Biomarkers predictive of a response to extended endocrine therapy in breast cancer: a systematic review and meta-analysis.

PURPOSE: Extension of adjuvant endocrine therapy beyond five years confers only modest survival benefit in breast cancer patients and carries risk of toxicities. This systematic review investigates the role of biomarker tests in predicting the clinical response to an extension of endocrine therapy. METHODS: We searched Ovid MEDLINE, Ovid Embase, Global Index Medicus, and the Cochrane Central Register of Controlled Trials using an iterative approach to identify full-text articles related to breast cancer, endocrine therapy, and biomarkers. RESULTS: Of the 1,217 unique reports identified, five studies were deemed eligible. Four investigated the Breast Cancer Index (BCI) assay in three distinct study populations. These studies consistently showed that BCI score was predictive of response to extended endocrine therapy among 1,946 combined patients, who were predominately non-Hispanic white and postmenopausal. CONCLUSIONS: Evidence in the setting of predictive tests for extended endocrine therapy is sparse. Most relevant studies investigated the use of BCI, but these study populations were largely restricted to a single age, race, and ethnicity group. Future studies should evaluate a variety of biomarkers in diverse populations. Without sufficient evidence, physicians and patients face a difficult decision in balancing the benefits and risks of endocrine therapy extension.

Is the CTS5 a helpful decision-making tool in the extended adjuvant therapy setting?

PURPOSE: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. METHODS: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. RESULTS: Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95%CI 2.26-7.15, p < 0.001 and HR 1.93, 95%CI 1.05-3.56, p = 0.035). An increasing continuous CTS5 was associated with increasing LDR risk (HR 2.23, 95% CI 1.74-2.85, p < 0.001). Miscalibration of CTS5 in high-risk patients could be observed. Although not reaching significance, high-risk patients benefitted the most from prolonged ET with an absolute reduction of the estimated 5-year LDR of - 6.1% (95%CI - 14.4 to 2.3). CONCLUSION: The CTS5 is a reliable prognostic tool that is well calibrated in the lower and intermediate risk groups with a substantial difference of expected versus observed LDR rates in high-risk patients. While a numerical trend in favoring prolonged ET for patients with a higher CTS5 was found, a significantly predictive value for the score could not be confirmed. CLINICAL TRIAL REGISTRATION: ABCSG-06 trial (NCT00309491), ABCSG-06A7 1033AU/0001 (NCT00300508).

Correlative studies of the Breast Cancer Index (HOXB13/IL17BR) and ER, PR, AR, AR/ER ratio and Ki67 for prediction of extended endocrine therapy benefit: a Trans-aTTom study.

BACKGROUND: Multiple clinical trials demonstrate consistent but modest benefit of adjuvant extended endocrine therapy (EET) in HR + breast cancer patients. Predictive biomarkers to identify patients that benefit from EET are critical to balance modest reductions in risk against potential side effects of EET. This study compares the performance of the Breast Cancer Index, BCI (HOXB13/IL17BR, H/I), with expression of estrogen (ER), progesterone (PR), and androgen receptors (AR), and Ki67, for prediction of EET benefit. METHODS: Node-positive (N+) patients from the Trans-aTTom study with available tissue specimen and BCI results (N = 789) were included. Expression of ER, PR, AR, and Ki67 was assessed by quantitative immunohistochemistry. BCI (H/I) gene expression analysis was conducted by quantitative RT-PCR. Statistical significance of the treatment by biomarker interaction was evaluated by likelihood ratio tests based on multivariate Cox proportional models, adjusting for age, tumor size, grade, and HER2 status. Pearson's correlation coefficients were calculated to evaluate correlations between BCI (H/I) versus ER, PR, AR, Ki67 and AR/ER ratio. RESULTS: EET benefit, measured by the difference in risk of recurrence between patients treated with tamoxifen for 10 versus 5 years, is significantly associated with increasing values of BCI (H/I) (interaction P = 0.01). In contrast, expression of ER (P = 0.83), PR (P = 0.66), AR (P = 0.78), Ki67 (P = 0.87) and AR/ER ratio (P = 0.84) exhibited no significant relationship with EET benefit. BCI (H/I) showed a very weak negative correlation with ER (r = - 0.18), PR (r = - 0.25), and AR (r = - 0.14) expression, but no correlation with either Ki67 (r = 0.04) or AR/ER ratio (r = 0.02). CONCLUSION: These findings are consistent with the growing body of evidence that BCI (H/I) is significantly predictive of response to EET and outcome. Results from this direct comparison demonstrate that expression of ER, PR, AR, Ki67 or AR/ER ratio are not predictive of benefit from EET. BCI (H/I) is the only clinically validated biomarker that predicts EET benefit.

