Introduction
The heterogeneity of metastatic breast cancer has historically been dichotomized by estrogen receptor (ER) expression vs lack thereof. The prognostic and predictive importance of the human epidermal growth factor receptor 2 (HER2) and its signaling pathways created a need to expand this oversimplified and somewhat “old-school” paradigm, and elucidated intrinsic subtypes[1,2] and other possible targets.[3] When ER is present, with perhaps the notable clinical scenario of impending visceral crisis, targeting ER-driven growth has been the standard first-line approach for treating metastatic breast cancer in postmenopausal women. The combination strategy of anastrozole with fulvestrant has yielded mixed results in two randomized clinical trials,[4,5] and endocrine monotherapy for postmenopausal women with ER-positive metastatic breast cancer has been the rule rather than the exception. However, median progression-free survival (PFS) is still measured in many months rather than many years, and resistance can be either de novo or acquired. Loss of ER expression (by epigenetic silencing or other mechanisms), ER mutations, altered expression of coregulators, and upregulation of alternative signal transduction pathways have all been implicated and are currently being targeted.
A rapidly expanding understanding of the genomic and biochemical pathways underpinning resistance to existing endocrine therapy has informed the preclinical and clinical development of new targeted agents to improve upon the efficacy of existing hormonal therapies, such as aromatase inhibitors and fulvestrant. Before examining the randomized trial data that inform how I-a “one-trick pony” oncologist who treats only breast cancer-integrate these agents into the care of my own patients, it is important to consider metastatic breast cancer as the multi-chaptered story that it is. What clinical trial endpoints should motivate us to change our standard of care? Overall survival (OS) advantages can clearly be garnered by “what comes next”-that is, subsequent post-endocrine cytotoxic chemotherapy.[6-8] My position, which is shared by others, is that sufficient incremental gains in PFS with “endocrine + X” that are accompanied by acceptable toxicity (a Pandora’s box phrase, for sure) should be strong motivation to include this strategy in routine patient care. Although we should continue to strive to develop first-line endocrine + X regimens that may extend survival by many years, at the moment, if we make each individual chapter of the story of metastatic breast cancer longer, the book will read more like War and Peace as opposed to Jonathan Livingston Seagull. If you buy into this proposition, read on.
Inhibition of mTOR or CDK4/6
The addition of the mammalian target of rapamycin (mTOR) inhibitor everolimus to exemestane was the first such US Food and Drug Administration–approved approach. Among patients who had recurrence or progression despite prior nonsteroidal aromatase inhibitors, the addition of everolimus improved median PFS from 4.1 to 10.6 months (hazard ratio [HR], 0.36 [95% CI, 0.27–0.47]; P < .001),[9] without an OS benefit (again, not the most robust endpoint).[10] Everolimus use was associated with more grade ≥ 3 stomatitis, hyperglycemia, fatigue, and pneumonitis, although the incidence of these events was modest. Undoubtedly, practitioner experience in optimizing supportive care for patients receiving this regimen has favorably impacted the therapeutic index.[11]
For Mrs. W, my 63-year-old patient with breast cancer metastatic to bone despite stable disease on letrozole (and denosumab) for 9 months as first-line therapy, I have no direct comparison between the BOLERO-2 regimen (exemestane plus everolimus) and fulvestrant monotherapy. Both options remain viable, yet must be considered in a rapidly changing landscape, as well as in the context of unique patient attributes and preferences. For example, if Mrs. W has poorly controlled diabetes mellitus or significant pulmonary disease, or prefers monthly intramuscular injection to daily oral therapy, then fulvestrant may be preferable for the next chapter. Its use in this context would not preclude subsequent downstream use of exemestane plus everolimus.
