Hormone Receptor-positive Early Breast Cancer Research Articles

Impact of Comorbidities and Age on Cause-Specific Mortality in Postmenopausal Patients with Breast Cancer.

The aim was to study the impact of comorbidities and age on breast cancer mortality, taking into account competing causes of death. Cohort analysis of Dutch and Belgian patients with postmenopausal, early hormone receptor-positive breast cancer included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. This is a randomized controlled trial of patients who had completed local treatment with curative intent and were randomized to receive exemestane for 5 years, or sequential treatment of tamoxifen followed by exemestane for a duration of 5 years. Patients were categorized by number of comorbidities (no comorbidities, 1-2 comorbidities, and >2 comorbidities) and age (<70 years and ≥70 years). Main outcome was breast cancer mortality considering other-cause mortality as competing event; cumulative incidences were calculated using the Cumulative Incidence Competing Risk Methods, and the Fine and Gray model was used to calculate the effect of age and comorbidities for the cause-specific incidences of breast cancer death, taking into account the effect of competing causes of death. Overall, 3,159 patients were included, of which 2,203 (69.7%) were aged <70 years and 956 (30.3%) were aged ≥70 years at diagnosis. Cumulative incidence of breast cancer mortality was higher among patients ≥70 without comorbidities (22.2%, 95% CI, 17.5-26.9) compared with patients <70 without comorbidities (15.6%, 95% CI, 13.6-17.7, reference group), multivariable subdistribution hazard ratio (sHR) 1.49 (95% CI, 1.12-1.97, p = .005) after a median follow-up of 10 years. Use of chemotherapy was lower in older patients (1%, irrespective of the number of comorbidities) compared with younger patients (50%, 44%, and 38% for patients with no, 1-2, or >2 comorbidities, p < .001). Older patients without comorbidities have a higher risk of dying due to breast cancer than younger counterparts, even when taking into account higher competing mortality, while use of chemotherapy in this group was low. These findings underline the need to take into account comorbidities, age, and competing mortality in the prognosis of breast cancer for accurate decision making. Older patients without comorbidity are at increased risk of dying from breast cancer, despite a higher other-cause mortality. This study shows that including age and comorbidity for the assessment of breast cancer mortality and other-cause mortality is indispensable for treatment decision making in older patients. Future prognostic tools for breast cancer prognosis should incorporate these items as well as risk of toxicity of adjuvant chemotherapy to adequately predict outcomes to optimize personalized treatment for older patients with early breast cancer.

Pretreatment anti-Mullerian hormone-based nomogram predicts menstruation status after chemotherapy for premenopausal women with hormone receptor-positive early breast cancer.

Ovarian function is important for optimizing endocrine treatment in patients with hormone receptor-positive (HR+) early breast cancer (eBC). The aim of the study was to determine whether patients' pretreatment levels of anti-Mullerian hormone (AMH) were associated with menses status after chemotherapy and to build a predictive nomogram model for amenorrhea in women with HR+ eBC. Between August 2013 and December 2014, 120 premenopausal patients with HR+ eBC were included retrospectively. The associations among age, prechemotherapy levels of AMH, follicle-stimulating hormone (FSH),and estradiol (E2) and the 2-year postchemotherapy menses status were analyzed. We determined the cutoff values of hormone levels by using the biostatistical tool (Cutoff Finder). A novel nomogram was established to predict the 2-year amenorrhea status based on the logistic analysis. Concordance index (C-index) was used to validate the capacity. One hundred nine women (90.8%) experienced amenorrhea after chemotherapy. AMH < 0.965ng/ml predicted amenorrhea at 2years (AUC 0.84, sensitivity 74% and specificity 81.8%), independent of age. The predictive nomogram based on age and pretreatment AMH and FSH levels was developed to predict the probability of 2-year postchemotherapy amenorrhea with a C-index of 0.88 (95% CI 0.84-0.91). In premenopausal patients with HR+ eBC, prechemotherapy AMH concentration was associated with the patient's 2-year amenorrhea status, independent of age. The nomogram model based on age and pretreatment AMH and FSH levels accurately predicted the 2-year amenorrhea status.

