Breast Cancer Research Sheds New Light on HR-Positive Disease

OncologyLive, Vol. 17/No. 4, Volume 17, Issue 4

Although metastatic breast cancer remains incurable for most women, recent research offers important new guidance for clinicians managing patients across the spectrum of advanced disease.

Adam M. Brufsky, MD

Although metastatic breast cancer remains incurable for most women, recent research offers important new guidance for clinicians managing patients across the spectrum of advanced disease, according to a panel of experts participating in an OncLive Peer Exchange® program.

In the area of hormone receptor (HR)—positive breast cancer, study findings reported in recent months in journals and at the 2015 San Antonio Breast Cancer Symposium (SABCS) have helped refine the optimal use of endocrine therapies including strategies for combining these agents with targeted drugs.

The panel members, who are leading researchers in the breast cancer field, put these findings into context as part of a wide-ranging discussion of treatment options in a program entitled “Update on Advanced Breast Cancer Treatment.”

Clues on Low-Risk Disease

“Better understanding of breast cancer biology has led to important advances in terms of developing novel targeted and immune therapies,” said Adam M. Brufsky, MD, who served as program moderator. “… As novel agents for treating advanced breast cancer continue to evolve, we need to continue to learn how to best use them, how to optimally sequence them, and how to safely combine them.”The panel first looked at the TAILORx low-risk registry,1 a prospective trial of endocrine therapy alone in patients with estrogen receptor (ER)— positive, HER2-negative, node-negative breast cancer. Of the 10,253 eligible patients enrolled, 1626 (15.9%) had favorable gene expression profiles. This was defined as <11 on the Oncotype Dx Score which, Christy A. Russell, MD, pointed out, has been validated in women with ER-positive, HER2-negative, lymph node-negative breast cancer.

Findings on patients with these low scores have been published in The New England Journal of Medicine.1 Sparano et al showed that the risk of distant metastases from this primary cancer within 5 years is 1%. “There’s no way you’re ever going to be able to see a benefit from chemotherapy for that group, obviously, and it’s really extraordinary to see how well that group of women is doing,” said Russell.

Panel members pointed out that tools that would help predict metastasis frequently are not being used. “The underuse of Oncotype to me was shocking across this country and so you don’t know what people’s motivations are in ordering it or not ordering it,” said Russell. She noted that it might be a reasonable decision not to order it “in a very old population,” where you will not administer chemotherapy in any case.

Refining Use of Fulvestrant

In the metastatic disease setting, panel members discussed how best to deploy fulvestrant, which the FDA approved in 2002 for postmenopausal women with HR-positive metastatic breast cancer with disease progression following antiestrogen therapy. Brufsky commented that he hopes “we’re gaining a little bit more knowledge about how to use it properly.”

Recent studies have shown the proper dose that should be used for fulvestrant, said Sara A. Hurvitz, MD. The 250-mg dose used in the early studies required 3 or 4 months for adequate blood levels to be achieved, during which time patients were progressing and being switched to alternative therapies.

The CONFIRM study used 500-mg monthly and a loading dose given at day 14 of the first month and demonstrated a significant improvement in outcomes for patients in the metastatic setting.

More recently, for first-line treatment of metastatic ER-positive, postmenopausal breast cancer, the FIRST trial2 compared the 500-mg dose of fulvestrant plus a loading regimen with anastrozole. FIRST data showed that the time to progression was significantly improved with fulvestrant, and findings presented at SABCS 2014 demonstrated that overall survival was improved with fulvestrant. Other studies have demonstrated that fulvestrant is not the only option for these patients, Hurvitz noted. Palbociclib, a novel CDK 4/6 inhibitor, showed benefit in combination with letrozole in the phase II PALOMA-1 study in terms of progression- free survival (PFS) in the frontline setting. That combination was approved in February 2015. “We now have two regimens and we don’t have any way of comparing their relative efficacy, both based on phase II data, not on phase III,” Hurvitz said.

More answers are expected to come from the FALCON trial, which is comparing 500-mg fulvestrant with anastrozole as first-line hormonal therapy in postmenopausal women with locally advanced or metastatic, HR-positive breast cancer.

“We’re waiting for the phase III FALCON study to inform us about time-to-progression and overall survival with fulvestrant,” Hurvitz said. “But I don’t know whether it’s going to replace palbociclib in this setting.”

