Tailoring Therapy for HR-Positive Breast Cancer

Adam M. Brufsky, MD, PhD

Adam M. Brufsky, MD, PhD

Although new targeted therapies have been introduced in recent years for patients with advanced hormone receptor (HR)-positive breast cancer, questions remain on the most effective ways to use these treatments throughout the continuum of disease, according to experts who participated in an OncLive Peer Exchange^® panel.

Multiparametric Genomic Assays

Several multiparametric genomic assays have been developed to predict recurrence in patients with early-stage disease, but the panelists agreed that more research is needed to clarify how these assays predict the need for and response to chemotherapy. The panelists also discussed prospective strategies for individualizing treatment for locally advanced and metastatic HR-positive breast cancer based on recent clinical trial data for extended adjuvant endocrine therapy and combinations, including aromatase inhibitors (AIs), cyclin-dependent kinase (CDK) 4/6 inhibitors, selective estrogen receptor (ER) degraders, mTOR inhibitors, and PI3K inhibitors.Panelists agreed that several multiparametric genomic assays that predict risk for recurrence can guide oncologists and patients when making clinical decisions for early-stage breast cancer. However, Mark E. Robson, MD, stated that the inability to predict benefit from chemotherapy is a key shortcoming with many of the assays. “When it comes down to conversations with the patients, you want to know are they or are they not going to benefit from incremental therapy,” said Robson.

The MINDACT trial¹ investigated whether a 70-gene signature test (MammaPrint) accurately predicted response to adjuvant chemotherapy in patients with breast cancer (≤3 positive lymph nodes). Use of the test led to a 14% reduction in administration of adjuvant chemotherapy for patients classified as low genomic/high clinical risk or high genomic/low clinical risk. The low genomic/high clinical risk patients who did not receive chemotherapy had a 5-year distant metastases-free survival of 94.7%, surpassing the null hypothesis of 92%. However, Robson cautioned that MINDACT was designed as a noninferiority trial, and was thus underpowered to determine conclusively the lack of chemotherapy benefit. Furthermore, he indicated that some patients and their oncologists may wish to pursue chemo- therapy, even if the predicted benefit is small. “Some people think that a 1 or 2 percentage point benefit in terms of chemotherapy benefit in that genomically low, clinically high-risk group is worthwhile,” Robson said.

The panelists also stated that results from the TransATAC trial² suggested that the predictive power of these genomic assays may depend on the presence of node-positive disease. The study, which compared the prognostic performance of 6 signatures over a 10-year follow-up in postmenopausal patients with HR-positive breast cancer, showed that the Clinical Treatment Score and EndoPredict were most prognostic for node-positive cancer, whereas the PAM50-based Prosigna was most prognostic for node-negative cancer.

Additionally, only EndoPredict accurately predicted relapse in the 5- to 10-year range (after cessation of treatment) for patients with node-positive cancer, which led Adam M. Brufsky, MD, PhD, the moderator of the panel, to question the utility of genomic assays for predicting long-term relapse and chemotherapy benefit in this group of patients. However, Kimberly L. Blackwell, MD, was less concerned about genomic assays for node-positive tests; she stated that she typically recommends extended adjuvant chemotherapy for all patients with node-positive, HR-positive cancer who can tolerate it regardless of the results on a genomic assay. Blackwell also noted that previous data validating the 21-Gene Recurrence Score in node-positive patients and the MINDACT trial provide “a consistent signal that these genomic predictors actually do work in node-positive [disease],” although she indicated that the ability of the assays to predict need for chemotherapy in this group remains to be determined.

Nevertheless, Blackwell emphasized that providing information on the biology of the tumor with a genomic assay is often more relevant for assessing clinical risk than tumor size and lymph node status, because they can guide treatment for a case, such as a grade 1, ER-negative tumor, that “doesn’t make any sense.”