LBA14_PR - The HOBOE-2 multicenter randomized phase III trial in premenopausal patients with hormone-receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole + zoledronic acid

LBA14_PR - The HOBOE-2 multicenter randomized phase III trial in premenopausal patients with hormone-receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole + zoledronic acid

204P - Analytical validation of OncoMasTR, a multigene test for predicting risk of distant recurrence in hormone receptor-positive early stage breast cancer

Background: OncoMasTR is a new multigene prognostic test that was discovered via a novel transcriptional network analysis method that identified upstream Master Transcription Regulators (MTRs), which regulate previously identified prognostic biomarkers. The optimised OncoMasTR signature incorporating clinicopathological information has been shown to be significantly prognostic for predicting distant recurrence in two independent cohorts (TransATAC & a subset of TAILORx from participating Irish centres). The analytical performance characteristics of the OncoMasTR test, comprising solely three prognostic MTRs, were determined. Methods: Relative gene expression levels were measured by RT-qPCR. Assay precision and input ranges were determined using a panel of samples representative of low and high recurrence risk tested across a number of runs incorporating different sources of variation. Serial dilutions of a pooled patient RNA sample was used to establish the linear range and efficiency of the individual gene assays. Results: The overall standard deviation of the OncoMasTR risk score was 0.15, which represents less than 2% of the 10-unit risk score range. The majority of the variability in OncoMasTR results was related to within-run variation (78.2%) with other between-run variation sources contributing relatively little (PCR instrument (0.6%), assay operator (5.2%), reagent lots (7.3%) or loading position (8.7%)). Consistent risk scores were measured for individual samples from 40ng down to 500-fold RNA input range corresponding to CT values of 23 – 36, demonstrating the ability of the test to reliably detect low level expression of the OncoMasTR panel. Importantly, PCR efficiencies were similar for the individual MTR and reference gene assays which ranged from 79 – 95%. Conclusions: The OncoMasTR prognostic test displays robust analytical and clinical performance and is being launched as a CE-marked test. The concise nature of the three gene signature and a simplified workflow that can be readily adopted using standard laboratory equipment will enable convenient qualification by local laboratories for decentralised use. (Less)

An Italian Delphi study to evaluate consensus on adjuvant endocrine therapy in premenopausal patients with breast cancer: the ERA project

BackgroundSeveral trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse.MethodsThe ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017.ResultsA total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed.ConclusionsThe SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.

Prognostic Value of the Detection of Lymphovascular Invasion in Hormone Receptor-Positive Early Breast Cancer in the Era of Molecular Profiling

Background: Lymphovascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its role in decision-making regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome. Methods: Patients with early estrogen receptor-positive breast cancer who underwent ODX analysis in 2005–2012 were retrospectively identified. Clinical data were collected from the medical records. The Cox proportional-hazards ratio was used to determine recurrence rates. The prognostic significance of LVI was evaluated by competing risks analysis. Results: LVI was detected in 38 of 657 patients (6%). LVI was not associated with ODX RS (p = 0.225). However, it was significantly associated with other known prognostic factors and with worse 5-year disease-free survival (HR 2.93; 95% CI 1.02–8.39; p = 0.04). Overall survival (OS) analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year OS (p = 0.04) only in the intermediate-risk group, while LVI had no effect on the low- or high-risk groups. Conclusions: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome, especially in ODX intermediate-risk patients.

Abstract 5243: Prognostic value of nuclear and non-nuclear estrogen receptor expression by immunohistochemistry with phosphor-integrated dots in hormone receptor-positive early breast cancer

