Changing paradigms in the treatment of hormone-receptor positive advanced breast cancer

KEYWORDS:

• Breast cancer
• endocrine therapy
• resistance
• palbociclib
• CDK 4/6

The concept that expression of the estrogen and/or the progesterone receptor (ER, PgR) is a necessary, yet not sufficient condition, for the antitumor activity of endocrine manipulation in breast cancer has been extensively studied for decades.[1] The formidable research efforts focusing on primary and acquired mechanisms of resistance to endocrine therapy have resulted in newer treatment paradigms. In particular, the rationale of combining endocrine therapy with a pharmacological ‘antidote’ of the putative biological mechanism of resistance has been tested in randomized clinical trials. Notable examples are combinations of endocrine therapy with epidermal growth factor receptor(s) family (EGFR-HER) targeting agents, and with inhibitors of the PI3K/Akt/mTOR pathway, of angiogenesis, and of the cyclin-dependent kinases (CDK) 4/6. The preclinical and clinical development of palbociclib, the first CDK 4/6 inhibitor approved for clinical use, has been elegantly summarized in a review article in this issue of Expert Opinion on Pharmacotherapy by Guenther Steger and colleagues.[2] Abnormal and dysregulated cell proliferation has long been identified as a hallmark of cancer.[3] In this context, biology suggests that Cyclin D1/CDK4/6/pRb protein interaction is important in sustaining a proliferative and possibly endocrine-resistant phenotype in luminal tumors.[4] As described in the review, the preclinical potentialities of this compound in the treatment of hormone-receptor positive breast cancer have been tested in the clinic, with results that have raised enthusiasm and hopes. Furthermore, considering the rapidity of enrolment in other randomized clinical trials with palbociclib and two other CDK 4/6 inhibitors (ribociclib and abemaciclib),[4] additional data on the clinical activity, safety, and efficacy will become available shortly. As it occurred with the mTOR inhibitor everolimus a few years ago, results with palbociclib suggest another treatment paradigm shift in the treatment of women with hormone-receptor positive metastatic breast cancer.

At the present time, endocrine therapy is synonymous with a low-toxic, effective and not demanding therapy both for the patient and the health-care system. For these reasons, guidelines recommend to consider endocrine therapy as a default option in a hormone-receptor positive metastatic breast cancer patient when there is ‘no concern or proof of endocrine resistance or there is disease needing a fast response’.[5] In general, adding a biologic to all patients with hormone-receptor positive disease will add substantial toxicity and costs and would likely change the general perception of ‘endocrine therapy’. Therefore, the authors of the review point out a series of open questions that need addressing to correctly estimate the positioning and impact of this novel therapeutic strategy. In our opinion, the first and foremost would be whether adding CDK 4/6 inhibitors to endocrine therapy prolongs overall survival (OS) in these patients. Paloma 1 and 3 show impressive prolongation of progression-free survival (PFS), which was the primary end point for both studies.[6,7] Similar improvements in PFS have been observed with mTOR inhibitors and angiogenesis inhibitors (Table 1).[8–11] Common to these studies are also a marginal to moderate overall response rate gain (with the exception of studies with bevacizumab) and a substantial increase in the clinical benefit rate, resulting from more patients achieving long-lasting disease stabilizations with the combined treatment. At this stage, with the exception of one Phase II randomized trial with tamoxifen and everolimus,[9] no advantage in OS has been reported in favor of any of the combination tested. Mature follow up of the Paloma 1 and 3 clinical trial and the results of large randomized clinical trials using the three CDK 4/6 inhibitors in late stage of clinical development will hopefully provide solid OS data. A clear OS advantage would undoubtedly confirm that this therapeutic strategy is a major advancement in the treatment of hormone-receptor positive metastatic breast cancer. Waiting for OS results, the question is whether a significant PFS advantage would support the widespread use of these compounds in the clinic. As the authors of this review correctly point out, PFS prolongation has positive effects for the individual patient because, for example, it ‘delays the time until the need for cytotoxic chemotherapy with its associated toxicity, side effects, and psychological distress’. The concept of delaying the use of chemotherapy by fully exploiting the potentiality of endocrine therapy has been postulated before the availability for clinical testing of biologics added to endocrine therapy.[12] In that context, it referred to the scenario where the patient took subsequent lines of ‘potentially’ non-cross resistant or ‘partially’ non-cross resistant endocrine therapies alone and could enjoy additional time without major toxicities, frequent hospital visits, lab work-ups, and staging procedures. Because of specific, although often manageable, toxicities, the therapeutic experience of a patient on endocrine therapy plus a biologic agent (i.e. everolimus or palbociclib) is profoundly different from that of a patient on endocrine therapy alone. In fact, even in the case of no major toxicities occurring, patients on biologics need more frequent lab work-ups, hospital visits to allow for dose and schedule adjustment and, perhaps, also instrumental staging procedures. Thus, the additional ‘time without chemotherapy’ comes in any case at the price of some burdens that are commonly associated with conventional chemotherapy. The BOLERO 2 and the PALOMA 3 trials show better quality of life (QoL) in patients receiving biologics with endocrine therapy despite higher toxicity. One reasonable explanation is that patients receiving the good news that a CT scan (restaging is performed every 6–8 weeks in these trials) shows stable disease, an occurrence that is more frequent in the experimental arms, cope better with treatment.[13] It must be considered, however, that hormone-receptor positive metastatic breast cancer patients are not usually staged every 6–8 weeks in the clinical practice. It is therefore unclear how these QoL results would apply in a population of patients with often asymptomatic and slowly growing disease, who may be managed on more relaxed assessment schedules.

