This article is more than 5 years old. Information may no longer be current.
Personalized approach must guide extended aromatase inhibitor therapy for breast cancer
Click Here to Manage Email Alerts
Approximately 75% of patients with breast cancer have hormone receptor–positive disease, in which growth and replication depends on estrogen signaling.
Thus, endocrine therapies — including tamoxifen, aromatase inhibitors and antiestrogens — have become the cornerstone of treatment for the majority of breast cancers.
The natural history of early-stage hormone receptor–positive breast cancer suggests patients are at risk for disease recurrence for many years, even after stopping therapy. Therefore, the rationale for using endocrine therapies beyond the initially recommended 5 years has become an important topic of debate.
Conflicting results
The ATLAS trial — published in 2013 in The Lancet — and the aTTom trial, published that same year in Journal of Clinical Oncology, first demonstrated that continuing tamoxifen therapy for 10 years rather than stopping at 5 years reduced risk for breast cancer recurrence, breast cancer mortality and overall mortality.
These practice-changing trials resulted in updates to ASCO guidelines recommending prolonged tamoxifen therapy for premenopausal women, or switching to an aromatase inhibitor for perimenopausal women.
Since then, the topic of whether to extend aromatase inhibitor therapy for postmenopausal women with hormone receptor–positive breast cancer has come into question.
Results from MA.17R — a randomized phase 3 trial — showed postmenopausal women with early-stage breast cancer demonstrated a 34% reduced risk for recurrence (HR = 0.66; P = 0.01) when adjuvant letrozole was extended from 5 to 10 years.
In addition, researchers reported no significant differences in quality of life between treatment groups. However, the population was highly selected for those who already tolerated the initial 5 years of aromatase inhibitor therapy, and it is evident that those who tolerate therapy early likely will continue to tolerate therapy for several years.
The subsequent NRG Oncology/NSABP B-42 trial — results of which were presented in December at San Antonio Breast Cancer Symposium — evaluated 5 years of letrozole vs. placebo in 3,966 patients who had completed 5 years of endocrine therapy.
Results showed a small but not statistically significant improvement in DFS (HR = 0.85) and no improvement in OS, although investigators reported significant improvements in breast cancer-free interval and distant recurrence.
Although the results seem strikingly different, the definition of the primary endpoints differed.
In the NRG Oncology/NSABP B-42 trial, DFS consisted of contralateral breast cancer, recurrence, non-breast cancers and deaths. In the MA.17R trial, DFS included only contralateral breast cancers and recurrence. When DFS in the MA.17R trial was modified to include deaths from any cause, the HR increased to 0.8 and the P value was no longer was statistically significant.
Two other trials presented in San Antonio examined extended therapy.
The phase 3 DATA study, which evaluated extending adjuvant anastrozole from 3 to 6 years for postmenopausal women who already received 2 to 3 years of adjuvant tamoxifen, showed no benefit in risk-adapted DFS.
The IDEAL trial, which compared 5 years vs. 2.5 years of letrozole for women who already underwent 5 years of endocrine therapy, also showed no improvement in DFS with extended therapy.
Risks vs. benefits
Extended aromatase inhibitor therapy can lead to additional side effects, including bone defects, fracture risk, arthralgia, hot flashes and menopausal-like symptoms. Joint pain — one of the most difficult-to-manage symptoms — is the most common reason for therapy cessation.
Precautions should be used to minimize fracture risks. These include baseline and serial bone mineral density tests or administration of bisphosphonates to high-risk patients.
The treatment-limiting nature of these adverse events are the primary reason for lack of compliance or treatment discontinuation, with up to half of patients stopping treatment before completion of 5 years.
Although the rate of cardiovascular deaths attributed to aromatase inhibitor therapy is low (approximately 1% to 2%), cardiac toxicity overall can be as high as 10% to 15%. Data suggests reduced endothelial function after treatment with an aromatase inhibitor may be a contributing factor to increased cardiovascular risk.
As the population ages, there is greater concern about increased cardiovascular risk, particularly when risk factors — such as sedentary lifestyle, obesity, hypertension and hyperlipidemia — already are present.
Placing women on aromatase inhibitor therapy for 10 years while subjecting them to burdensome toxicities, countered by no apparent true benefit in DFS or OS — not to mention the costs associated with extended therapy — appropriately raises the question of whether one should adopt this practice.
Potential biomarkers
Alterations in many genes — including PIK3CA, ESR1, ERBB2, AKT1 and RB1 — can be acquired during breast cancer progression, and preliminary data suggest they can contribute to endocrine therapy resistance.
The genomic landscape of ER–positive breast cancer tumors also can change during therapy with an aromatase inhibitor.