Extended Adjuvant Endocrine Treatment in Luminal Breast Cancers in the Era of Genomic Tests.

In patients with early-stage endocrine receptor-positive (ER+) breast cancer (BC), adjuvant endocrine therapy (ET) for 5 years is the standard of care. However, for some patients, the risk of recurrence remain high for up to 15 years after diagnosis and extended ET beyond 5 years may be a reasonable option. Nevertheless, this strategy significantly increases the occurrence of side effects. Here we summarize the available evidence from randomized clinical trials on the efficacy and safety profile of extended ET and discuss available clinical and genomic tools helpful to select eligible patients in daily clinical practice.

Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer.

PURPOSE: Clinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer. METHODS: The validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5-10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan-Meier curves were used with associated 10-year DR risks (%). RESULTS: 2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78-2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32-2.56)). The 10-year DR risks were 2.9% (1.9-4.5), 7.2% (5.3-9.9), and 12.9% (10.0-16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2-6.7), 6.9% (4.4-10.8), and 11.1% (7.4-16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded. CONCLUSIONS: The CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.

Extended Endocrine Therapy for Early-Stage Breast Cancer: How Do We Decide?

PURPOSE OF REVIEW: While the majority of hormone receptor-positive breast cancers are diagnosed at an early stage, a significant proportion of patients will develop disease recurrence, especially late disease recurrence, despite current therapeutic approaches. In this review, we examine the data pertaining to the choice of endocrine and extended endocrine therapy, outline how to identify patients that may benefit from extended therapy, and discuss prognostic tools to assist with patient selection. RECENT FINDINGS: The risk of breast cancer recurrence persists after 5 years, is cumulative, and is indefinite. In attempts to mitigate these risks, studies have evaluated the use of extended endocrine therapy. Overall survival benefit has been demonstrated with extended tamoxifen, whereas extended aromatase inhibitors have shown modest disease-free survival benefit. Therapeutic approaches for individual patients will depend on the perceived risk of recurrence, likely benefit of extended therapy, tolerability of current endocrine therapy, and patient preference.

Extended endocrine therapy in premenopausal breast cancer patients: Where are we now?

Approximately 25% of new breast cancers are diagnosed in premenopausal patients, 50%-70% presenting as estrogen receptor-positive (ER+) breast tumors. Five-year adjuvant endocrine therapy (ET) with Tamoxifen is the cornerstone treatment for those patients but the evidence that up to 50% of ER + breast cancer distant recurrences develop after this time has now raised some questions. ATLAS and aTTom trials are the only two studies addressing the extension of Tamoxifen beyond 5 years in premenopausal patients. They showed significant DFS and OS benefits at a cost of increased rates of endometrial cancer and pulmonary embolus. Therefore, the selection of the patients at higher recurrence risk and hence deemed to get the most benefit from an extended endocrine therapy has become a major concern. Many clinical and genomic prognostic tools have shown validity in identifying patients at high late recurrence risk, but only the BCI prognostic score was shown to also be predictive of response to extended endocrine therapy. Nevertheless, all the evidence available on extended endocrine therapy in premenopausal patients was derived from trials in which patients were treated with tamoxifen alone and are hardly applicable to the current clinical scenario. In fact, the results of the SOFT and TEXT trials demonstrated the superiority of the addition of ovarian function suppression (OFS) and its association with the aromatase inhibitor (AI) Exemestane to Tamoxifen alone. However, the introduction in the clinical practice of AI + OFS-based endocrine therapy for the premenopausal patients will very soon lead to an impasse since neither data exist on extended therapy after this treatment schedule nor is there an ongoing trial intended to obtain new evidence.