Abstract Background: Estrogen receptor α (ERα) is associated to cell proliferation and survival through genomic (nuclear) and non-genomic (non-nuclear) signaling pathway. Endocrine therapy is the most effective therapies for patients with hormone receptor(HR) positive breast cancer. Recent progress shows that both nuclear and non-nuclear crosstalk was considered to contribute to endocrine resistance. Clinically, ERα is predominantly observed using immunohistochemistry(IHC) as a nuclear protein while unable to detect nuclear and non-nuclear ERα separately. Our group recently created new fluorescent nanoparticles called phosphor-integrated dots (PIDs). PIDs has extremely brightness so that it could be double stained with hematoxylin and quantitated without influence. In addition, the localization of biomarker protein can be visualized and analyzed on cell as PIDs score by this method. Methods: 65 HR+/HER2- breast cancer patients from 2001 to 2003 who treated with postoperative endocrine therapy were selected in this study. Expression levels of total ERα, nuclear-ERα, non-nuclear-ERα, progesterone receptor (PR) was examined by IHC with PIDs. Nuclear-ERα was recognized by double staining using hematoxylin. IHC with DAB was carried out to analyze the expression levels of ER and PR and H score was automatically calculated. In addition, PIDs score of non-nuclear-ERα can be calculated through PIDs score of total ERα and nuclear-ERα by PID analyzer. Optimal cutoff value of PIDs score of each receptor to predict survival were derived and independently tested. The correlation among every clinical characteristic and pathological feature was examined. Result: PIDs score of total ERα(χ2=5.17, p=0.023) and nuclear-ERα is negative correlated with relapse (χ2=6.46, p=0.011), ratio of non-nuclear-ERα to total ERα is positive correlated with relapse (χ2=5.82, p=0.016).The cutoff value as 37.46 of nuclear-ERα PIDs score was statistically proved significant for predicting disease-free survival(DFS) (log-rank p=0.020).We also found that cutoff value as 0.32 which represents ratio of non-nuclear-ERα PIDs score to total ERα PIDs score was statistically proved significant for predicting DFS (log-rank p=0.022). H score of ER, PR and PIDs score of non-nuclear-ERα, PR has no predictive value for recurrence. Conclusion: Our result demonstrates that nuclear-ERα PIDs score obtain a higher prognostic value than that of total-ERα PIDs score and H score detected by DAB-IHC. Ratio of non-nuclear-ERα to total ERα may play a role of prognostic factor in HR positive breast cancer. Citation Format: Zhaorong Guo, Hiroshi Tada, Narufumi Kitamura, Yoh Hamada, Shin-ichi Hayashi, Noriaki Ohuchi, Kosuke Gonda, Takanori Ishida. Prognostic value of nuclear and non-nuclear estrogen receptor expression by immunohistochemistry with phosphor-integrated dots in hormone receptor-positive early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5243.

Abstract 2577: Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early breast cancer

Abstract Our risk score based on a combination of multigene expression and clinical variables was validated to predict the risk of distant metastasis in hormone receptor-positive and human epidermal growth factor 2-negative (HR+/HER2-) early breast cancer in our previous study. In addition to its prognostic value, we investigated the predictive value of the risk score for adjuvant chemotherapy benefit in lymph node-negative (LN-), HR+/HER2- breast cancer. 346 patients who treated with hormone therapy (n = 203) alone or hormone therapy plus chemotherapy (n = 143) were classified as low-risk and high-risk group according to the risk score. There was a significant improvement in 10-year distant metastasis-free survival (DMFS) by the addition of adjuvant chemotherapy to hormone therapy in patients with a high risk score (26.5%, P = 0.003), whereas no benefit of chemotherapy was observed in those with a low risk score. The test for interaction between chemotherapy treatment and risk score was significant. The risk score also identified patients who will not benefit from chemotherapy among clinical high-risk group. Our study suggests that the risk score predicts the benefit of adjuvant chemotherapy in LN-, HR+/HER2- breast cancer and the addition of the risk score in the traditional cliniopathological factors may aid the improved treatment decisions. Citation Format: Mi Jeong Kwon. Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2577.

Cyclin-dependent kinase 4/6 inhibitors in hormone receptor-positive early breast cancer: preliminary results and ongoing studies.

The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting.

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study

BackgroundEndocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor–positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. Patients and methodsPost-menopausal hormone receptor–positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. ResultsAmong 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90–3.42), sleep disorders (HR 1.95; 95% CI, 1.41–2.70) and other AEs (HR 2.03; 95% CI, 1.51–2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74–1.84). ConclusionsThese results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. Clinical Trials NumberCFEM345DDE19.

Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer

BackgroundExtended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. MethodsIn the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). ResultsNodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76–1.37). ConclusionsIn this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS.

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46-72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7-90·0) with the switch strategy and 89·8% (88·2-91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9-91·7) with anastrozole (124 events), 88·0% (85·8-89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3-4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3-4 adverse events occurred in less than 2% of patients in either group. 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Italian Drug Agency.

