Clinical Strategies to Prevent Relapse
Current standard of care: adjuvant anti-estrogen therapy
The long-term benefits of 5 years of adjuvant tamoxifen(Drug information on tamoxifen) use continue to show improvement over time. In the latest EBCTCG analysis, the absolute reduction in breast cancer mortality with 5 years of adjuvant tamoxifen continued to increase over time, and was about three times greater at 15 years after diagnosis than at 5 years after diagnosis.[1] The current clinical recommendation is that any positive level of ER expression is considered sufficient to justify adjuvant anti-estrogen therapy[28]; therefore 5 years of tamoxifen is the standard of care in the adjuvant treatment of HR+ breast cancer in premenopausal women.[29] This recommendation is based on retrospective analyses using older methods of ER assessments demonstrating that patients with tumors expressing low levels of ER appear to obtain some degree of benefit from tamoxifen.[1,30] A recent retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial comparing patients with HR+ tumors who received a 5-year course of tamoxifen or placebo, found that patients whose tumors had the highest tertile of quantitative ER mRNA expression by RT-PCR had the highest distant recurrence–free survival at a median follow-up of 10 years, while the group with the lowest tertile fared far less well (hazard ratios [HRs] = 0.39 and 1.2, respectively).[31] In light of the potential toxicities with the long duration of adjuvant anti-estrogen therapies, many clinicians appropriately question the degree of benefit in patients with low levels of ER expression.
More recently, a number of well-conducted randomized trials have provided clear evidence of benefit of adjuvant third-generation aromatase inhibitors (AIs), such as anastrozole(Drug information on anastrozole) (Arimidex), letrozole(Drug information on letrozole) (Femara), and exemestane(Drug information on exemestane) (Aromasin), compared with tamoxifen in postmenopausal women. These trials have typically been of 5 years’ duration, with tamoxifen in the control arm, and either an AI or a sequential combination of tamoxifen followed by an AI in the other arm. A meta-analysis of these trials reported a lower recurrence rate with AIs than with tamoxifen, either when used upfront or following 2 to 3 years of tamoxifen, with an absolute benefit of approximately 3% at 5 years.[9] The absolute difference in OS was minimal at a median follow-up of 5.8 years, and longer-term follow-up is required to determine whether there will be a more substantial benefit. In the 10-year analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which compared 5 years of adjuvant anastrozole vs tamoxifen, the annual HR of recurrence was 2% to 3%, and consistent with the meta-analysis data, there was no significant survival advantage.[32] Interestingly, the absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2.7% at 5 years and 4.3% at 10 years), with the difference lowest in the first 2 years, compared with 0 to 5 years and more than 5 years following the start of therapy (HR = 0.68, 0.77, and 0.81, respectively). The additional benefit of anastrozole beyond that achieved with tamoxifen appeared to wane after 8 years, and the difference in annual HRs for recurrence between the two treatments was minimal after this time. Although the inclusion of an AI in the adjuvant therapy of postmenopausal women is the current standard of care,[29] in light of the relatively small benefits of AIs over tamoxifen, clinicians should be comfortable tailoring the choice of anti-estrogen therapy in postmenopausal women according to the patient's tolerance of the drug’s side-effect profile, especially in patients with lower-risk disease.
Addition of chemotherapy to adjuvant anti-estrogen therapy
While it is clear that adjuvant chemotherapy does benefit a subset of HR+ breast cancer patients, the challenge has been in identifying the patient subgroup for which chemotherapy is most effective. The use of adjuvant chemotherapy with anti-estrogen treatment appears not to reduce the risk of late recurrence, as most of the benefit occurs during the first few years after diagnosis.[2] In deciding which patients should be recommended for adjuvant chemotherapy, what ultimately matters is not the risk of recurrence but rather, the likely benefit from addition of chemotherapy. The EBCTCG overview did not identify a subgroup of patients with HR+ breast cancer who did not benefit from chemotherapy, but it is possible that this finding was influenced by limitations in HR testing and the lack of centralized review of ER and PR status.[2] Chemotherapy responsiveness is considered to be directly correlated with cell proliferation activity and inversely correlated with anti-estrogen responsiveness.[33] It is likely that both endocrine therapy responsiveness and chemotherapy responsiveness are independent but interrelated tumor characteristics that exist along a continuum. The 2011 St. Gallen Conference consensus panel concurred that the luminal A subtype was less responsive to chemotherapy than other subtypes, and no particular chemotherapy regimen was favored over others for luminal tumors.[34]
More recently, multigene prognostic signatures, derived from high-throughput analyses of clinically annotated tumor specimens for gene expression patterns, have identified subsets of patients with HR+ breast cancers who benefit from the addition of chemotherapy to endocrine therapy.[8,35] Importantly, these assays also identify subsets of patients who do not benefit from chemotherapy and therefore may be spared its toxicity. Both the 21-gene Oncotype DX and 70-gene MammaPrint multigene signatures were validated in retrospective datasets, and prospective validation of these two multigene signatures is underway. TAILORx (Trial Assigning IndividuaLized Options for treatment ([Rx]) (ClinicalTrials.gov identifier NCT00310180) will study the utility of the Oncotype DX score to predict for chemotherapy benefit in the intermediate score range, while MINDACT (Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy) (ClinicalTrials.gov identifier NCT00433589) will study the outcomes of patients with discordant risk assessments when using the 70-gene expression signature of MammaPrint compared to using clinicopathological features with the Adjuvant! Online program.[36,37] The results from these large, well-designed prospective studies are eagerly anticipated, as they will shed light on the best strategies to individualize adjuvant treatment in luminal breast cancer.
