Endocrine-responsive Early Breast Cancer Research Articles

Abstract P2-11-15: Focal ESR1 gene amplification is an independent prognostic marker in postmenopausal patients with endocrine-responsive early breast cancer

Abstract Purpose: Estrogen receptor (ER) expression predicts response to endocrine therapy and is a prognostic biomarker. However, no ER-associated biomarker is able to identify patients with particularly favorable outcome among ER+ tumors. We investigated the value of ESR1 amplification in predicting long-term outcome in tamoxifen-treated postmenopausal women with early breast cancer with and without nodal involvement. Patients and Methods: 394 patients with ER+ breast cancer (235 node-negative, 159 patients node- positive), who had received adjuvant tamoxifen for 5 years in the prospective randomized ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. ER alpha immunoreactivity was evaluated using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis. Results: Focal ESR1 amplification was detected in 187 (47%) tumors, and was associated with a favorable outcome. After a median follow-up of 10 years, women with focal ESR1 amplification had a significantly longer distant recurrence-free survival (DRFS; adjusted HR 0.48; 95% CI 0.26-0.91; p=0.02) and breast cancer-specific survival (BCSS; adjusted HR 0.47; CI 0.27-0.80; p=0.01) compared to women without ESR1 amplification. The association between ESR1 amplification and improved DRFS and BCSS was only found in node-positive tumors, but not in nodal-negative tumors. ER alpha immunoreactivity, evaluated by Allred score, correlated significantly with focal ESR1 amplification (p< 0∙0001; Chi-squared test), but without prognostic significance. Conclusion: We suggest focal ESR1 amplification as predictor of improved long-term outcome in postmenopausal women with node-positive ER+ early breast cancer. Citation Format: Christian F. Singer, Frederik Holst, Stefan Steurer, Eike Burandt, Sigurd Lax, Raimund Jakesz, Margaretha Rudas, Herbert Stöger, Richard Greil, Guido Sauter, Martin Filipits, Ronald Simon, Michael Gnant. Focal ESR1 gene amplification is an independent prognostic marker in postmenopausal patients with endocrine-responsive early breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-15.

Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer.

Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations. Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.

Independent validation of stromal uPA in ABCSG-08: Level 1b evidence for the prognostic value of uPA immunohistochemistry

PurposeTo validate the prognostic role of urokinase-type plasminogen-activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) protein expression in FFPE archived tumor samples when assessed by immunohistochemistry. Patients and methodsFresh-frozen, paraffin-embedded (FFPE) samples from 303 postmenopausal women with hormone receptor-positive, early breast cancer were investigated. The patients had received 5 years of endocrine therapy in the prospectively randomized ABCSG-8 trial. Immunohistochemistry for stromal uPA and PAI-1 protein expression was correlated with distant recurrence-free survival (DRFS) and overall survival (OS). ResultsWe detected stromal uPA in 132 of 297 tumors (44.4%) and stromal PAI-1 expression in 74 out of 299 samples (24.7%). Co-expression of uPA and PAI-1 was present in 48 of 294 (16.3%) cases. Neither uPA nor PAI-1 expression was associated with tumor size, age, nodal status, grading, or quantitative receptor status. Patients whose tumor stroma expressed uPA protein had a significantly shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31–5.93; p = 0.008 Cox regression analysis) than women without uPA expression. No such association was seen for PAI-1 and the uPA/PAI1 ratio. After a median follow-up of 5.6 years, women with uPA-positive tumors demonstrated significantly shorter DRFS (93.3% vs. 84.8%; p < 0.013 log-rank test), and tended to have a worse OS (83.0% vs. 77.3%; p = 0.106) compared to women with uPA negative tumors. ConclusionThis independent validation in archived tumor samples from a large prospective randomized trial confirms the clinical utility of stromal uPA evaluation by immunohistochemistry. This provides level 1b evidence for the prognostic role of stromal uPA in women with endocrine-responsive early breast cancer.

