Clinical Challenges: Acquired Endocrine Resistance in Breast Cancer

Most patients with hormone receptor (HR)-positive metastatic breast cancer should receive up to three lines of endocrine therapy as part of guideline-recommended care before starting chemotherapy, said Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center of the University of California San Francisco.

“Almost every patient will acquire resistance to endocrine therapy over time,” Rugo told MedPage Today. “Some patients will develop resistance in the first year of treatment — sometimes within months — and some can stay on their first-line endocrine therapy for 7 to 10 years. We don’t have a clear understanding of the specific factors that control time to development of acquired resistance, although there are clearly clinical and biologic indications of risk.”

There are a variety of mechanisms believed to be responsible for acquired resistance to endocrine therapy, which is what can make it a challenge to select second-line therapy.

“Sometimes we see a loss of expression of the estrogen receptor in the tumor cells, or the cancer can develop mutations in the estrogen receptor 1 gene [ESR1], which changes the way the cancer responds to hormonally directed treatment,” explained Halle Moore, MD, of the Cleveland Clinic Taussig Cancer Center.

There may also be changes in growth factor signaling or activation of cellular pathways that promote cancer growth, she told MedPage Today.

The most common mutation in HR-positive breast cancer is a mutation in phosphoinositide (PI) 3 kinase, which occurs in about 40% of this breast cancer subtype, Rugo said.

CDK4/6 Exposure

CDK4/6 inhibitors are designed to overcome resistance to endocrine therapy by interfering with cyclin-dependent kinases, which are involved with one of the cell pathways that lead to cell division. There are currently three FDA-approved CDK4/6 inhibitors: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

All three drugs were initially approved in combination with endocrine therapy for treatment of patients who had disease progression on endocrine therapy. All three drugs, however, have now moved into the front-line treatment in combination with an aromatase inhibitor, Rugo noted.

Despite that, clinicians may still encounter women with long-term responses to endocrine therapy who have not yet been exposed to a CDK4/6 inhibitor and can thus receive these agents as second-line therapy.

“What we don’t understand now is whether all patients whose cancer progresses on a first-line CDK4/6 inhibitor combined with endocrine therapy has developed resistance to the endocrine therapy alone or also to the CDK4/6 inhibitor,” Rugo said. “There are currently studies evaluating the use of a CDK4/6 inhibitor after progression on a CKD4/6 inhibitor combined with an alternative endocrine therapy. Hopefully these studies will provide more insight into this question.”

Moore agreed, explaining that although the strategy of switching endocrine therapy or the CDK4/6 inhibitor is often employed, there are very little data guiding those decisions.

“There are some data to support abemaciclib as a single agent,” she said. “If patients have exhausted other endocrine therapies and perhaps been on palbociclib or ribociclib, one could try abemaciclib in later-line settings.”

Other Options

If a patient progressed on a CDK4/6 inhibitor in combination with endocrine therapy, the next decision is based on the availability of a clinical trial, the presence of a PIK3CA mutation, and in some cases, the presence of ESR1 mutations.

“I haven’t found ESR1 mutations to be helpful outside of a clinical trial because we generally sequence fulvestrant [Faslodex] after aromatase inhibitors, so in this case the presence of an ESR1 mutation would not impact decision-making. However, we generally have this information because it comes along with the analysis for the PIK3CA mutation,” Rugo said.

There is one FDA-approved PIK3CA inhibitor indicated for postmenopausal women with advanced HR-positive, HER2-negative breast cancer: Alpelisib (Piqray) in combination with fulvestrant was approved based on the results of the SOLAR-1 trial, which showed improved progression-free survival for patients whose tumors had a PIK3CA mutation (median of 11 months vs 5.7 months for placebo).

It should be noted, however, that this trial almost completely accrued prior to the availability of CDK4/6 inhibitors, which patients now will likely have been exposed to in the first-line setting.

For patients who do not have a PIK3CA mutation and for whom a clinical trial is not available, one option is to add everolimus to fulvestrant, Rugo said. This strategy is based on results of the Phase II PrE0102 trial, which showed improved progression-free survival with everolimus plus fulvestrant compared with placebo (10.3 vs 5.1 months).

“These results showed reasonably similar efficacy to the registrational BOLERO-2 trial, where exemestane was the endocrine partner,” she said. “Because most of us use fulvestrant in the second-line setting, that is a potential and appealing option.”

Clinical Trials

Beyond these options, patients may qualify for a clinical trial, Moore said, noting that she believes clinicians are seeing only the beginning of the use of targeted therapies in combination with endocrine therapy.

For example, there are a number of studies evaluating the use of AKT inhibitors in combination with fulvestrant in patients who progress on endocrine therapy, and in combination with aromatase inhibitors and CDK4/6 inhibition in the first-line setting. Oral selective estrogen receptor degraders are also being studied in this setting, along with newer endocrine therapies with potential efficacy in cancer with ESR1 mutations.

Another intriguing area of research is in patients whose tumor has somatic mutations in the HER2 gene, Rugo said, noting that interestingly, these mutations have been seen more frequently in lobular cancer.

“Research has shown responses to oral tyrosine kinase inhibition with neratinib, a HER1– and HER2-targeting therapy, and in combination with hormone therapy. Current research is evaluating a triplet approach with trastuzumab, as well as newer TKIs in this setting,” she explained.

She noted that there are not a lot of data on the use of immunotherapy in patients with hormone-receptor positive but hormone-resistant disease, but clinical trials testing these therapies may also be an option.

“I published a phase Ib basket trial in a small number of patients, where we saw a low response to immunotherapy with single-agent pembrolizumab, but the few responses were generally durable,” Rugo said. “We were not able to discover factors that predicted response.”

There is a small window of insight into who might respond to immunotherapy from the phase II I-SPY2 neoadjuvant trial. Patients received standard backbone paclitaxel followed by doxorubicin and cyclophosphamide with or without four doses of pembrolizumab in patients with MammaPrint genomic score high-risk HR-positive disease or triple-negative breast cancer (TNBC), Rugo said.

In that study, pathological complete response was increased in TNBC, as well as in the small number of patients who had MammaPrint-positive high-risk disease, and particularly in those patients with very high MammaPrint scores, she said.

“It brings up the question of whether we need to look at these more proliferative, less endocrine sensitive patients with HR-positive disease and see if this is where we will see a significant benefit from immune checkpoint inhibitor therapy,” Rugo noted.

She added that in the metastatic setting, there is a trial planned with the immune checkpoint inhibitor pembrolizumab and backbone chemotherapy agents in endocrine-resistant HR-positive breast cancer, and there are several ongoing chemotherapy studies in the neoadjuvant setting, as well as studies combining checkpoint inhibition with endocrine therapy as well as other targeted agents.

“We need to have the numbers and molecular analyses to dissect out the subset of patients who are more likely to benefit,” Rugo said. “A one-size-fits-all approach will not work in HR-positive disease.”