Abstract GS4-03: Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial

Abstract Background: The primary results of SOFT at 5.6 years median follow-up found adding OFS to T did not provide a significant benefit in the overall study population of premenopausal women with HR+ BC (Francis et al, NEJM 2015). For those women at sufficient risk for recurrence to warrant adjuvant chemotherapy (CT) and who remained premenopausal, the addition of OFS improved disease outcomes. Follow-up was immature for overall survival (OS). We report a planned update with visit cut-off of 31Dec16 after 8 yrs median follow-up. Methods: SOFT randomized premenopausal women with HR+ BC from Nov 2003 to Jan 2011 to 5 yrs of T vs T+OFS vs Exemestane(E)+OFS. OFS was by choice of GnRH agonist triptorelin, oophorectomy or ovarian irradiation. SOFT was stratified by the use of prior CT; 47% received no CT and 53% remained premenopausal after prior CT, determined by premenopausal estradiol level within 8 months of CT completion. The primary endpoint was invasive disease-free survival (DFS; randomization until invasive local, regional, distant recurrence or contralateral breast; invasive second malignancy; death). Secondary endpoints included invasive breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and OS. NCT00066690. Results: DFS for patients assigned T+OFS (n=1015) was significantly improved over T (n=1018; HR=0.76 [95%CI 0.62-0.93]) and 8yr DFS was 83.2% vs 78.9%, respectively; BCFI and DRFI results were supportive (see Table). Hazard ratios for these 3 endpoints showed no heterogeneity by use of prior CT. For patients with prior CT, 8yr DFS was 76.7% with T+OFS vs 71.4% with T (Δ=5.3%); in those without CT, 8yr DFS was 90.6% vs 87.4% (Δ=3.2%). E+OFS (n=1014) improved outcomes relative to T (Table); 8yr DFS for E+OFS was 85.9% (80.4% with use of prior CT and 92.5% for those without CT). OS was improved with T+OFS vs T (8yr OS 93.3% vs 91.5%). 8yr OS was 92.1% with E+OFS. 201/225 deaths occurred in women with prior CT. For women without CT there have been 10, 5 and 9 deaths in the T+OFS, T and E+OFS groups (total n=1419), respectively, only half of these deaths after breast cancer event. N. EventsHazard Ratio (95% CI)Endpoint(3 arms)T+OFS vs TE+OFS vs TDFS5180.76 (0.62-0.93) P=0.0090.65 (0.53-0.81)BCFI4370.76 (0.61-0.95)0.64 (0.51-0.81)DRFI3060.86 (0.66-1.13)0.73 (0.55-0.96)OS2250.67 (0.48-0.92)0.85 (0.62-1.15) Overall toxicity was worse with T+ OFS than with T, including 32% vs 25% grade 3+ targeted AEs. Early cessation of tamoxifen occurred for 19% assigned T+OFS and 22% of women assigned T; the cumulative incidence of early cessation of triptorelin on the T+OFS arm was 23% by 4yrs. Early cessation of exemestane occurred for 28% and of triptorelin for 21% by 4yrs on the E+OFS arm. Conclusions: With additional follow-up to a median of 8yrs, SOFT further supports the value of OFS for some premenopausal women. Follow-up continues, which will further clarify the safety and the benefit of OFS for late recurrence and overall survival. Oncologists appear to be able to select a low risk group (no chemotherapy) for whom treatment escalation is unlikely to improve survival. Citation Format: Fleming G, Francis PA, Láng I, Ciruelos EM, Bellet M, Bonnefoi HR, Climent MA, Pavesi L, Burstein HJ, Martino S, Davidson NE, Geyer Jr CE, Walley BA, Coleman RE, Kerbrat P, Buchholz S, Ingle JN, Rabaglio-Poretti M, Colleoni M, Regan MM. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-03.

Abstract GS3-01: A prospective randomized multi-center phase-III trial of additional 2 versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy – results from 3,484 postmenopausal women in the ABCSG-16 trial