Table 1. Summary of randomized studies comparing endocrine therapy alone or with a biologic agent in metastatic, hormone-receptor positive breast cancer.

Author (Year)	Setting	ET alone	ET+ biologic	∆RR (∆CBR)^a Months	∆PFS^a Months	∆OS^a Months
Cristofanilli (2016) [7]	Failing prior endocrine therapy	Fulv.	Fulv+Palbo.	10% (27%)*	4.9*	-
Finn (2015) [6]	First-line metastatic	Letroz.	Letroz.+Palbo	9% (21%)*	10*	4.2
Piccart (2015) [8]	Failing prior NSAIs	Exem.	Exem.+ Everolimus	9.1%* (25%)*	4.1*	4.4
Bachelot (2012) [9]	Failing prior AIs	Tam.	Tam.+Everolimus	1% (19%)*	4.1*	0.45 (HR)*
Dickler (2015) [10]	First-line metastatic	Letroz.	Letroz.+ Bevacizumab	20%*^b (18%)*^b	4*	3
Martin (2015) [11]	First-line metastatic	Letroz.	Letroz.+Bevacizumab	18.9%* (9.4%)*	4.9*	N.S.

^aIncrease in response rate (RR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) of combined therapy vs. endocrine therapy alone.

^bCalculated in patients with measurable disease.

*Increase is statistically significant

Abbreviations: ET, endocrine therapy; NSAIs, non-steroidal aromatase inhibitors; AIs, aromatase inhibitors; HR, hazard ratio. Fulv, fulvestrant; Letroz., letrozole; Exem., exemestane; Tam., tamoxifen.

Despite these and other open questions, we fully concur with the authors of the review that palbociclib, and more in general CDK 4/6 inhibitors, represent a significant achievement and have the potential to play a major role in the treatment of hormone-receptor positive breast cancer. This role would be even more dramatic if the scientific community could solve the eternal problem of identification and clinical validation of biomarkers of susceptibility or resistance to biologically targeted therapies to guide clinical decision-making. In-vitro and in vivo mechanisms accounting for resistance to CDK 4/6 inhibitors have been recently described, which can be explained by the adaptability of proliferation and survival biological networks in hormone-receptor positive breast cancer cells.[14,15] These intriguing observations offer hopes for better treatment tailoring and suggest newer combinatorial approaches (i.e. CDK 4/6 with mTOR inhibitors or CDK 4/6 with CDK 2 inhibitors) to be tested in future studies.

Declaration of interest

F Montemurro is a recipient of Fondazione Piemontese per la Ricerca sul Cancro (FPRC Onlus) 5 X 1000 fondi Ministero della Salute 2012 and Italian Association for Cancer Research (AIRC) Investigator Grant IG-2013 Ref. 14,451 and a member of the speakers’ bureau for HoffmannLaRoche and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.