Managing Menopausal Symptoms in Young Women With Breast Cancer: When Medicine Is Not All. The Take Care Project

In the last decade, endocrine therapy strategies in perimenopausal women with hormone-responsive early breast cancer (BC) have changed and now ovarian function suppression (OFS) is recommended for the majority of patients. Side effects of OFS mimic menopausal symptoms, including hot flushes, sweats, weight gain, and sexual dysfunction, which may negatively impact quality of life (QoL). Aims of the Take Care Project are the education of physicians and patients to have all the information (medical and nonmedical) they need to manage menopausal symptoms by distributing educational materials useful to face menopause. Four different areas have been identified by surveys conducted among physicians and young patients: for each area, interventions and tools have been elaborated by a doctor and nonphysician professionals of these identified areas, to offer the widest information available. Clinical and practical suggestions have been provided. Based on the evidence given, we strongly suggest setting up a multidisciplinary team for the treatment planning of young patients with BC, which could help patients to face and manage their new menopause condition. The reduction of side effects and the improvement in QoL should be the best ally to treat young patients with BC.

Abstract OT1-04-02: POSITIVE: A study evaluating pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/big 8-13)

Abstract Background: Young patients with breast cancer (BC) are often diagnosed before completing their families. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcomes overall and in patients with endocrine responsive disease, and is safe for the offspring. However, given also the possibility of extended adjuvant endocrine therapy (ET) (5-10 years), it is not feasible for many of these women to delay pregnancy until completion of therapy. Prospectively evaluating the safety of temporary interruption of ET to allow conception is an unmet, patient-oriented, medical need. Trial Design: Young patients with endocrine responsive early BC who desire pregnancy will interrupt ET for up to 2 yrs to attempt child-bearing. As resumption of menses and conception depends on many factors (e.g. patient’s age and adjuvant treatment received), the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos), conception (~3-6 mos), delivery (~9 mos), and breast feeding (~6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts/deliveries are concluded, and to complete the planned 5-10 yrs of ET. Major Eligibility Criteria - Histologically-proven stage I-III endocrine-responsive BC. - Patient’s wish to become pregnant. - Age ≥ 18 and ≤ 42 years at enrollment. - Adjuvant ET (selective estrogen receptor modulator [SERM] alone, GnRH analogue plus SERM or aromatase inhibitor) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. - Premenopausal status at BC diagnosis. Specific Aims 1. To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy. 2. To evaluate pregnancy success rate and offspring outcome. Statistical Methods: With 500 pts enrolled and followed for a median of 3 years, the statistical design is based on the 95% CI for the 3-year BC recurrence rate. Interim monitoring assumes a 2% BC recurrence risk/yr with continuous ET and a recommendation to stop the study early if the BC risk exceeds 4%/yr with ET interruption. Translational Research will evaluate fertility, pregnancy and BC biology determinants (e.g. ovarian function, uterine evaluation and circulating tumor DNA). Fresh frozen paraffin embedded tissue of the primary tumour will be collected to evaluate parameters related to the biology of BC in young women. All material will be banked centrally. Psycho-oncological Companion Study (POCS) will evaluate fertility concerns, psychological well-being and decisional conflict. It is mandatory in North America and open to interested centers elsewhere. Accrual: Target: 500; Actual: 421 (30 June 2019) Psycho-oncological Companion Study Accrual: Target: ~200; Actual: 196 (30 June 2019) Contact Information: POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. The Alliance for Clinical Trials in Oncology is the US sponsor for NCTN. Contact Monica Ruggeri, IBCSG Coordinating Center, monica.ruggeri@ibcsg.org, or Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Olivia Pagani, Ann H Partridge, Fedro A Peccatori, Hatem A Azim, Chikako Shimizu, Cristina Saura, Ellen Warner, Anna B Sætersdal, Judith R Kroep, Monica Ruggeri, Richard D Gelber. POSITIVE: A study evaluating pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/big 8-13) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-02.

