A biomarker that could identify patients with estrogen receptor–positive breast cancer who do just as well with endocrine therapy alone and may not benefit from the addition of a second agent would be useful, sparing women both the expense and additional side effects of the combination.

— Richard S. Finn, MD

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Hormone receptor–positive breast cancer represents the largest therapeutic subgroup of the disease. The development of endocrine therapies has shaped the treatment paradigm for both advanced- and early-stage disease for decades.¹ Still, despite their significant impact, advanced breast cancer remains incurable.

There has been extensive laboratory research in understanding the mechanisms of both de novo and acquired endocrine resistance, but most attempts at overcoming these mechanisms in the clinical setting have failed. Only in the past few years have we seen the approval of the mTOR (mammalian target of rapamycin) inhibitor everolimus (Afinitor) in combination with exemestane for hormone receptor–positive breast cancer with progression on a nonsteroidal aromatase inhibitor.² And more recently, we have seen the approval of palbociclib (Ibrance) and letrozole in the first-line setting based on the randomized open-label phase II PALOMA-1 study.³

The PALOMA-3 study was a global, randomized, double-blind, placebo-controlled study of palbociclib and fulvestrant vs placebo and fulvestrant (Faslodex).⁴ The study was stopped early given the efficacy of the combination. The final results—reported by Cristofanilli et al and summarized in this issue of The ASCO Post—confirm the safety and efficacy of the combination seen at the interim analysis and also confirm the side-effect profile of palbociclib seen in the PALOMA-1 study.⁵ Palbociclib has since been approved by the U.S. Food and Drug Administration (FDA) in combination with fulvestrant for advanced estrogen receptor–positive breast cancer that has progressed after endocrine therapy.

Unlike PALOMA-1, which focused on postmenopausal patients, ­PALOMA-3 included pre- and perimenopausal women as well with the addition of the luteinizing hormone–releasing hormone agonist goserelin (Zoladex). Now with a median follow-up of 8.9 months, median progression-free survival was 9.5 months (95% confidence interval [CI] = 9.2–11.0 months) in the palbociclib plus fulvestrant arm vs 4.6 months (95% CI = 3.5–5.6 months) in the placebo plus fulvestrant arm (hazard ratio = 0.46, 95% CI = 0.36–0.59, P < .0001)—and this benefit is consistent across clinical subgroups. The most common grade 3 or 4 adverse events were still neutropenia, anemia, and leukopenia, though the incidence of neutropenic fever was not significantly increased. This is consistent with the noncytotoxic effects of CDK 4/6 inhibition on the bone marrow, as compared with cytotoxic chemotherapy.⁶

Estrogen Receptor Positivity

Preclinical data with palbociclib suggested that the most important predictive marker for benefit in breast cancer was estrogen receptor positivity.⁷ To date, clinical data with palbociclib and the other CDK4/6 inhibitors in development, abemaciclib and ribociclib, have supported this observation.

Proposed markers associated with endocrine resistance include quantitative estrogen receptor expression levels and PI3-kinase mutational status in circulating DNA at baseline—the latter of which has been recently evaluated in the phase III BELLE-2 study investigating the PI3-kinase inhibitor buparlisib and fulvestrant vs placebo and fulvestrant.⁸ In PALOMA-3, neither of them improved upon estrogen receptor positivity alone. For patients with PI3-kinase wild-type disease at study entry, the hazard ratio was 0.45 (95% CI = 0.31–0.64, P < .0001), compared with 0.48 (95% CI = 0.30–0.78, P = .002) for those with PI3-kinase mutations. In the BELLE-2 study, however, the magnitude of benefit with the combination was greater in those patients with PI3-kinase mutations in circulating tumor DNA at study entry (HR = 0.56, P < .001) vs the entire population (HR = 0.78, P < .001).

The evolving data with CDK4/6 inhibitors in breast cancer would suggest that interrupting the cyclin D1/CDK4/6/Rb pathway is striking at a critical position in control of estrogen receptor–positive breast cancer. This includes those tumors that are still dependent on estrogen receptor signaling as well as those that are or have become resistant to antiestrogen approaches. It is interesting to note that many of the proposed mechanisms of estrogen receptor resistance—such as peptide growth factor signaling and receptor tyrosine kinase activation including through the HER pathway, insulin-like growth factor, and fibroblast growth factor receptor, among others—converge on the CDK4/6 pathway, potentially explaining the significant activity we are seeing with CDK4/6 inhibitors.

Endocrine Doublets Continue to Gain Traction

The clinical benefit rates in PALOMA-1 and PALOMA-3 are quite high—81% and 67%, respectively. With this in mind, it may prove challenging to find a better predictive marker for response than estrogen receptor positivity. This is in contrast to identifying markers of resistance, such as Rb loss, a relatively uncommon event in estrogen receptor–positive disease.

On the other hand, a biomarker that could identify patients with estrogen receptor–positive breast cancer who do just as well with endocrine therapy alone and may not benefit from the addition of a second agent would be useful, sparing women both the expense and additional side effects of the combination. Until we know who those patients are, it would appear that endocrine-based doublets will continue to gain traction in the treatment of estrogen receptor–positive breast cancer, and the role of palbociclib in early breast cancer is currently being evaluated (PALLAS study, NCT02513394).

Finally, the impact of palbociclib on the important endpoint of overall survival in advanced estrogen receptor–positive breast cancer has not been established. Further follow-up of the PALOMA studies is required to determine whether there is a survival benefit. ■

Disclosure: Dr. Finn is a consultant for Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

References

1. Chlebowski RT: Changing concepts of hormone receptor-positive advanced breast cancer therapy. Clin Breast Cancer 13:159-166, 2013.

2. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

3. 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 16:25-35, 2015.

4. Turner NC, Huang Bartlett C, Cristofanilli M: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:1672-1673, 2015.

5. Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. March 2, 2016 (early release online).

6. Hu W, Sung T, Jessen BA, et al: Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 22:2000-2008, 2016.

7. Finn RS, Dering J, Conklin D, et al: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11:R77, 2009.

8. Baselga J, Im S-A, Iwata H, et al: PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrine-resistant HR+/HER2–advanced breast cancer: First results from the randomized, phase III BELLE-2 trial. 2015 San Antonio Breast Cancer Symposium. Abstract S6-01. Presented December 11, 2015.