centers (ACCC) and National Institutes of Health as well.

Patient Management and Available Resources for Patients With MBC

At the 2023 American Society of Clinical Oncology Annual Meeting, we had presentations focused on safety and efficacy by age (> 65 years). For example, the monarchE presentation of the CDK4/6 inhibitor abemaciclib combined with ET for the adjuvant treatment of HR-positive/HER2-negative, node-positive, high-risk early breast cancer showed that in older patients, drug discontinuations happened even before dose reductions. Identifying side effects in a timely way and providing maximal support for management of these side effects including appropriate dose reductions will help patients stay on active therapy and derived the intended benefit from such treatments.  This is also important in the metastatic and recurrent settings, where you do not want a patient to come off an active therapy that has demonstrated improved outcomes for this population.

We should provide patients with appropriate resources from the American Society of Clinical Oncology and the European Society for Medical Oncology, as well as point them to patient advocacy groups for resources and available information on clinical trials. In addition, we can refer patients to large foundations such as Susan G. Komen, the American Cancer Society, the Livestrong Foundation, Breastcancer.org, and MBC support groups. This is the right thing to do, and patients need to be educated about reliable resources online where they can find information on their treatment journey and available therapies. For example, Susan G. Komen and the American Cancer Society provide great resources that often describe relevant clinical trials. As healthcare professionals, we can create checklists of what efforts are currently successful and what resources are accessible to patients, and as a medical community, we must prioritize and focus on steps that do not leave any patient behind.

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