Abstract Background: While extended adjuvant therapy with aromatase inhibitors (AI) after initial tamoxifen has been demonstrated to improve disease-free-survival (DFS) of postmenopausal patients with hormone-receptor positive breast cancer, the optimal duration of extended AI is unknown. Moreover, it remains unclear whether patients after AI in the first 5 years benefit similarly from extended adjuvant AI therapy as patients after Tamoxifen. Methods: From February 2004 to June 2010, 3484 women with postmenopausal stage I-III hormone-receptor positive early breast cancer were randomized in 71 centers in Austria to receive either 2 years or 5 years of additional Anastrozole (1 mg daily) as extended adjuvant therapy, after initial 5 years of adjuvant endocrine treatment. Eligible patients had to be recurrence-free at 60 months of initial adjuvant therapy with Tamoxifen (Tam) or AI or Tam→AI, and younger than 80 years of age. Stratification factors were tumor stage, nodal status, initial endocrine therapy, adjuvant chemotherapy, and quantitative hormone receptors. Patients were followed-up at least annually. Primary end point of ABCSG-16 was DFS, secondary end points included overall survival (OS), fractures, contralateral breast cancer, and toxicity. Results: As of June 30, 2016, the median follow-up of the 3468 patients included in the analysis of ABCSG-16 was 105.9 months (IQR 102.2-110.3 months) after randomization (i.e. approx. 14 years after diagnosis). Median patient age was 64 years, 2507 (72%) patients had tumors smaller than 2 cm, 2301 (66%) patients were node-negative, 674 (19%) patients had high-grade tumors, 2683 (77%) patients had tumors both ER and PR positive. 2764 (80%) patients were treated with breast conserving surgery. Before randomization into ABCSG-16, 1000 (29%) patients had undergone (neo)adjuvant chemotherapy, 1774 (51%) patients had received 5 years of Tamoxifen, whereas 1688 (49%) patients had received other (AI containing) regimens in the first five years. As of June 30, 2016, 757 DFS events have been recorded, 377 (22%) in the 2-year group, and 380 (22%) in the 5-year group. There was no significant difference in DFS (HR 0.997, 95%CI 0.86-1.15, log rank p=0.982), in OS, time to secondary carcinoma and time to contralateral breast cancer. With respect to drug adherence, 81.2% of patients in the 2-year arm were taking the study drug still at 2 years, and 80.1% at 2 years in the 5-year arm. At 5 years, 65.6% of patients in the 5-year arm were still on the assigned medication. Bone fractures were more frequent in the 5-year arm (i.e. years 3 to 5 after randomization: 6% vs 4 %, HR=1.405, 95%CI 1.03-1.91, p=0.029). Conclusion: After 5 years of adjuvant endocrine therapy (Tamoxifen or AI or Sequence), 2 additional years of Anastrozole are sufficient for extended adjuvant therapy – a further extension to 5 additional years did not yield additional outcome benefit but added toxicity. Support: AstraZeneca Citation Format: Gnant M, Steger G, Greil R, Fitzal F, Mlineritsch B, Manfreda D, Tausch C, Balic M, Dubsky P, Moik M, Thaler J, Egle D, Bjelic-Radisic V, Selim U, Exner R, Singer C, Melbinger-Zeinitzer E, Haslbauer F, Stöger H, Helfgott R, Sevelda P, Trapl H, Wette V, Sölkner L, Jakesz R. A prospective randomized multi-center phase-III trial of additional 2 versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy – results from 3,484 postmenopausal women in the ABCSG-16 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-01.

Abstract P3-12-02: Predictors of adherence to adjuvant endocrine therapy (ET) for early breast cancer (BC) in a prospective clinic-based cohort

Abstract Background: Adjuvant ET is associated with improved survival in women with hormone receptor-positive early BC. Nonetheless, more than a quarter of women are non-adherent or discontinue therapy early. We aimed to identify whether baseline characteristics and changes in weight and patient-reported outcomes (PRO) early during the course of ET are associated with medication adherence behavior (MAB) in a prospective cohort. Methods: We enrolled women initiating or switching adjuvant ET for stage 0-III BC in a prospective clinic-based cohort. Participants completed PRO questionnaires at baseline, and 3, 6, and 12 months (mo) after initiating ET. PRO questionnaires included FACT-ES, the NIH PROMIS measures for pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance, and the MOS Sexual Functioning Scale. MAB was assessed by the Medication Adherence Questionnaire (MAQ). MAB was defined as high (MAQ score=0), or medium/low (MAQ score&amp;gt;0). Questionnaires were administered through the PatientViewpoint web-based interface. We tested changes in mean PRO scores from baseline to follow-up time points with paired t-tests. We explored associations between baseline characteristics, and changes in weight and PRO at 6 mo with MAB at 12 mo using Fisher's exact test, Wilcoxan rank sum tests and t-tests. P-values &amp;lt;0.05 were considered significant. Results: From March 2012 to December 2016, 336 women enrolled in the cohort. Mean age was 60 (range 26-90), 84% were Caucasian, and 67% were post-menopausal. Overall, 57% received an aromatase inhibitor, 43% received tamoxifen, and 28% received prior taxane chemotherapy. Median follow-up was 12 mo. At baseline, 61% were overweight/obese, and 21% gained &amp;gt;5% of baseline weight by 12 mo. Mean baseline and follow-up scores at 3, 6 and 12 mo were within 1 standard deviation of reference population means for all PRO measures. Compared to baseline, endocrine symptoms were increased at 3, 6 and 12 mo (p&amp;lt;0.05), while sexual function and depression did not differ between baseline and any follow-up time point (p&amp;gt;0.05). At 6 mo, anxiety was reduced, physical function was improved and pain impact was reduced compared to baseline (p&amp;lt;0.05). MAB was high for 71% of participants at 12 mo. Preliminary data demonstrate that, compared to those with high MAB at 12 mo, women with medium/low MAB at 12 mo took fewer concomitant medications at baseline, and had more improvement in anxiety and sexual function at 6 mo. MAB at 12 mo did not differ according to race, type of ET, baseline weight or PRO measures, or 6 mo change in weight or other PRO measures. Conclusions: Early changes in anxiety and sexual function during the course of adjuvant ET and the number of baseline concomitant medications may separate women with subsequent high versus medium/low MAB risk. Weight loss interventions and symptom management are needed for women receiving adjuvant ET during the first year of treatment. Our data will be used to create a model to predict MAB for validation studies and as the basis to devise interventions to improve adherence to adjuvant ET. Citation Format: Smith KL, Yeruva SLH, Blackford A, Huang C-Y, Westbrook KE, Harding BA, Smith A, Fetting J, Wolff AC, Jelovac D, Miller RS, Connolly R, Armstrong D, Nunes R, Visvanathan K, Stearns V. Predictors of adherence to adjuvant endocrine therapy (ET) for early breast cancer (BC) in a prospective clinic-based cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-02.