Clinicopathologic features of hormone-receptor-positive breast cancer patients with late recurrence.

The number of long-term breast cancer survivors with a risk of late recurrence is increasing. Hormone-receptor-positive patients have greater risks of late recurrence. Although several studies demonstrated that extended adjuvant endocrine therapy reduces the incidence of late recurrence, it remains unclear which hormone-receptor-positive patients have greater risks of late recurrence. Hormone-receptor-positive breast cancer patients were retrospectively selected from the prospective database of primary breast cancer patients treated at Keio University Hospital from January 1989 to December 2003. Late recurrence was defined as initial recurrence after 5 years from the initial surgery. We evaluated the clinicopathologic features of breast cancer patients with late recurrence. At a median follow-up of 10.9 years (range, 5.1-23.8), 371 patients had no recurrence, 90 had early recurrence (within 5 years), and 83 had late recurrence. Multivariate analysis revealed that >4 involved lymph nodes were significant risk factors for late recurrence (P < .001), whereas 1-3 positive nodes were not. Endocrine therapy significantly reduced the incidence of late recurrence (P < .001). After menopause, adjuvant therapy with aromatase inhibitors resulted in longer disease-free survival than tamoxifen (10-year disease-free survival: 97.6% vs 89.7%, P = .0955). High nodal involvement was significantly correlated with late recurrence in hormone-receptor-positive breast cancer patients. Hormone-receptor-positive breast cancer patients who receive adjuvant endocrine therapy with tamoxifen alone might be candidates for extended endocrine therapy.

Extended Endocrine Therapy: Is 5 Years Enough?

PURPOSE OF REVIEW: Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy. RECENT FINDINGS: Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5 years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment. Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

Highlights of the San Antonio Breast Cancer Symposium 2016: Part 2.

The 39th annual San Antonio Breast Cancer Symposium (SABCS) was convened in San Antonio, Texas, on 9-13 December 2016. More than 7000 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, locoregional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with Part 1 focusing onmetastatic breast cancer, extended endocrine therapy and the prognostic significance of BRCA1/2 gene mutations. The second part of this report will discuss a range of topics including anti-HER2 directed treatments, the impact of radiotherapy on implant and autologous flap based reconstruction, biological risk predictors for ductal carcinoma-in situ (DCIS), longer term effects of dietary fat modification and the influence of aromatase inhibitors on endothelial cell function.

Extended Adjuvant Endocrine Therapy in Early Breast Cancer Patients-Review and Perspectives.

Seventy percent of all breast cancer subtypes are hormone receptor-positive. Adjuvant endocrine therapy in these patients plays a key role. Despite the traditional duration of a 5-year intake, the risk of relapse remains elevated in a substantial proportion of patients. Several trials report that the risk of late recurrence is reduced by the extension of adjuvant endocrine therapy beyond 5 years. However, the optimal duration of endocrine therapy is still a matter of debate. The newer data only show a marginal benefit resulting from extension beyond 7 to 10 years. Furthermore, extension may be associated with more side effects. Thus, the adequate selection of patients qualifying for an extended adjuvant therapy is of importance. Tools/genomic tests, which include the characteristics of the patient and the tumor, may help to better identify patients with a risk of a late relapse. Taken together, the magnitude of benefit for extended adjuvant endocrine therapy is based on the precise estimation of the risk of relapse after 5 years. This must be balanced against the long-term side effects of endocrine treatment and the competing risks. For patients with an intermediate risk, 7 years appears to be the optimal duration, and in those with high-risk features, endocrine therapy up to 10 years may be considered.

Preventing late recurrence in hormone receptor-positive early breast cancer: a review.

