An Unmet Need in HR-Positive Endocrine-Resistant Breast Cancer

2021 Year in Review - Triple-Negative Breast Cancer —February 18, 2022


Breast Cancer

HR-positive, HER2-negative breast cancer is the most common type of breast cancer.1 The mainstay of first-line treatment is endocrine therapy, but endocrine resistance is common.1 For patients with HR-positive breast cancer, 3 types of antiestrogen therapies are currently available.1 Endocrine therapy is still the most effective treatment for HR-positive early-stage breast cancer prophylaxis, both primary and secondary.1 Selected estrogen receptor modulators such as tamoxifen; aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane; and selective estrogen receptor degraders such as fulvestrant are all currently accessible endocrine therapies.1 Tamoxifen or AIs are the standard endocrine therapies for early-stage breast cancer.1 Endocrine therapy is the most common first-line treatment for HR-positive metastatic breast cancer patients.1 Breast cancer that exhibits endocrine resistance has the potential to metastasize and cause death.2

Antiestrogen resistance, on the other hand, is a key roadblock to long-term illness control and avoiding chemotherapy.1 Several novel targeted medicines, including CDK4/6 inhibitors, mTOR/PIK3 inhibitors, and histone deacetylase inhibitors, have shown higher performance in combination with antiestrogen therapy over the past decade, with the potential to overcome endocrine resistance.1

The adjuvant CDK4/6 inhibitor abemaciclib in combination with an AI has shown efficacy in high-risk disease in preliminary data. However, no targeted monotherapy is approved for endocrine-resistant HR-positive breast cancer, meaning patients with endocrine resistance only have chemotherapy as a real option.1 Clinically, there are 2 types of endocrine therapy resistance: primary, inherent resistance, in which estrogen receptor–positive tumors never respond effectively to endocrine treatment, and secondary, acquired resistance, which develops after an initial response.3 Intrinsic resistance mechanisms may overlap in certain ways, but they are still poorly understood.3

Endocrine therapy is the primary treatment for most women with advanced HR-positive breast cancer.1 Recent research has linked the use of CDK4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors in combination with hormone therapy to improved outcomes and a delay in chemotherapy initiation. For HR-positive breast cancer, several new agents are being investigated.1 To improve HR-positive breast cancer results, the future of overcoming resistance to focused therapy, new therapies, and predictive indicators is critical.1 Treatment with antiestrogens has been linked to improved overall survival in patients with both early and advanced HR-positive breast cancer.1

For patients with HR-positive advanced breast cancer, the current standard treatment is a combination of an AI or fulvestrant plus a CDK4/6 inhibitor.1 An alternate endocrine treatment in combination with another targeted medication is a beneficial choice as the disease progresses.1 The best sequence of multiple targeted drugs is unknown, and pathways of resistance to currently available therapies must be identified.1 The therapy landscape for HR-positive breast cancer is rapidly developing, thanks to a greater knowledge of physiological processes and the discovery of novel biomarkers.1

The role of immunotherapy in hormone-positive breast cancer is not as important as it is in triple-negative and HER2-positive cancers.4 Hormone-positive breast cancer has a diverse set of genes and phenotypes.4 As a result, greater research into combining immunotherapy and conventional therapy (chemotherapy, radiotherapy, and hormone therapy) based on more detailed gene expression or tumor microenvironment alteration is warranted.4 Breast cancer is molecularly complex; the more we learn about the variety of molecular and genetic characteristics associated with breast cancer, the more precise treatment decisions we may make.4


  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. Lin Y, Lin J, Liu YE, et al. Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression. Transl Oncol. 2022;15:101302.
  3. Grote I, Bartels S, Kandt L, et al. TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer. Cancer Med. 2021;10:8581-8594.
  4. Chien T. A review of the endocrine resistance in hormone-positive breast cancer. Am J Cancer Res. 2021;11:3813-3831.
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Last modified: August 10, 2023

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