Overcoming Drug Resistance in the Treatment of Metastatic Breast Cancer

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The management of metastatic breast cancer resistant or refractory to hormonal treatments, while still challenging, is rapidly improving.
The management of metastatic breast cancer resistant or refractory to hormonal treatments, while still challenging, is rapidly improving.

Long-term endocrine therapy is the mainstay treatment of hormone receptor (HR)-positive breast cancer, while trastuzumab, the monoclonal antibody targeting HER2, is used for patients with HER2-positive disease.

New approaches are, however, needed to treat disease resistant to these therapies. Triple negative breast cancer (TNBC), which is HR-negative (progesterone receptor negative, estrogen receptor negative) and HER2-negative, is notoriously challenging to treat.

Resistance to endocrine therapy may arise from several mechanisms, including mutations in the endocrine receptor, overexpression of other growth factor receptors such as HER2, and signaling between endocrine receptor and growth factor receptor pathways.1-3

An education session and several oral and poster presentations at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, provided data on published studies and offered ideas about how resistance mechanisms may be overcome. 

Ingrid A. Mayer, MD, MSCI, associate professor of medicine and director of breast cancer clinical research at Vanderbilt University in Nashville, Tennessee, and a presenter at the education session “Novel Targeted Agents and Immunotherapy in Breast Cancer,” described to Cancer Therapy Advisor how the education session covered new strategies to overcome resistance to endocrine and other therapies.

Clinical Strategies To Overcome Endocrine Resistance

Combining endocrine therapy with inhibitors of upregulated growth factor–dependent pathways is one method for overcoming endocrine resistance.

The phase 2 BOLERO-4 study (ClinicalTrials.gov Identifier: NCT01698918) reported at the meeting evaluated the combination of everolimus and letrozole in the first-line treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. It also presented data from patients receiving everolimus and exemestane after progressing on first-line treatment.

Among the first-line group, median follow-up was 23.5 months, median progression-free survival (PFS) was 21.7 months, and overall response rate (ORR) was 4.8%. All-grade adverse events for the first-line group were stomatitis (69%), weight loss (44%), diarrhea (40%), nausea (37%), and anemia (35%). Second-line adverse events included stomatitis (19%) and weight loss (19%).4

Much attention has been given to the use of CDK4/6 inhibitors in the clinical management of breast cancer. Palbociclib, ribociclib, and abemaciclib have positive data in metastatic breast cancer that progresses on endocrine therapy.

Data about abemaciclib, which were highly anticipated before the meeting, are promising.5 In the phase 3 MONARCH 2 trial (ClinicalTrials.gov Identifier: NCT02107703), women with HR-positive/HER2-negative breast cancer were randomly assigned 2:1 to receive abemaciclib plus fulvestrant (446 patients) or placebo plus fulvestrant (223 patients).

At baseline, 56% of patients had visceral disease, 25% showed primary resistance to endocrine therapy, and 82% of women were postmenopausal. For the intent-to-treat group (379 patients), median PFS — the primary endpoint — was 16.4 months for patients on abemaciclib plus fulvestrant vs 9.3 months for those on placebo plus fulvestrant (P < .0000001).

Among patients with measurable disease, ORR was 48.1% (3.5% complete response) for the abemaciclib plus fulvestrant arm and 21.3% (0% complete response) for the placebo plus fulvestrant arm.6

“Strategies to overcome resistance from CDK4/6 inhibitors are going to use the combination of PI3K and mTOR inhibitors,” Dr Mayer said.

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