Experts Focus on New Ways of Attacking Resistance in ER+ Breast Cancer

Adam M. Brufsky, MD, PhD

Approximately 75% of invasive breast cancers are estrogen receptor (ER)—positive¹. Although ER-positive breast cancer typically responds well to initial endocrine therapy, most patients eventually become resistant to treatment and experience disease progression.¹ The discovery that ER gene mutations contribute to endocrine therapy resistance has led to the development of novel targeted therapies for progressive ER-positive breast cancer.

ESR1 Mutations and Endocrine Therapy Resistance

At an OncLive Peer Exchange panel titled “Expert Perspectives on the Latest Advancements in Breast Cancer,” a group of breast cancer specialists led by Adam M. Brufsky, MD, PhD, discussed recent progress in the understanding and management of ER-positive tumors. They reviewed emerging data presented at the 2016 ASCO Annual Meeting in June and expressed optimism about what those data suggest for the future of patients with heavily pretreated, metastatic, ER-positive disease.Efforts to determine how ER-positive breast cancer escapes endocrine deprivation led to the identification of ESR1 mutations in hotspot regions of the ligand-binding domain (LBD) of ER, which Carlos L. Arteaga, MD, hailed as a “major discovery.”

The ESR1 gene encodes ER, and ESR1 mutations facilitate ligand-independent, constitutive ER activity in women receiving an aromatase inhibitor (AI).² Because ESR1 mutations affect <1% of newly diagnosed breast cancers, their clinical significance was not fully appreciated until recently, when a series of studies detected a greater prevalence of ESR1 mutations in metastatic ER-positive breast cancer that became resistant to AI therapy.^2,3

“Up to 30% of patients who progress on AI therapy in the metastatic setting have these alterations,” Arteaga said.⁴ The panel discussed abstracts presented at the 2016 ASCO Annual Meeting that addressed ESR1 mutations and their significance.

The PALOMA3 study was a randomized phase III trial that compared palbociclib (Ibrance) plus fulvestrant (Faslodex) versus fulvestrant plus placebo in 360 patients with metastatic breast cancer who had progressed during endocrine therapy.^1,5 In PALOMA3, researchers analyzed circulating tumor DNA (ctDNA) in 395 plasma samples for ESR1. All 106 patients whose tumors tested positive for an ESR1 mutation had previously received an AI.⁵ “They didn’t see any [ESR1 mutations] in patients who had prior tamoxifen, so it’s a very treatment-dependent effect,” explained Sunil Verma, MD.

An ESR1 mutation independently predicted shorter progression-free survival (PFS). Median PFS was 5.7 months for patients with an ESR1 mutation versus 9.2 months for patients without one.⁵

In updated data from PALOMA3 published in the Journal of Clinical Oncology in September, the authors reported median PFS for patients with an ESR1 mutation of 9.4 months for those treated with palbociclib/fulvestrant compared with 3.6 months for those taking fulvestrant/placebo (P = .002).¹ For ESR1 wild-type patients in the palbociclib/fulvestrant arm, median PFS was 9.5 months compared with 5.4 months for those in the fulvestrant/placebo arm (P <.001).¹

“Despite these mutations, there was a benefit favoring palbociclib,” Verma said. Palbociclib is a CDK 4/6 inhibitor, and he said the findings are important because they suggest CDK 4/6 inhibitors are effective in patients with an ESR1 mutation.

Arteaga said he found it interesting that “the patients who had prior response to endocrine therapy—who showed some evidence of being luminal and hormone-dependent&mdash;were the ones who developed acquired ER mutations.”

He said the fact that patients who did not respond to endocrine therapy did not acquire mutations suggests their tumors had found other ways to circumvent ER inhibition.

He predicted that selective estrogen down-regulators (SERDs) could eventually become the standard of care for patients with an ESR1 mutation and suggested the ease of detecting the mutations (in plasma with no biopsy required) means “we may need to start thinking of incorporating measuring these mutations into our standard of care for patients who progress on an AI.”

Joyce A. O’Shaughnessy, MD, agreed that the findings from PALOMA3 are important and might have interesting implications for the adjuvant setting but said she was not ready to order ER assays for her patients based on the data. “I don’t think it’s really specifically actionable right now... we’re not going to change our practice patterns because we are going to use the CDK 4/6 inhibitors,” O’Shaughnessy explained.

She compared the findings with those of the BOLERO-2 trial. Although ESR1 mutations predicted shorter overall survival (OS), patients who received everolimus plus exemestane had similar median PFS regardless of whether they had an ESR1 mutation.⁶

“The everolimus is going to work no matter whether patients have the mutation or not [and] we’re going to continue to treat patients as we do anyway, so I don’t think we need to check it out,” she said.

Both Kimberly L. Blackwell, MD, and Arteaga proposed that testing for an ESR1 mutation could help determine whether a patient should receive fulvestrant—the only SERD approved for metastatic ER-positive breast cancer&mdash;or enroll in a clinical trial for a novel SERD.

“There are trials now that enroll based on these mutations...it’s probably important that [those patients] know there are options for them,” said Arteaga.

CDK 4/6 Inhibitors

Blackwell said that because an ESR1 mutation predicts worse OS with subsequent treatments,⁴ having the mutation essentially means the patient “is no longer eligible for endocrine therapy.”Palbociclib and abemaciclib are both CDK 4/6 inhibitors.

In February 2016, the FDA approved palbociclib in combination with fulvestrant for women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy. It was already approved in combination with letrozole as first- line therapy for women with this cancer who are postmenopausal.