Palbociclib is the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to be approved for the management of postmenopausal, ER-positive/HER2-negative, metastatic breast cancer. In a randomized, open-label, phase II trial (N = 165), the combination of palbociclib plus letrozole improved PFS from 10.2 to 20.2 months (HR, 0.488 [95% CI, 0.319–0.748]; one-sided P = .0004).[12] Grade ≥ 3 neutropenia was noted in 54% of patients receiving palbociclib, and in 1% receiving letrozole; febrile neutropenia was not encountered. Fatigue, anemia, and nausea were more common with palbociclib, although were not usually severe. Notably, unlike patients on typical endocrine therapy, patients on palbociclib require monitoring of their complete blood counts, and also have greater potential to develop alopecia (22% vs 3% in PALOMA-1).[12] Results of the larger PALOMA-2 confirmation trial are awaited at the time of writing this piece. For patients like Mrs. G, a 59-year-old woman presenting with de novo ER-positive/HER2-negative breast cancer metastatic to bone, lung, and pleura, or Mrs. R, a 55-year-old who completed adjuvant tamoxifen 7 years ago and is now postmenopausal with breast cancer metastatic to liver and bone, these data offer the promise of a longer “first chapter,” without excessive toxicity.
KEY POINTS
- Intrinsic and de novo resistance to current endocrine therapies results in a median time to progression of months, not years, for postmenopausal women with ER-positive/ HER2-negative metastatic breast cancer.
- A greater understanding of the molecular mechanisms responsible for resistance has led to the study and incorporation of CDK4/6 and mTOR inhibitors into clinical practice; PIK3CA inhibitors and other agents are being actively investigated.
- Thoughtful consideration of the anticipated incremental gain in efficacy balanced by encountered toxicity is integral to decision-making for an individual patient.
A Rapidly Changing Landscape
This landscape of endocrine therapy for metastatic breast cancer is changing rapidly. The recent report that palbociclib improved median PFS from 3.8 to 9.2 months (HR, 0.422; P < .001) when combined with fulvestrant in patients with progression despite prior endocrine therapy is compelling.[13] The effectiveness of CDK4/6 inhibition through multiple lines of therapy or following mTOR inhibition with everolimus is largely unexplored territory. Whether prior CDK4/6 inhibition with palbociclib alters subsequent efficacy of everolimus is similarly unstudied. To date, even though there is no specific biomarker to best select patients for either strategy, correlative investigations continue. Definitive trials of abemaciclib and ribociclib are awaited. Phase III trials of inhibitors of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are well underway and will be reported in coming months and years and, if positive, will further alter the treatment algorithm, perhaps (or not) guided by PIK3CA mutational status.
So, how do I integrate these data into the care of my own patients? For me, 6 or more months of improved PFS wins compared with modest/acceptable toxicity with endocrine monotherapy. If endocrine + X were to prolong PFS by merely 2 months, and was associated with a 30% incidence of grade ≥ 3 diarrhea, for example, I would not consider this an attractive option. Moving forward, the oncology community and regulatory agencies might consider formalizing an aggregate measure of benefit that balances the trade-off of improved PFS against adverse events. Certainly, patient/doctor discussions regarding benefits vs toxicities are part and parcel of informed, shared decision-making in the medical oncology clinic. This seems particularly apropos in scenarios in which OS may not be the most robust endpoint and financial toxicity is very real.[14]
Nuanced and granular decision-making for patients with ER-positive/HER2-negative metastatic breast cancer should certainly be informed by clinical trial data and risk/benefit trade-off considerations. Decisions about appropriate therapy may also be finessed by recognizing unique patient attributes such as age; performance status; extent of disease; degree of symptoms; tempo of progression; comorbidities; hepatic, renal, and pulmonary organ function; bone marrow reserve; and the nature of and time since prior adjuvant/neoadjuvant therapy. The results of genomic profiling of metastases, beyond ER, progesterone receptor, and HER2, will likely join these attributes. Although expert guidelines take us so far, I believe that it is inevitable that we will soon leverage computer-assisted physician decision support tools in the oncology clinic to help parse the more difficult therapeutic decisions.[15] Filtered through all of this, the patient’s own unique voice must be heard.
Financial Disclosure:Dr. Seidman is a consultant for Genentech, Novartis, and Pfizer; he is also a speaker for Genentech and Novartis.
References:
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