Abstract OT1-01-06: POSITIVE: A study evaluating Pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsIVE breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13)

Abstract Background Young patients with breast cancer (BC) are often diagnosed with the disease before completing their families. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcomes in patients with endocrine responsive BC and is safe for the offspring. However, given the possibility of extended adjuvant endocrine therapy (ET) (5-10 years), it is not feasible for many of these women to delay pregnancy until completion of therapy and thus there is a need to study the safety of interrupting ET to allow pregnancy. To date, no prospective study has been conducted in BC survivors attempting future pregnancy. Trial Design Young patients with endocrine responsive early BC who desire pregnancy will interrupt ET for up to 2 yrs to attempt pregnancy. As resumption of menses and conception depends on many factors (e.g. patient's age and adjuvant treatment received), the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos), conception (˜3-6 mos), delivery (˜9 mos), and breast feeding (˜6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts/deliveries are concluded, and to complete the planned 5-10 yrs of ET. Major Eligibility Criteria - Histologically-proven stage I-III endocrine-responsive BC. - Patient's wish to become pregnant. - Age ≥ 18 and ≤ 42 years at enrollment. - Adjuvant ET (selective estrogen receptor modulator [SERM] alone, GnRH analogue plus SERM or aromatase inhibitor) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. - Premenopausal status at BC diagnosis. Specific Aim To assess the risk of BC relapse associated with the interruption of ET to permit pregnancy, and to evaluate pregnancy success rate and offspring outcome. Statistical Methods With 500 pts enrolled and followed for a median of 3 years, the statistical design is based on the 95% CI for the 3-year BC recurrence rate. Interim monitoring assumes a 2% BC recurrence risk/yr with continuous ET and a recommendation to stop the study early if the BC risk exceeds 4%/yr with ET interruption. Translational Research will investigate various ovarian function and uterine parameters and circulating tumour DNA. Fresh frozen paraffin embedded tissue of the primary tumour will be collected to evaluate parameters related to the biology of BC in young women. All material will be banked centrally. Psycho-oncological Companion Study (POCS) will evaluate fertility concerns, psychological well-being and decisional conflict. It is mandatory in North America and open to interested centers elsewhere. Accrual: Target: 500; Actual: 262 (30 June 2018) Psycho-oncological Companion Study Accrual: Target: 200; Actual: 138 (30 June 2018) Citation Format: Pagani O, Partridge AH, Peccatori F, Azim HA, Colleoni M, Saura C, Kroep JR, Warner E, Gombos A, Sætersdal AB, Ruggeri M, Gelber RD, Sun Z. POSITIVE: A study evaluating Pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsIVE breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-06.

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. NCT00066690 and NCT00066703.

Independent validation of stromal uPA in archived tumor samples from the prospectively randomized ABCSG8 trial to provide level 1b evidence for a prognostic value of uPA immunohistochemistry in endocrine-treated postmenopausal breast cancer patients.

536 Background: We have recently demonstrated that urokinase Plasminogen Activator (uPA), together with its inhibitor PAI-1, have prognostic value in hormone-receptor positive early breast cancer, and can be measured in FFPE archived tumor samples. We have now aimed to validate the prognostic role of uPA protein expression in FFPE archived tumor samples in an independent cohort of endocrine-treated breast cancer patients. Methods: 303 postmenopausal women with hormone receptor–positive, early breast cancer who had received 5 years of endocrine therapy in the prospectively designed ABCSG-08 trial, and in whom FFPE tumor tissue was available, were included in this analysis. Stromal uPA and PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). Results: Stromal uPA was detected in 132 of 297 tumors (44.4%), and 74 out of 269 samples (27.5%) exhibited stromal PAI-1, while co-expression of both proteins was found in 48 of 294 (16.3%) samples. Neither uPA nor PAI-1 expression were associated with tumor size, age, nodal status, grading, or receptor status. Patients whose tumor stroma expressed uPA protein were more likely to have a shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31-5.93; p=0.008 Cox regression analysis) and OS (adjusted HR for death: 1.29; 95% CI 0.86-12.50; p=0.161) than women without uPA expression. No such association was observed for PAI-1 and for the uPA/PAI1 ratio. After a median follow-up of 5.6 years women with uPA-positive tumors experienced a significantly shorter DRFS (93.3% vs 84.8%; p&lt;0.013 log rank test) and tended to have a worse OS (83.0.4% vs 77.3%; p=0.106) compared to women with uPA negative tumors. Conclusions: By confirming the clinical utility of stromal uPA IHC in archived breast cancer samples from an independent prospective randomized trial, we now provide level 1b evidence for a prognostic role of stromal uPA in women with endocrine-responsive early breast cancer.