Extended Adjuvant Endocrine Therapy

“The most important thing for the practicing oncologist is to gure out how these assays work, pick one, and make certain that women facing breast cancer are somewhat entitled to those results in their decision making about whether or not to receive chemotherapy,” she said.The conflicting data on the benefits of extended adjuvant endocrine therapy have introduced the question of its role in long-term management of patients with early-stage HR-positive breast cancer, according to Brufsky. Administration of letrozole for 5 years did not significantly improve disease-free or overall survival for patients in the NRG Oncology/NSABP B-42 study.³ Blackwell noted that the decrease in breast cancer-free interval events (which include recurrence or incidence of primary cancer in the contralateral breast) indicate that prevention of a secondary cancer was the primary benefit of extended therapy. “We’re creating a whole population of breast cancer survivors who are at risk of a secondary breast cancer. And, if they have residual breast tissue...one of the major drivers for that very small difference in breast cancer—free survival is really the prevention of a secondary breast cancer,” Blackwell said.

Because the clinical benefits are small, Aditya Bardia, MBBS, MPH, said that the patient’s tolerance and risk for osteopenia must be considered when deciding whether to continue AI therapy. Similarly, Robson stated that although the current data support extended therapy as a “default” recommendation, oncologists “have to acknowledge that the bene t is small and that if somebody decides they want to walk away from that, they’re not necessarily forgoing a huge benefit.”

Blackwell also said that the 21-Gene Recurrence Score may not provide a clear-cut indication of which patients would benefit from extended adjuvant therapy because a low recurrence score may indicate presence of a hormonally driven cancer that would respond particularly well to extended endocrine therapy. “We see people at 6 years because that’s when the breast cancer comes back, because we’ve stopped the endocrine therapy at 5 years. That’s where the prediction of the 21-gene [score] for extended adjuvant [therapy] falls short,” she said.

Metastatic Disease

However, she and Bardia indicated that that the genomic assays may help decide whether to continue AIs in patients who experienced adverse events (AEs) in the initial 5 years of treatment. Brufsky noted that the increased risk for osteoporosis and related bone fractures should be considered when prescribing long-duration AI therapy, although Blackwell indicated that most of the bone loss occurs in the first 2 years of therapy and can be minimized by prescribing a bone-protective agent (such as denosumab) for 5 years, and by following up with annual bone mineral density assessments.Fulvestrant

According to Bardia, the combination of letrozole, a nonsteroidal estrogen synthesis inhibitor, with palbociclib (Ibrance), a CDK4/6 inhibitor, is generally considered to be the first-line choice for metastatic ER-positive breast cancer based on the improvement in progression-free survival (PFS) over letrozole alone in the PALOMA-1 trial.⁴

However, he indicated that results from the FALCON trial⁵ suggest that fulvestrant (Faslodex), a selective ER degrader, may become a suitable option for older, treatment-naïve patients with a minimal number of metastatic lesions. In this trial, patients with locally advanced or metastatic HR-positive breast cancer who had not received prior hormonal therapy had longer PFS with fulvestrant than with anastrozole (median 16.6 vs 13.8 months, respectively). Bardia recommended that letrozole with palbociclib still be used as first-line therapy for patients who have received prior endocrine therapy since these individuals were not included in the FALCON trial.

Meanwhile, therapeutic strategies for patients who progress on letrozole/palbociclib are still unclear, according to Bardia, who said that the PrECOG study⁶ showing improved PFS with fulvestrant plus everolimus (Afinitor), an mTOR inhibitor, over fulvestrant monotherapy could provide a second-line option for patients resistant to AI therapy. Although he indicated that more research is needed to investigate responses in patients with prior use of a CDK4/6 inhibitor, Bardia noted that patients who develop ESR1 gene mutations, which cause the tumor to become estrogen independent, following AI therapy may benefit from addition of fulvestrant in the second-line setting.

