Latest Updates on Targeted Therapy in HR-Positive and HER2-Negative Breast Cancer

2021 Year in Review - Breast Cancer - Breast Cancer

The most frequently diagnosed breast cancer is hormone receptor (HR)-positive and HER2-negative breast cancer.1 In women with high-risk, early-stage, HR-positive, HER2-negative breast cancer, first-line endocrine therapy with selective estrogen receptor modulators and aromatase inhibitors (AIs) has reduced mortality, but treatment resistance is common.1 Fortunately, when combined with endocrine therapy, novel targeted medicines have significantly improved the outcomes for patients with HR-positive, HER2-negative breast cancer.1

Fulvestrant is the only approved selective estrogen receptor degrader that competitively blocks the estrogen receptor.1 It has shown the same efficacy as exemestane and improved efficacy to anastrozole in women with metastatic breast cancer after disease progression with AI treatment.1 Studies of fulvestrant in combination with AIs showed mixed results.1

Adding cyclin-dependent kinase (CDK)4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors to endocrine therapy has been demonstrated to improve patient outcomes.1 With multiple innovative medicines and prognostic indicators in the pipeline, targeted treatment for HR-positive, HER2-negative breast cancer has gone a long way.1 Palbociclib, ribociclib, and abemaciclib are 3 CDK4/6 inhibitors that have been approved as adjuvant treatment to AIs in HR-positive, HER2-negative, metastatic breast cancer.1 A number of trial results have shown that adding CDK4/6 inhibitors to an AI nearly quadrupled median progression-free survival (10 months) while maintaining a tolerable toxicity profile.1 Abemaciclib was linked to a significantly longer median progression-free survival in the MONARCH-3 study, similar to other CDK4/6 inhibitors.1 The MONALEESA-7 study found that the ribociclib group had a better overall survival rate.1 MONALEESA-7 showed that combining CDK4/6 inhibitors with tamoxifen yields a similar increase in progression-free survival as AIs.1

The US Food and Drug Administration approved neratinib, an irreversible pan-HER tyrosine kinase inhibitor, in 2020 for adult patients, in combination with capecitabine (Xeloda), with advanced or metastatic HER2-positive breast cancer who had previously received ≥2 anti–HER2-based metastatic regimens.2 In early-stage, HER2-positive breast cancer, neratinib improved invasive disease-free survival.3

The PI3K/AKT/mTOR pathway has resulted in endocrine resistance and has become the target of a number of new drugs for estrogen receptor–positive breast cancer. Alpelisib is the first approved PI3K inhibitor, in combination with fulvestrant, for patients with HR-positive, HER2-negative, metastatic breast cancer.4 Everolimus, an mTOR inhibitor, inhibits breast cancer tumor cell growth and was the first-in-class approval for patients with HR-positive, HER2-negative breast cancer.4 Everolimus showed improved progression-free survival in several clinical trials.4 Other therapies include histone deacetylase inhibitors and anti-VEGF used in combination with endocrine therapy or chemotherapy for HR-positive, HER2-negative breast cancer.1

The standard treatment for HR-positive, HER2-negative, metastatic breast cancer is a combination of an AI or fulvestrant and a CDK4/6 inhibitor.1 On progression, an alternate endocrine agent in combination with another targeted agent is a valuable option.1 The ideal sequence of targeted therapies is not known and there is a need to identify mechanisms of resistance in established therapies, but advances in targeted therapies mean HR-positive, HER2-negative breast cancer outcomes are rapidly improving.1

References

  1. Andrahennadi S, Sami A, Manna M, et al. Current landscape of targeted therapy in hormone receptor-positive and HER2-negative breast cancer. Curr Oncol. 2021;28:1803-1822.
  2. US Food and Drug Administration. FDA approves neratinib for metastatic HER2-positive breast cancer. February 26, 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer. Accessed December 12, 2021.
  3. Chan A, Moy B, Mansi J, et al; for the ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21:80-91.e7.
  4. Dong C, Wu J, Chen Y, et al. Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer. Front Pharmacol. 2021;12:628690.
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