Late recurrences are a key challenge for patients with early-stage oestrogen receptor-positive breast cancer, with the risk of disease relapse continuing steadily from 5 to more than 20 years after diagnosis. Five years of adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor was shown many years ago to improve survival. More recently, the trials of extended adjuvant endocrine therapy for more than 5 years have shown a further small gain, but with an associated small risk of increased long-term toxicity including bone loss, cardiovascular impairment and impaired quality of life. This review describes the efficacy and safety of extended endocrine therapy, the optimal selection criteria for patient benefit and the potential for novel agents to improve long-term outcomes.

Impact of clinicopathological factors on extended endocrine therapy decision making in estrogen receptor-positive breast cancer.

Purpose: In our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making. Patients and methods: The retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5-5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making. Results: Two hundred thirty-five patients were received; 4.5-5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219-0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831-157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336-9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)-treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846-168.309, p = 0.003) remained an independent predictor for the recommendation of EET. Conclusions: Our study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients.

Competing Nomogram for Late-Period Breast Cancer-Specific Death in Patients with Early-Stage Hormone Receptor-Positive Breast Cancer.

BACKGROUND: More than half of early breast cancer recurrences occur after 5 years from the initial diagnosis. An individualized estimate of the risk of late-period breast cancer-specific death (LP-BCSD) after 5 years of endocrine therapy (ET) can improve decision-making for extended endocrine therapy (EET). MATERIALS AND METHODS: A total of 147,059 eligible patients with breast cancer who survived 5+ years after diagnosis between 1990 and 2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses based on the competing risk regression model were used to evaluate predictive factors for high risk of LP-BCSD or late-period non-breast cancer-specific death (LP-non-BCSD). Significant factors were used to build a nomogram to individualize estimates of LP-BCSD or LP-non-BCSD. RESULTS: The 5- and 10-year LP-BCSD rates were 5.7% and 10.1%, respectively, and the 5- and 10-year LP-non-BCSD rates were 6.7% and 15.5%, respectively. Young age, black race, single marital status, poor differentiation, large tumor size, lymph node metastasis, and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) status were independent predictive factors for high risk of LP-BCSD. Age was the most important factor for predicting high risk of LP-non-BCSD. The nomograms, which were based on significant factors identified by the competing risk regression model. A risk score system based on the competing risk nomogram was established to describe the relative risk of LP-BCSD and LP-non-BCSD. CONCLUSION: This study explored the novel endpoint of LP-BCSD for further clinical trials. The risk score system might be highly useful for patient counseling, especially in discussing EET options with elderly or comorbid patients.

Extending Adjuvant Endocrine Therapy for 10 Years: A Mixed-Methods Analysis of Women's Decision Making in an Online Breast Cancer Forum.

An additional 5 years of treatment with adjuvant hormonal therapy, to complete 10 years of medication, is recommended to reduce the risk of breast cancer recurrence. Yet professionals and patients should balance this benefit against side effects and toxicities. Little is known about women's decision making regarding persistence with extended endocrine therapy. In this study, we collected data from a UK online breast cancer forum to analyse patterns of persistence and its associated factors. A mixed-methods exploratory sequential design was used, with a qualitative analysis of text (n = 61 individuals) informing the development of a quantitative instrument to statistically analyse the prevalence of the findings (n = 130). Our findings identified three different groups of women who had to make decisions regarding persistence with treatment: those about to complete 5 years of therapy, those who decided to extend treatment, and those who were initially prescribed 10 years. Factors affecting persistence were, lack of self-efficacy in managing side effects, lack of reassurance about individual risk of recurrence, and impact on quality of life. Interventions such as training of healthcare professionals including risk communication, medication reviews by clinical pharmacists, and re-planning of services in follow-up care, should better support women's needs in extended hormonal therapy.

Evaluation of the ability of the Clinical Treatment Score at 5 years (CTS5) compared to other risk stratification methods to predict the response to an extended endocrine therapy in breast cancer patients.

