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