Extended adjuvant anti-estrogen therapy
The timing and duration of adjuvant anti-estrogen therapy are potential areas for intervention in addressing the risk of late relapse in HR+ breast cancer. Extending the duration of adjuvant anti-estrogen therapy has, in some settings, clearly reduced the risk of recurrence in HR+ breast cancer. Three trials have compared 5 years of adjuvant tamoxifen vs 5 years of tamoxifen followed by an additional 3 to 5 years of an AI in postmenopausal women, demonstrating an improved disease-free survival with extended therapy (HR = 0.58 to 0.68).[7,38,39] Present
trials comparing 5 vs 10 years of treatment aim to identify the optimum duration of adjuvant AI therapy. There is no standard treatment available to reduce late recurrence risk in women who remain premenopausal after 5 years of tamoxifen, and clinical trials have generally excluded this subgroup of patients. Our group at Dana-Farber is currently exploring the effi-cacy of 2 years of extended letrozole in combination with an LHRH agonist following 5 years of tamoxifen in premenopausal women with stage I-III node-positive disease (ClinicalTrials.gov identifier NCT00903162). Extended anti-estrogen therapy is not without toxicities, and as the annual recurrence risk is modest, there will be important quality-of-life tradeoffs if this approach ultimately proves beneficial. One potential strategy to minimize diminishment in quality of life is intermittent anti-estrogen therapy, which is under investigation in the International Breast Cancer Study Group (IBCSG) SOLE (Study of Letrozole Extension) trial (ClinicalTrials.gov identifier NCT00553410). In SOLE, postmenopausal patients with node-positive HR+ breast cancer who have completed 4 to 5 years of an adjuvant endocrine therapy are randomized to receive an additional 5 years of letrozole given either continuously or intermittently in a 9-months-on, 3-months-off fashion.
Insights from metastatic HR+ breast cancer
Given the heterogeneity of luminal breast cancer, it is not surprising that refinements to basic endocrine therapies have been largely unsuccessful to date. In anti-estrogen–resistant breast cancer, there is reciprocal cross-talk between ER and other signal transduction pathways, including those involving receptor tyrosine kinases and insulin-like growth factor. HER2, for example, can signal through nongenomic ER, and as a result, most HR+ HER2+ tumors are less responsive to endocrine therapy.[40] The combined targeting of both the ER and HER2 pathways is therefore a clinically reasonable approach in HR+ HER2+ tumors; however, these tumors comprise only about 8% of HR+ breast cancers.[11] Both trastuzumab(Drug information on trastuzumab) (Herceptin) and lapatinib (Tykerb) have been tested in combination with AIs, with improvements in progression-free survival (PFS) but little impact on OS.
The phosphatidylinositol 3-kinase (PI3K) pathway is frequently hyperactivated and promotes anti-estrogen resistance in HR+ breast cancer.[41] Two phase II clinical trials have demonstrated promising efficacy with the combination of everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin (mTOR), which is downstream of PI3K, with tamoxifen[42] and with letrozole.[43] The first of these trials was conducted in patients with metastatic disease who had prior exposure to anti-estrogen therapy, and the second included patients with newly diagnosed HR+ breast cancer. In a phase III trial comparing exemestane plus everolimus vs exemestane plus placebo, the subset of patients who had received prior nonsteroidal AIs in the adjuvant or metastatic setting had a median PFS of 10.6 months with combination therapy vs 4.1 months with exemestane alone (HR = 0.36). Although these results are not achieved without toxicity, they represent an important step forward in the treatment of anti-estrogen–resistant HR+ breast cancer, and co-targeting the PI3K pathway in the adjuvant setting is an attractive strategy to improve outcomes if the side effect profile can be improved.