Abstract P2-09-05: 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer

Abstract Background The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five yrs of adjuvant treatment with letrozole, tamoxifen, or their sequence in postmenopausal women with hormone-receptor–positive early breast cancer. The study is conducted by the International Breast Cancer Study Group (IBCSG) on behalf of BIG. 8010 patients (pts) were enrolled between March 1998 and May 2003, and first results demonstrating a significant DFS benefit favoring letrozole compared with tamoxifen were reported in 2005 at 25.8 months' MFU. Subsequent updates showed continuing DFS benefit and updated results published in 2011 at 8.1 yrs' MFU showed OS benefit. Industry-sponsorship of the original BIG 1-98 ended in 2010; IBCSG launched an observational, non-interventional long-term follow-up study (BIG 1-98 LTFU) to collect survival, disease status and adverse events for an additional 5 yrs. We report results from BIG 1-98 LTFU at 12 yrs' MFU. Methods The original trial includes the 8010 patients enrolled. The potential BIG 1-98 LTFU cohort consisted of 148 academic medical centers with a maximum of 6843 pts who were alive and continuing follow-up when the original study ended. Response bias was addressed using weighting class adjustments estimated using multivariable logistic regression. Unadjusted incidence rates are reported here per 1000 pt-yrs with 95% Poisson confidence intervals. An updated abstract will include adjusted incidence rates, as well as estimates of OS and DFS based on a weighted Kaplan-Meier approach. The database will close in July 2016. Results As of May 2016, 81 centers participated in the BIG 1-98 LTFU study, contributing data from approximately 3900 pts (57%) and extending MFU to 12 yrs. Compared with the potential cohort of 6843 pts, the ~3900 in the LTFU analytic cohort were more likely to be under age 65 yrs at enrollment, have node-positive disease, and have tumors that were &amp;lt; 2 cm, PgR positive (≥1%), and with no evidence of peritumoral vascular invasion. Extended adjuvant endocrine therapy for primary BC was continued in 2% of pts. Unadjusted incidence estimates of myocardial infarction increased during LTFU, while incidence of thromboembolic events and osteoporosis decreased (Table). Variations in incidence rates were noted depending on recording mechanism (e.g. registry, clinic visit, telephone, information from family). Unadjusted Incidence Rate/1000 pt-yrs (95% CI)Adverse EventDuring original studyDuring LTFUMyocardial Infarction1.7 (1.4-2.0)3.5 (2.7-4.5)Thromboembolic event6.0 (5.4-6.6)2.5 (1.8-3.3)Osteoporosis23.6 (22.5-24.9)18.2 (16.3-20.3)Bone fractures17.2 (16.2-18.3)15.0 (13.2-16.9) Overall 1845 deaths were reported; the unadjusted incidence of death was lower in the original study compared with during LTFU (21.9 vs. 26.6/1000 pt-yrs); incidence remained relatively stable for pts assigned to tamoxifen (24.9 vs. 25.2/1000 pt-yrs), and increased for pts assigned to letrozole (22.0 vs. 27.1/1000 pt-yrs). Conclusions The BIG 1-98 LTFU study has been successfully conducted. The additional data from the BIG 1-98 LTFU study provides important long-term clinical information about OS, DFS and adverse events. Citation Format: Thürlimann B, Giobbie-Hurder A, Colleoni M, Jensen M-B, Ejlertsen B, de Azambuja E, Neven P, Láng I, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Price K, Piccart-Gebhart M, Regan MM, Gelber RD, Coates AS, Goldhirsch A. 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-05.