PURPOSE: Extension of adjuvant endocrine therapy (ET) reduces the risk of recurrence in women diagnosed with ER-positive breast cancers, but a significant benefit is unlikely to happen to all individual patients. This study is aimed at evaluating the ability of different clinical late distant recurrence (LDR) risk stratification methods and in particular the clinical treatment score at 5 years (CTS5) to predict the response to extended adjuvant ET. METHODS: 783 patients diagnosed with ER+ BC between 1988 and 2014 at Umberto I Hospital of Turin, of which 180 received an extended adjuvant ET, were retrospectively selected. They were stratified according to pT, pN, disease stage, tumor grade, Ki67 level, progesterone receptor status and CTS5. The primary endpoint was LDR rate. LDR rates according to ET duration were confronted in each subgroup. RESULT: The median duration of extended ET was 7 years (6-10). Median follow-up from diagnosis was 9 years (6-26). Retrospective risk stratification according to tumor size, nodal status, disease stage, tumor grade, Ki67 level, and progesterone receptor status did not appear to be able to predict the response to extended ET. In the CTS5 high-risk subgroup instead, the risk of developing an LDR was significantly lower in the patients who underwent extended ET compared to standard ET (HR 0.37, 95% CI 0.15-0.91), while no significant benefit was demonstrated for low and intermediate-risk patients. CONCLUSIONS: Risk stratification according to CTS5 appeared to be predictive of the response to extended endocrine therapy in our population of real-life pre and postmenopausal patients.

Optimal duration of endocrine therapy with extended aromatase inhibitors for postmenopausal patients with hormone receptor-positive breast cancer: a meta-analysis.

BACKGROUND: The optimal duration of endocrine therapy for patients with hormone receptor-positive (HR-positive) breast cancer is still unclear. This meta-analysis aims to determine the optimal duration of endocrine therapy with extended aromatase inhibitors (AI) for postmenopausal patients with HR-positive early breast cancer who have finished 5 years of endocrine therapy. METHODS: Eligible randomized controlled trials were classified into three categories according to the whole duration of endocrine therapy (10 years versus 5 years, 7-8 years versus 5 years, and 10 years versus 7-8 years). For each category, hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS), and risk ratio (RR) for the incidence of adverse events were pooled. RESULTS: Altogether 9 RCTs enrolling a total of 22,313 postmenopausal women with HR-positive breast cancer were included. Pooled data showed an improvement in DFS when extending endocrine therapy from 5 to 7-8 years (HR = 0.79 [0.69, 0.91]), specifically among those who had been treated with only tamoxifen (HR = 0.40 [0.22, 0.73]) or sequential tamoxifen followed by AI (HR = 0.82 [0.71, 0.95]), with tumors that were node-positive (HR = 0.72 [0.56, 0.93]), estrogen receptor (ER) and progesterone receptor (PR) positive (HR = 0.61 [0.47, 0.78]), or ≥ 2 cm in size (HR = 0.72 [0.51, 0.98]). However, no improvement in DFS was obtained when extending from 7-8 to 10 years (HR = 0.98 [0.87, 1.11]). In addition, the extension of endocrine therapy was not associated with an improvement in OS, but was associated with an increased risk of bone fracture and osteopenia/osteoporosis. CONCLUSION: Patients who have been treated with AI for 5 years, with tumors that are node-negative, ER+/PR- or ER-/PR+, and < 2 cm in size do not need to receive extended AI therapy. For those who have been treated with only tamoxifen or sequential tamoxifen followed by an AI for a total of 5 years, with tumors that are node-positive, ER+/PR+ or ≥ 2 cm in size, 2-3 years of extended AI is necessary and maybe enough.

Validation of CTS5 on a Retrospective Cohort of Real-Life Pre- and Postmenopausal Patients Diagnosed With Estrogen Receptor-Positive Breast Cancers: Is It Prognostic?

