Apocrine breast cancer, ESR1 mutations at center of tumor board review

Dr. Bardia said that if he has a patient who has an androgen receptor-positive triple-negative breast cancer, the patient would be considered for an androgen receptor antagonist clinical trial. “It’s not something that can be used in routine clinical practice, but if the institution does have a clinical trial with an androgen receptor antagonist, I think this information could be helpful.”

Dr. Dillon estimates that the breast pathologists at Brigham and Women’s receive requests for androgen receptor testing once or twice a month. “We run the immunohistochemistry in our regular CLIA lab,” she said. “We’re not using the sequencing results for that, although the sequencing results do feed back to the oncologists.”

In case No. 2, a 70-year-old woman was first diagnosed with ER-positive breast cancer in 2000. She had surgery followed by adjuvant tamoxifen, which was discontinued after two years because of weight gain and bloating. In 2003, a pleural biopsy was performed that revealed the presence of an ER-positive and HER2-negative tumor, for which the patient received letrozole. It was discontinued in 2012 due to disease progression and the patient was started on fulvestrant. After two years, further disease progression prompted a switch to vinorelbine (“one of the few chemotherapy agents that does not cause alopecia,” which the patient wanted to avoid, Dr. Bardia said).

She remained on vinorelbine for about a year before her disease progressed. She was then seen in the metastatic breast cancer clinic at Massachusetts General Hospital for a discussion of treatment options.

One option is whether, in this patient with disease progression on various regimens, there is a role for tumor genotyping and, if so, what the potential actionable alterations would be. In general, for hormone receptor-positive breast cancer, PIK3CA and HER2 mutations would potentially be actionable, Dr. Bardia said. A third consideration would be ESR1 mutations.

PI3K is a heterodimer composed of two subunits: an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit (p110), Dr. Dillon said. “The PIK3CA gene encodes the p110α, one of the catalytic subunits.”

PI3K works when growth factor binds to the RTK and activates signaling along two pathways: the MAPK (RAS-​RAF-​MEK-ERK) pathway ​and the PI3K (PI3K-AKT-​mTOR) pathway.

“When we see mutations in PIK3CA in breast cancer, typically these are missense mutations. They occur at hotspots,” Dr. Dillon said. The large majority of missense mutations occur at hotspots in exon 9, the helical domain, and exon 2, the kinase domain, and are present in 35 percent of estrogen receptor-positive/HER2-negative breast cancers. So this is “a high frequency event in breast cancer.”

The Sandpiper trial, presented at the 2018 American Society of Clinical Oncology annual meeting, looked at targeting PIK3CA with taselisib (Roche), a PIK3CA inhibitor. “This was a somewhat disappointing trial,” she said. “However, this still remains a target of considerable interest with other agents.”

Dr. Bardia compared the results with the positive results of the Solar-1 trial of Novartis’ alpelisib (presented at the 2018 European Society for Medical Oncology), a PI3K inhibitor expected to be approved for PIK3CA-mutant metastatic breast cancer.

“Why was one trial positive and the other negative?” he said. “Some of the answers would lie in the specific type of PI3K inhibitor that was utilized for therapy selection, and management of adverse events in the clinical trials.”

HER2 mutations in breast cancer are rare gain-of-function missense mutations clustered in the kinase domain, Dr. Dillon said. They are capable of activating HER2 signaling, even in cases that have normal HER2 copy number.

Fifteen percent of all high-grade, HER2-negative, invasive lobular cancers will have a HER2 mutation, and 50 percent of HER2-mutated breast cancers are high-grade solid variant lobular cancers.

In preclinical models, many HER2 mutations are activating mutations that significantly increase tumor cell growth and thus represent an alternative mechanism of HER2 activation in tumors. Many of these show less sensitivity to trastuzumab and lapatinib than do HER2 amplified cancers, but most are sensitive to the tyrosine kinase inhibitor neratinib (Nerlynx, Puma Biotechnology). Knowing which tumor had a HER2 mutation versus HER2 amplification might change the choice of drug.

“In fact, we are beginning to see data coming out using neratinib in tumors that have HER2 mutations,” Dr. Dillon said. The Summit trial was a multi-histology, phase two basket trial, a molecularly driven trial of solid tumors with HER2 or HER3 mutations. The study, presented at the 2017 American Association for Cancer Research annual meeting, showed an objective response rate of 21 percent for neratinib plus fulvestrant in ERBB2-mutant, HER2-non-amplified, ER-positive metastatic breast cancer.

Dr. Dillon further pointed out that the study’s breast data showed response rates to be considerably better in breast as opposed to other organs, such as bladder, where these mutations are also present.

Mutations in the gene coding for the estrogen receptor, ESR1, are extremely rare in primary tumors but are present in a significant portion of patients who have metastatic ER-positive disease and who have received endocrine therapy, Dr. Dillon said. “These mutations are clustered in the ligand-binding domain. They lead to constitutive ER activity, and they are associated with acquired endocrine resistance.”