Abstract P1-10-05: Omitting radiotherapy in women ≥ 65 years with early breast cancer and favorable histopathology after breast-conserving surgery, sentinel node biopsy and adjuvant endocrine therapy is safe

Abstract Background: The benefit of radiotherapy in older women with endocrine responsive early breast cancer treated with breast-conserving surgery and endocrine therapy is unclear. The aim of this study was to verify if omission of radiotherapy in a predefined cohort of patients with good prognosis early breast cancer after breast conservation is safe. Methods: Eligibility criteria were: consecutive patients with age ≥ 65 years, breast-conserving surgery (sector resection + sentinel node biopsy), clear margins, unifocal T 1 N0, Elston grade 1 and 2, estrogen receptor-positive. After informed consent adjuvant endocrine therapy, either tamoxifen or an aromatase inhibitor, was prescribed for 5 years. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer, recurrence-free survival (RFS) and overall survival (OS). Results: Between 2006 and 2012, we included 603 women from 14 Swedish centers. Two patients did not fulfill the inclusion criteria and were excluded from the analysis. Median age was 71 years (range 65 to 90). At a median follow-up of 59 months (range 2 to 110) 13 IBTR (cumulative incidence at five years, 1.3% (95% CI, 0.6% to 2.7%), 4 regional recurrences (one combined with IBTR), 2 distant recurrences both without IBTR or regional recurrence and 11 contralateral breast cancers was observed. Twenty-nine patients were diagnosed with tumors of other origin. Seven of them were endometrial cancers. There were 39 deaths. Only one of the deaths (2.6%) was due to breast cancer and 11 (28.2%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.9% (95% CI, 91.4% to 95.7%). Conclusion: This study demonstrates, with a median follow-up of 59 months, that breast-conserving surgery and endocrine therapy without radiotherapy is a safe treatment option in women with early breast cancer and favorable histopathology aged ≥ 65 years. The risk of IBTR is comparable to the risk of contralateral breast cancer. The low rate of breast cancer deaths indicates that breast cancer mortality is of secondary importance in this subset of women. Citation Format: Villman KKA, Wickberg Å, Killander F, Lindman H, Bjöhle J, Edlund P, Tennvall-Nittby L, Bachmeier K, Carlberg M, Blomqvist C, Ahlgren J, Liljegren G. Omitting radiotherapy in women ≥ 65 years with early breast cancer and favorable histopathology after breast-conserving surgery, sentinel node biopsy and adjuvant endocrine therapy is safe [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-05.

Abstract OT3-02-01: POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine-responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13)