CDK4/6 Inhibitors

Interim analysis of the MONALEESA-2 trial⁷ showed that addition of ribociclib, a CDK4/6 inhibitor, to letrozole significantly improved PFS at 18-months’ follow-up compared with letrozole alone (63.0% vs 42.2%, respectively) in postmenopausal women with HR-positive recurrent or metastatic breast cancer. Further subgroup analyses8 demonstrated improved PFS in patients with visceral and bone-only metastases, respectively. Based on the trial results, the FDA in mid-March approved ribociclib under the brand name Kisqali in combination with an AI as initial endocrine therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic disease.

The panelists said that the results from the MONALEESA-2 and PALOMA-1 trials, taken together, support combination of a CDK4/6 inhibitor and an AI for recurrent or metastatic breast cancer.

The CDK4/6 inhibitors differ slightly in their targeting of CDK4 versus CDK6, although Robson stated that the clinically meaningful differences between palbociclib and ribociclib are likely minor based on current data. Neutropenia was the most common AE for both agents, and Blackwell stated that the few cases of QTc prolongation in phase II studies of ribociclib warrant continued surveil- lance to determine whether this AE is significant.

Furthermore, whether patients would benefit from switching from 1 CDK4/6 inhibitor to another if they do not tolerate the first drug is unclear, according to Bardia. Blackwell stated that patient costs and payer-negotiated contracts with the pharmaceutical company may be the deciding factor for selecting a CDK-4/6 inhibitor if clinical differences are negligible.

Abemaciclib is another CDK4/6 inhibitor that has antitumor activity in patients with breast cancer⁹ and may have a lower incidence of neutropenia than other CDK4/6 inhibitors. The neoMONARCH phase II trial showed that abemaciclib, when given as monotherapy or in combination with anastrozole, a nonsteroidal estrogen synthesis inhibitor, suppressed Ki-67 more than anastrozole monotherapy. This antitumor activity in isolation could be valuable for patients and oncologists seeking to minimize the number of drugs they are taking. “That’s kind of exciting when you see single-agent activity that, at least to my knowledge, we really haven’t seen with the other CDK inhibitors,” said Blackwell.

PI3K Inhibitors

The panel discussed the addition of PI3K inhibitors to treatment regimens for patients with HR-positive breast cancer previously treated with an AI. In the BELLE-3 trial, adding the pan-PI3K inhibitor buparlisib to fulvestrant improved PFS compared with fulvestrant alone (median 3.9 vs 1.8 months, respectively) in patients with locally advanced or metastatic breast cancer who had received previous mTOR inhibitor therapy, with greater improvements observed in patients with PIK3CA-mutated tumors. However, Bardia noted that the potential toxicity of buparlisib, including depression, suicidality, and liver function test abnormalities, has increased interest in developing more selective, less toxic PI3K inhibitors.

Need for Participation in Clinical Trials

Taselisib, a selective inhibitor of the p110alpha protein in mutant PI3K pathway genes, blocks kinase signaling and downregulates mutant p110alpha protein in cell culture and xenograft models without affecting wild-type p110alpha. Although this increased selectivity may reduce AEs, Brufsky expressed concern that the small, albeit statistically significant, improvement in PFS in early results of a phase III trial may not be worth pursuing development of the drug from the pharmaceutical industry perspective. However, Blackwell noted that the follow-up analysis revealed that patients with activating mutations in cell-free DNA PI3K pathway mutations had a PFS that was 3.6 months longer than patients who did not have the mutation. Thus, she concluded that greater fine-tuning of genomic analysis will be important when predicting which patients might benefit from taselisib and other highly selective agents.As the segment concluded, Blackwell stated that genomic predictors will continue to play a role in treating patients with early-stage breast cancer and that increasing clinical trial participation for patients with metastatic disease would also help clarify which patients bene t from different combinations of therapy.

Similarly, Robson said that the next steps for optimizing treatment are to increase the specificity by which the tumors from patients are characterized throughout the disease process. “We need to perhaps start thinking about the deepest possible characterization of patients, both from a genomic level and potentially from a germline level, so that we can figure out which is the best way of putting these things together for each individual,” he said.

References

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4. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35. doi: 10.1016/S1470- 2045(14)71159-3.
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