A high-risk 70-gene signature is not associated with the detection of tumor cell dissemination to the bone marrow.

The 70-gene signature (70-GS) is a prognostic tool, grouping patients in risk groups to assess their need for adjuvant chemotherapy. Tumor cell dissemination to the bone marrow is a marker of minimal residual disease and associated with impaired survival. In this study, we aimed to evaluate whether 70-GS is associated with the presence of disseminated tumor cells (DTCs) in the bone marrow of patients with early breast cancer. In patients with hormone receptor-positive HER2-negative early breast cancer, the 70-GS was obtained and the presence of DTCs was immunohistochemically evaluated using cytokeratin staining with the A45-B/B3 antibody. 149 patients were included into the analysis. 40 (27%) had a high-risk 70-GS and 35 (23%) had detectable DTCs in their bone marrow. 9 (22%) of the 40 patients with high-risk 70-GS and 26 (24%) of the 109 patients with a low-risk 70-GS were positive for DTCs (p=0.863). As both 70-GS and DTC detection are known prognostic factors but do not seem to correlate, a follow-up on a larger cohort is warranted to evaluate if a combination of the two is able to better stratify the relapse risk in early breast cancer patients.

PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer.

Purpose The PAM50-based Prosigna risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR). The value of Prosigna for predicting DR was examined in a comprehensive nationwide Danish cohort consisting of postmenopausal women with hormone receptor-positive early breast cancer treated with 5 years of endocrine therapy alone. Patients and Methods Using the population-based Danish Breast Cancer Cooperative Group database, follow-up data were collected on all patients diagnosed from 2000 through 2003 who, by nationwide guidelines, were treated with endocrine therapy for 5 years. Primary tumor blocks from 2,740 patients were tested with Prosigna and, after determination of human epidermal growth factor receptor 2 (HER2) status, data from 2,558 hormone receptor-positive/HER2-negative samples were analyzed, including 1,395 node-positive patients. Fine and Gray models were applied to determine the prognostic value of ROR for DR. Results Median follow-up for recurrence was 9.2 years. Twenty-six percent of the node-positive patients were classified as low ROR (n = 359) with a DR risk of 3.5% (95% confidence interval [CI], 1.9% to 6.1%) versus a DR risk of 22.1% (95% CI, 18.6% to 25.8%) at 10 years for patients classified as high ROR (n = 648). Node-negative patients classified as low and high ROR had a risk of DR of 5.0% (95% CI, 2.9% to 8.0%) and 17.8% (95% CI, 14.0% to 22.0%), respectively. Luminal B tumors (n = 947; DR risk, 18.4% [95% CI: 15.7% to 21.3%]) had a significantly worse outcome than luminal A tumors (n = 1,474,;DR risk, 7.6% [95% CI: 6.1% to 9.2%]; P < .001). Conclusion Prosigna ROR score improved the prediction of outcome in this nationwide Danish population. In a real-world setting, Prosigna can reliably identify node-negative patients and a significant proportion of patients with one to three positive nodes who can be spared treatment with adjuvant chemotherapy.

Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients

Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer

PurposeFor postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.MethodsIn the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.ResultsIn node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.ConclusionsThis study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial

The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen. DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457. Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83·1% (95% CI 80·0-86·3) in the 6-year group and 79·4% (76·1-82·8) in the 3-year group (hazard ratio [HR] 0·79 [95% CI 0·62-1·02]; p=0·066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]). We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. AstraZeneca.