Abstract Background Young breast cancer (BC) patients often face the disease before completing their family planning. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcomes in patients with endocrine-responsive BC and is safe for offspring. However, given the possibility of prolonged adjuvant endocrine therapy (ET) (5-10 yrs), it is not feasible to wait until completion of therapy in many of these women and thus there is a need to explore the safety of temporary interruption of ET to allow pregnancy. To date, no prospective study has been conducted in young women attempting future pregnancy. Trial Design Young patients with endocrine-responsive early BC and pregnancy desire will interrupt ET for up to 2 yrs to attempt pregnancy. As resumption of menses and conception depends on many factors, e.g. patient's age and adjuvant treatment received, the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos) conception (∼3-6 mos), delivery (∼9 mos), breast feeding (∼6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts are concluded and to complete the planned 5-10 yrs ET. Major Eligibility Criteria * Histologically-proven stage I-III endocrine-responsive BC. * Age ≥ 18 and ≤ 42 years at enrollment. * Adjuvant ET (SERM alone, GnRH analogue plus SERM or AI) for ≥18 mos but ≤30 mos, stopped within 1 mo prior to enrollment. * Patient wishes to become pregnant. * Premenopausal status at BC diagnosis. Specific Aim To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy and to evaluate pregnancy success and offspring outcome. Statistical Methods A true risk of BC recurrence of 2% per year is assumed for patients who do not interrupt ET. With 500 patients enrolled in 4.0 yrs and an additional 1.6 yrs of follow up, there will be approximately 1600 patient-yrs of follow up and a median follow up of approximately 3 yrs at the time of the primary analysis, anticipated to occur 5.6 yrs after enrolment of the first patient. If the true risk of BC recurrence is 2% per yr, we anticipate 31 BC recurrences and an estimated 3-yr breast cancer free interval (BCFI) event of 5.6% (95% CI 4.0% to 7.9%). Translational Research will investigate different ovarian function and uterine parameters; and circulating tumour DNA. FFPE tissue of the primary tumour will be collected to integrate different parameters related to biology of BC arising in young women. All material will be banked centrally. Psycho-oncological Companion Study on fertility concerns, psychological well-being and decisional conflicts is mandatory in the US and open to interested centers elsewhere. Accrual: Target: 500; Actual: 39 (30 Apr 2016) Psycho-oncological Companion Study Accrual: Target: 200; Actual: 29 (30 Apr 2016) Contact Information POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. The Alliance for Clinical Trials in Oncology is the US sponsor for NCTN network. Contact Monica Ruggeri, IBCSG Coordinating Center, monica.ruggeri@ibcsg.org, or Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Pagani O, Partridge AH, Azim Jr. HA, Peccatori F, Ruggeri M, Sun Z. POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine-responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-01.

Abstract OT2-01-08: POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13)

Abstract Background Young breast cancer (BC) patients often face the disease before completing their family planning. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcome in patients with endocrine sensitive BC and is safe for the offspring. However, given the need for prolonged adjuvant endocrine therapy for 5-10 years, it is not feasible to wait until completion of therapy in most of these women and thus there is a need to explore the safety of temporary interruption of endocrine therapy to allow pregnancy. To date, no definitive prospective study has been conducted in young women desiring future pregnancy. Trial Design Young patients with endocrine responsive early BC and pregnancy desire will interrupt endocrine treatment for up to 2 yrs to attempt pregnancy. As resumption of menses and conception depends on many factors, e.g. patient's age and adjuvant treatment received, the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos) conception (∼3-6 mos), delivery (∼9 mos), breast feeding (∼6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts are concluded, and to complete 5-10 yrs ET at the local investigator discretion. Major Eligibility Criteria -Histologically-proven stage I-III endocrine-responsive BC. -Age ≥ 18 and ≤ 42 years at enrollment. -Adjuvant endocrine therapy (SERM alone, GnRH analogue plus SERM or AI) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. -Patient wishes to become pregnant. -Premenopausal status at BC diagnosis. Specific Aim To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy and to evaluate pregnancy success. Statistical Methods A true risk of BC recurrence of 2% per year is assumed for patients who do not interrupt endocrine treatment. With 500 patients enrolled in 4.0 yrs and an additional 1.6 yrs of follow up, there will be approximately 1600 patient-yrs of follow up and a median follow up of approximately 3 yrs at the time of the primary analysis, anticipated to occur 5.6 yrs after enrollment of the first patient. If the true risk of BC recurrence is 2% per yr, we anticipate 31 BC recurrences and an estimated 3-yr breast cancer free interval (BCFI) failure of 5.6% (95% CI 4.0% to 7.9%). Translational Research will investigate different ovarian function parameters; uterine evaluation; and circulating tumor DNA. FFPE tissue of the primary tumor will be collected to integrate different parameters related to biology of BC arising in young women. All material will be banked centrally. Psycho-oncological Companion Study on fertility concerns, psychological well-being and decisional conflicts is mandatory in the United States and open to interested centers elsewhere. Accrual: Target: 500; Actual: 4 (31 May 2015) Contact Information POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. Alliance for Clinical Trials in Oncology is US sponsor for NCTN network. Contact Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Pagani O, Partridge A, Azim Jr HA, Peccatori FA, Ruggeri M, Sun Z. POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-08.