BACKGROUND: More than 50% of estrogen receptor (ER)-positive breast cancer (BC) distant recurrences (DR) develop after the completion of 5 years of adjuvant endocrine therapy (ET). Its extension is beneficial on disease-free survival and overall survival but increases therapy-related side effects. Selecting patients who could benefit the most from an extended regimen has become an increasing need. Clinical Treatment Score at 5 Years (CTS5) is a prognostic tool using clinicopathologic data to estimate DR risk after 5 years of ET for ER+ BC. We sought to validate the prognostic value of CTS5 in a retrospective cohort of real-life pre- and postmenopausal patients diagnosed with ER+ BC. PATIENTS AND METHODS: CTS5 was calculated for 603 patients diagnosed with ER+ BC at Umberto I Hospital of Turin and DR-free after 5 years of ET. Primary endpoint was late DR (LDR) rate. RESULTS: Median follow-up was 8 years (range, 6-26 years). The 426 postmenopausal women were categorized by CTS5 as follows: 152 low risk, 139 intermediate risk, and 135 high risk. LDR rates were 3.9%, 7.2%, and 15.6%, respectively. CTS5 results were prognostic for LDR: patients with CTS5-high showed a fourfold risk of developing an LDR compared to patients with CTS5-low (hazard ratio, 4.48; 95% confidence interval, 1.80-11.1). The same analysis was conducted for the 177 premenopausal women: 88 low risk, 40 intermediate risk, and 49 high risk. LDR rate were 5.6%, 7.5%, and 20.4%, respectively, proving CTS5 to be prognostic for premenopausal patients as well (CTS5-high vs. CTS5-low: hazard ratio, 3.40; 95% confidence interval, 1.06-11.0). CONCLUSION: CTS5 was shown to be prognostic of the risk of LDR in our population of real-life pre- and postmenopausal patients. Our results support its use in clinical practice to better tailor the prescription of extended ET.

Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Endocrine therapy with a standard duration of 5 years is well known as an effective treatment for endocrine-sensitive breast cancer. SUMMARY: In the adjuvant setting this treatment reduces the 15-year mortality rates by about 30 and 40% with tamoxifen and aromatase inhibitor, respectively. The well-known long-term recurrence risk of luminal cancers led to multiple trials examining the benefit of extended endocrine treatment for up to 15 years. Additional benefit with extended therapy was seen for patients with high recurrence risk. Also, additional ovarian suppression for premenopausal women exhibited a significant benefit for patients at higher risk. KEY MESSAGES: The data of the last years will be summarized and discussed, also considering the side effects of the different treatment options.

Considering the biology of late recurrences in selecting patients for extended endocrine therapy in breast cancer.

Extended endocrine therapy can reduce recurrences occurring more than 5 years after diagnosis (late recurrences) in estrogen receptor (ER)-positive breast cancer. Given the side effects of endocrine therapy, optimal patient selection for extended treatment is crucial. Enhanced understanding of late recurrence biology could optimize patient selection in this setting. We therefore summarized the current knowledge of late recurrence biology, clinical trials on extended endocrine therapy, and tools for predicting late recurrence and benefit from treatment extension. Extending 5 years of tamoxifen therapy with 5 years of tamoxifen or an aromatase inhibitor (AI) reduces late recurrence risk by 2-5%, but results of extending AI-based therapy are inconsistent. Although several clinicopathological parameters and multigene assays are prognostic for late recurrence, selection tools predicting benefit from extended endocrine therapy are sparse. Therefore, we additionally performed a pooled analysis using 2231 mRNA profiles of patients with ER-positive/human epidermal growth factor receptor 2-negative breast cancer. Gene Set Enrichment Analysis was applied on genes ranked according to their association with early and late recurrence risk. Higher expression of estrogen-responsive genes was associated with a high recurrence risk beyond 5 years after diagnosis when patients had received no systemic therapy. Although 5 years of endocrine therapy reduced this risk, this effect disappeared after treatment cessation. This suggests that late recurrences of tumors with high expression of estrogen-responsive genes are likely ER-driven. Long-term intervention in this pathway by means of extended endocrine therapy might reduce late recurrences in patients with tumors showing high expression of estrogen-responsive genes.