When Dr. Bardia received the sequencing report for his patient, he saw that she had one of the most common ESR1 mutations, D538G.

“The estrogen receptor mutations have been a game changer in the field of estrogen receptor-positive breast cancers,” he said. ESR1 mutations were not even included in The Cancer Genome Atlas network’s comprehensive genomic analysis of hundreds of primary tumors published in Nature in 2012.

Then in 2015, three papers published in Nature Genetics and Clinical Cancer Research reported the presence of ESR1 mutations in the sequencing of metastatic tumors. “That was the key,” Dr. Bardia said. “These mutations were not seen in the primary tumor.”

Dr. Bardia’s group saw the same ESR1 mutations when they isolated circulating tumor cells in patients with metastatic breast cancer (Yu M, et al. Science. 2014;345[6193]:216–220). Three of six patients had the ESR1 mutations in the circulating tumor cells but not in the primary tumor, suggesting the acquired nature of the mutations.

“That is potentially a role for circulating tumor cells or circulating tumor DNA, to look at acquired mutations that would not be present in the primary tumor,” he said. “Based on circulating tumor DNA, up to 50 percent of patients with hormone receptor-positive breast cancer who have received a prior endocrine agent would have ESR1 mutations.”

In the normal ER pathway, estrogen binds to the estrogen receptor and sends signals to the estrogen response element, which causes proliferation, Dr. Bardia said. ESR1 mutations cause a conformational change in the estrogen receptor.

“The switch for the estrogen receptor is constantly on and it becomes ligand independent,” he said. “You can have the best aromatase inhibitor in the world, you can have the estrogen levels to zero, but the tumor would still signal because it’s estrogen independent.”

While the tumors are resistant to aromatase inhibitors, they can still be targeted with estrogen receptor degraders. “If we have a drug that targets the estrogen receptor, those drugs could still work because while the tumor is estrogen independent, it is still estrogen receptor dependent.”

In preclinical models, a number of selective estrogen receptor degraders have shown activity, much more than fulvestrant or tamoxifen, which also blocks the estrogen receptor for ESR1-mutant cancers.

In the SoFEA trial, published in 2013, patients with hormone receptor-positive metastatic breast cancer were randomized to receive the aromatase inhibitor exemestane versus fulvestrant. Since the trial took place before ESR1 mutations were discovered, “the authors recently went back and looked at the banked plasma specimens to look at ESR1 mutations and they could really see the separation of the curves,” Dr. Bardia said. “Tumors that were ESR1 mutant did not have any benefit with exemestane but still derived some benefit with fulvestrant.”

“The next question is, can we do better than fulvestrant?” Dr. Bardia said.

A number of clinical trials investigating selective estrogen receptor degraders, or SERDs, are ongoing in metastatic breast cancer. Among the various SERDs, probably the one that is clinically most advanced is elacestrant (Radius Health). Elacestrant, an oral SERD, is moving into a phase three trial after previous clinical trial results revealed better progression-free survival than what one would historically anticipate with fulvestrant, Dr. Bardia said. “The activity was seen in this agent even in the tumors that had received fulvestrant as well as a prior CDK4/6 inhibitor.”

Fifty percent of the elacestrant trial participants (20/40) had tumors with ESR1 mutations, and based on plasma sequencing, Dr. Bardia said, the mutant-allelic fraction of ESR1 mutation decreased. However, not all mutations were the same: While L536R decreased, D538G was found to increase after initially showing a decrease. “There might be some difference in the response to the selective estrogen receptor degrader based on the type of ESR1 mutation,” he said.

Dr. Bardia said the index patient, the 70-year-old woman with ESR1-mutant metastatic breast cancer, enrolled in a clinical trial with an oral SERD and remained on treatment for 14 months, deriving some benefit from the agent.

Dr. Dillon summed up: Acquired mutations can develop under selective pressure from aromatase inhibitor treatment and result in estrogen-independent activation of the estrogen receptor. “The selection of tissue for testing matters, because if you test just the primary tumor, you’re going to miss it,” she said. “And if you test one metastatic site, you might miss it as well, which is why Dr. Bardia’s point about profiling the circulating tumor DNA or circulating tumor cells is important, because if you sequence different metastatic sites, not all of them may have resistance mutations.”

The advantage of enrolling patients who have ESR1 mutations in SERD trials, Dr. Bardia said, is “not only would you potentially get disease control but you can also monitor the ESR1 mutant allele fraction, so it can serve as a pharmacodynamic marker. There might be patients who do not have a drop in the ESR1 mutant allele fraction for whatever reason, and maybe for that patient it’s not a good idea to use the SERD,” and better to switch to a different therapy. “So you use the ESR1 mutation both for therapy selection and as a pharmacodynamic marker.”

Amy Carpenter Aquino is CAP TODAY senior editor. This session was an ASCO-CAP collaboration. Case No. 1 had been discussed online as part of the ASCO/CAP/AMP molecular oncology tumor board series.