The likelihood of acquired mutations in ESR1 may approach 50% in the metastatic setting after treatment with aromatase inhibitors, whereas only 1% are de novo. This suggests extended therapy may select for mutations that ultimately promote cancer growth.
ESR1 mutations occur in the ligand — or estrogen — binding domain, where they result in ligand-independent activation of the receptor. Even with inhibition of estrogen production, the receptor remains in an active state, thereby activating its downstream signaling pathways.
Analyzing ESR1 mutation status may allow for better selection of therapies or combinations.
A subgroup analysis of patients from the SOFEA trial showed patients whose tumors harbored ESR1 mutations — most commonly D538G, Y537 and Y537S — achieved longer DFS with fulvestrant than exemestane (HR = 0.52; P = 0.02). Results showed no difference among patients with ESR1 wild-type disease.
A subgroup analysis from the PALOMA-3 study showed the addition of palbociclib (Ibrance, Pfizer) to fulvestrant improved DFS irrespective of ESR1 mutation status, suggesting this resistant mutation is specific to aromatase inhibitor therapy.
Cohen and colleagues performed whole exome sequencing of the tumor and germline on 149 biopsies of ER–positive metastatic breast cancers, as well as 44 matched primary tumors. Their analysis revealed several variations in the mutational landscapes between metastatic breast cancer and primary tumors, including acquired mutations in ESR1 (24%), ERBB2 (8%) and RB1 (6%).
Polymorphisms in CYP19A1 — the enzyme responsible for estrogen production — and CYP1A2, the enzyme responsible for converting estrogens into inactive or weak metabolites, also may contribute to aromatase inhibitor therapy response. However, the data are less compelling.
Genetic polymorphisms in phase I and II enzymes (eg, CYP2A6, CYP3A4, UGT1A4, UGT2B17) may alter the plasma concentrations of aromatase inhibitors; however, there is a paucity of data linking these polymorphisms to drug response or toxicity.
Serial testing for resistant mutations in genes such as ESR1 are the most promising and may allow for earlier detection of recurrence and improved prognostication for selection of extended therapy, switching therapies or combining therapies.
Personalized approaches
The benefit–risk ratio is greatest during the first 1 to 5 years of therapy; thus, at least 5 years of therapy with an aromatase inhibitor is recommended for postmenopausal patients.
Even 5 years of endocrine therapy can provide protection against breast cancer recurrence for 10 to 15 years. However, the benefit–risk profile becomes more complex during the second 5 to 10 years of therapy.
Despite data from large randomized clinical trials, it remains unknown whether extending aromatase inhibitor therapy prolongs DFS and OS in patients with hormone receptor–positive breast cancer. It is likely that some patients may benefit and others do not.
Thus, a personalized approach to extending therapy — or the selection of combination therapies — is essential.
Risk factors should be assessed when deciding when to stop therapy with an aromatase inhibitor.
These include:
The patient voice also is important, as one must understand the person’s willingness to continue prolonged therapy.
This risk-adapted, personalized approach — assigning extended therapy to those who are younger, at high risk for recurrence, demonstrate good tolerability and lack comorbidities — should be accepted as standard practice in the absence of additional clinical and genomic data.
Future studies should continue to investigate the influence of genomics on extended aromatase inhibitor therapy.
Genomic classifiers — such as appearance of ESR1 mutations — may inform when to stop therapy, specifically by identifying those unlikely to benefit from extended aromatase inhibitor therapy or other alternative therapies (eg, fulvestrant instead of another aromatase inhibitor, or combination therapy with palbociclib).
Further, presence of resistant mutations may inform second-line therapy selection (eg, inactivation of RB1 predicts resistance to CDK4/6 and PIK3CA inhibitors; thus, these drugs may not be the best choice for second-line therapy). Also, these mutations can be present in circulating free DNA, thus providing a noninvasive approach to serial monitoring for genomic changes in the blood indicative of drug resistance.
There often is a large concern about undertreatment of patients with cancer; however, overtreatment may be overlooked.
The risks associated with overtreatment with aromatase inhibitors — including adverse events, quality of life and costs — should be strongly considered before recommending extended aromatase inhibitor therapy, and a risk-adapted personalized approach should be used to shift the balance toward increased benefit.
References:
Chandarlapaty S, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.1279.
Davies C, et al. Lancet. 2013;381:805-816.
Fribbens C, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.67.3061.
Goss PE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1604700.
Gray RG, et al. Abstract 05. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.
Rugo HS, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.67.1487.
The following were presented at San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio:
Blaes AH, et al. Abstract S5-07.
Blok EJ, et al. Abstract S1-04.
Cohen O, et al. Abstract S1-01.
Mamounas EP, et al. Abstract S1-05.
Tjan-Heijnen VC, et al. Abstract S1-03.
For more information:
Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.
Disclosure: Patel reports no relevant financial disclosures.