Approvals were based on findings from the PALOMA series of trials. PALOMA-2 and PALOMA-1 compared palbociclib plus letrozole versus letrozole monotherapy in women with ER-positive/HER2-negative advanced breast cancer.⁷

“We now have 3 trials that basically look at the addition of palbociclib to antiestrogen therapy,” Blackwell said. “What we see across the board is almost a near doubling—give or take a month or two&mdash;in PFS with the addition of palbociclib to the endocrine therapy backbone,” she said, calling the results exciting.

The trials have yet to show an OS benefit with palbociclib, which Blackwell said is difficult to achieve in this population. She predicted palbociclib will become the standard of care for patients with metastatic breast cancer who require endocrine therapy. Brufsky agreed the PFS findings for palbociclib—based regimens in the PALOMA trials were impressive.

Abemaciclib is not FDA approved but was designated a breakthrough therapy for patients with advanced breast cancer in 2015 based on data from the MONARCH trial series.

O’Shaughnessy said abemaciclib inhibits CDK4 more than CDK6 and therefore causes less myelosuppression than palbociclib. “It can be given daily, so you don’t have to have the 3 weeks on, 1 week off—which may end up being a therapeutic advantage at the end of the day,” she said.

At the ASCO meeting, investigators presented data from the phase II MONARCH1 trial of abemaciclib in HR-positive/HER2-negative metastatic breast cancer refractory to endocrine therapy or chemotherapy.⁸ The response rate was 17%, which Brufsky said failed to meet the study’s primary endpoint.

O’Shaughnessy said early chemotherapy trials showed that clinical benefit rate (CBR) is a more important measure of efficacy in the endocrine therapy setting and that the CBR in MONARCH1 was an impressive 42%.

She said abemaciclib also showed exciting potential for patients with brain metastases because it penetrates the central nervous system (CNS).

“I have a patient with multiple brain metastases who has been on it for over 3 years now and another patient who went to the University of Colorado to participate in their ongoing CNS-directed therapy. Right now, she’s responding,” O’Shaughnessy said.

“What was really appealing to me when we looked at the data is the duration of response,” Verma said. He described the approximately 10-month duration of response as a “good result” for such a heavily pretreated population.

Despite the underwhelming response rate in MONARCH1, PFS was 5.7 months, which Blackwell said was nearly double the PFS observed in trials of first-line endocrine therapy. “The PFS and the duration of response are the really exciting things to come out of that study,” she said.

Brufsky highlighted the nearly 18-month OS, noting that OS in trials of eribulin (Halaven) in heavily pretreated patients was only about 13 months. He predicted the CDK 4/6 inhibitors would bring a “sea change” in practice. Everyone agreed the findings with these drugs in HR-positive breast cancer were exciting.

Arteaga said CDK 4/6 inhibitors may improve quality of life for women with ER-positive disease by allowing them to forgo antiestrogen therapy. Ongoing trials are studying abemaciclib plus letrozole or fulvestrant in metastatic breast cancer. “It’s an unmet need, and I really want [abemaciclib], so I’m hoping that it will get approved,” O’Shaughnessy said.

Another CDK 4/6 inhibitor being investigated for this patient population is ribociclib. In May 2016, the Data Monitoring Committee for the phase III MONALEESA-2 trial of ribociclib plus letrozole recommended halting the trial early because it had already met its primary endpoint of improved PFS.

According to Verma, the data cumulatively point to a class effect for CDK 4/6 inhibitors in HR-positive breast cancer but that “it really remains to be seen how we can take this and how we identify those patients early on to potentially potentiate this effect.”

The panel debated whether the promising findings mean CDK 4/6 inhibitors should be given first. “The fact that the control arm [in MONALEESA-2] had such prolonged PFS...probably suggests that we should consider this in all patients as first-line [therapy] in the metastatic setting and not wait,” Arteaga said.

O’Shaughnessy said she would first like longer follow-up and more biomarker data. Brufsky said he wants data on sequencing strategies for women whose cancer progresses after palbociclib therapy, including where exemestane and everolimus fit into the plan.

Despite the many outstanding questions, Verma said it was an exciting time in HR-positive breast cancer, with paradigms starting to shift dramatically. “We’ve got a lot of great stuff going on,” Brufsky agreed.

References

1. Fribbens C, O’Leary B, Kilburn L. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34(25):2961-2968. doi: 10.1200/ JCO.2016.67.3061.
2. Lauring J, Wolff AC. Evolving role of the estrogen receptor as a predictive biomarker: ESR1 mutational status and endocrine resistance in breast cancer. J Clin Oncol. 2016;34(25):2950-2952. doi: 10.1200/JCO.2016.68.4720.
3. Jeselsohn R, Buchwalter G, DeAngelis C, et al. ESR1 mutations as a mechanism for acquired endocrine resistance in breast. Cancer. Nat Rev Clin Oncol. 2015;12(10):573-583. doi: 10.1038/ nrclinonc.2015.117.
4. Augusto L, Sarafan-Vasseur N, Perdrix A, et al. Prognostic and predictive value of circulating ESR1 mutations in metastatic breast cancer patients progressing under aromatase inhibitor (AI) treatment. J Clin Oncol. 2016;34(suppl; abstr 511).
5. Turner NC, Jiang Y, O’Leary B, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients(pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA). J Clin Oncol. 2016;34(suppl; abstr 512).
6. Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial [published online August 11, 2106]. JAMA Oncol. doi:10.1001/jamaoncol.2016.1279.
7. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2—advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl; abstr 507).
8. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: results from a phase II study of abemaciclinb, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2—breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl; abstr 510).