Exploring Palbociclib

Hope S. Rugo, MD pointed out that some patients in the adjuvant setting with highrisk disease will not take oral therapy because of problems with aromatase inhibitors or tamoxifen. “The biggest impact of the FIRST Trial for me is that I used fulvestrant in those patients,” she said, although Brufsky added that such use is off-label.The PALOMA-3 trial compared the combination of palbociclib and fulvestrant with fulvestrant and placebo among patients who had failed first-line endocrine therapy. Median PFS was 9.2 months with the palbociclib combination versus 3.8 months in the placebo arm (HR, 0.42; P <.001).3 The FDA is currently evaluating that combination under its priority review program and is expected to make a decision by April 2016.

“Although a third of the patients had received one line of prior chemo, there was no real difference in toxicity” between those patients and patients who had not received prior chemotherapy, said Rugo.

Inhibiting PI3K

In fact, compared with PALOMA-1, fewer patients stopped the drug due to toxicity, she said, although she noted that “we all got kind of used to the neutropenia in managing the drug.” There are no survival data yet because, thankfully, “there were not enough events,” Rugo said. Subset analyses from PALOMA-3 as reported in San Antonio showed that “even in patients who have had several lines of [prior] therapy, there was still nice benefit” with fulvestrant and palbociclib, said Joyce A. O’Shaughnessy, MD. The findings showed a 9.9-month median PFS with the combination of palbociclib and fulvestrant compared with 1.8 months for among patients who had failed 2 lines of estrogen therapy. (HR, 0.20; P <0.001).4BELLE-25 enrolled patients with endocrine-resitant HR-positive/HER2-negative advanced diseas who had progressed on a nonsteroidal aromatase inhibitor. Patients were randomized to receive either fulvestrant plus the pan-PI3K inhibitor buparlisib, an oral agent, or fulvestrant plus placebo. “It was technically a positive trial,” said O’Shaughnessy, although “the consensus is that it really wasn’t clinically meaningful because of the toxicity of buparlisib.” Adverse events included liver toxicity, hyperglycemia, mood disorders, and additional problems.

Role for Everolimus

However, the trial furnished very important information. “The biggest thing out of the whole paper,” said Brufsky, “was that it was a real proof of concept” of the value of pan-PI3K inhibitors, although “they’re going to have to be more targeted— alfa-specific or whatever” and he remains “concerned about the toxicity.”The panel then turned its attention to the place of everolimus in the therapeutic landscape. The oral mTOR inhibitor has been approved since 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. Rugo asserted that everolimus “has a continued place” in the armamentarium. She has been studying ways to address adverse events associated with everolimus therapy including mouth sores and stomatitis.

She hopes to present data from a single-arm trial showing that you can “essentially get close to eliminating any significant mouth sores” with a commercial steroid preparation with dexamethasone. “That makes everolimus a lot easier to use because I think that those early mouth sores—most of them occur in the first 6 to 8 weeks—are a really big issue,” she said. Rugo also said she is in the process of publishing a meta-analysis of clinical trial data in which everolimus was utilized in the treatment of different solid tumors. Her analysis shows that patients who developed stomatitis and “who got delayed and had dose reductions did just as well, if not better than, the people who didn’t have stomatitis.” She said that she has seen patients respond well with everolimus and exemestane even after failing palbociclib and receiving three lines of chemotherapy.

Russell said she also has been using a commercially available dexamethasone elixir and that she no longer sees stomatitis in patients receiving everolimus. However, she said, she does see intermittent noninfectious pneumonia. “That’s the toxicity that I’m targeting now,” Russell said. Brusky suggested such symptoms can be managed without abandoning everolimus. He derscribed a patient who has been receiving everolimus for 6 months and presents with coughing and shortness of breath and evidence suggestive of lymphangitic spread on a CT scan. “This is a pneumonitis,” he said. “Before you immediately go to chemo, withdraw the everolimus for a while and see if she gets better.” Unfortunately, there are no markers to guide clinicians about which patients would respond better to everolimus. “We would love to have a mutation in some gene that predicts response to everolimus,” said Brufsky. But currently, “that’s pie in the sky,” he said.

References

  1. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014.
  2. Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST Study. J Clin Oncol. 2015;33(32):3781-3787.
  3. Turner NC, Ro J, André F, Loi S, et al. Palbociclib in hormone- receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.
  4. Cristofanilli M, Bondarenko I, Ro J, et al. Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety. Presented at 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P4-13-01.
  5. Baselga J, Im S-A, Iwata H, et al. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2— advanced breast cancer (BC): first results from the randomized, phase III BELLE-2 trial. Presented at 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S6-01.