Predicting benefit of endocrine therapy for early breast cancer

Adjuvant endocrine therapy is a mainstay of treatment for patients with endocrine-responsive early breast cancer. Questions remain concerning which patients should receive what type of endocrine therapy and for how long. Several factors have been considered as potential indicators to predict benefit of endocrine therapy, including patient factors, clinico-pathological factors and multigene assays. To date, factors associated with risk of recurrence have been the most widely adopted to influence treatment selection. The International Breast Cancer Study Group (IBCSG)-led adjuvant endocrine therapy trials BIG 1-98, for postmenopausal women, and SOFT and TEXT, for premenopausal women, can shed light on the role for risk of recurrence in identifying who should receive which type of adjuvant endocrine therapy and for how long.

The PAM50 Risk-of-Recurrence Score Predicts Risk for Late Distant Recurrence after Endocrine Therapy in Postmenopausal Women with Endocrine-Responsive Early Breast Cancer

To assess the prognostic value of the PAM50 risk-of-recurrence (ROR) score on late distant recurrence (beyond 5 years after diagnosis and treatment) in a large cohort of postmenopausal, endocrine-responsive breast cancer patients. The PAM50 assay was performed on formalin-fixed paraffin-embedded whole-tumor sections of patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8). RNA expression levels of the PAM50 genes were determined centrally using the nCounter Dx Analysis System. Late distant recurrence-free survival (DRFS) was analyzed using Cox models adjusted for clinical and pathologic parameters. PAM50 analysis was successfully performed in 1,246 ABCSG-8 patients. PAM50 ROR score and ROR-based risk groups provided significant additional prognostic information with respect to late DRFS compared with a combined score of clinical factors alone (ROR score: ΔLRχ(2) 15.32, P < 0.001; ROR-based risk groups: ΔLRχ(2) 14.83, P < 0.001). Between years 5 and 15, we observed an absolute risk of distant recurrence of 2.4% in the low ROR-based risk group, as compared with 17.5% in the high ROR-based risk group. The DRFS differences according to the PAM50 ROR score were observed for both node-positive and node-negative disease. PAM50 ROR score and ROR-based risk groups can differentiate patients with breast cancer with respect to their risk for late distant recurrence beyond what can be achieved with established clinicopathologic risk factors.

Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial

IntroductionOsteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis.MethodsWe measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/− octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14).ResultsPlasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels.ConclusionsThe hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study.Trial registrationNCT00002864, http://clinicaltrials.gov/show/NCT00002864

Abstract P1-08-13: Predictive value of intrinsic luminal subtypes in premenopausal women with endocrine-responsive early breast cancer: Results from Austrian breast and colorectal cancer study group trial 5

Abstract Purpose: The aim of the present study was to assess the predictive value of intrinsic luminal subtypes in premenopausal hormone receptor-positive early breast cancer patients who received adjuvant endocrine treatment or chemotherapy. Patients and Methods: Intrinsic luminal breast cancer subtypes were centrally assessed by immunohistochemistry on whole tissue sections of breast cancer patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 and received either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 &amp;lt;20%, Luminal B/HER2-negative subtype as Ki67≥20%. Luminal B/HER2-positive subtype displayed HER2 overexpression by IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathological factors. Results: 155 (36%), 217 (50%) and 59 (14%) of 431 tumors were classified as Luminal A, Luminal B/HER2-negative and Luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with Luminal B tumors had a significantly shorter RFS (adjusted hazard ratio [HR] for recurrence: 2.29, 95% confidence interval [CI] 1.44-3.64, P &amp;lt; 0.001) and OS (adjusted HR for death: 3.97, 95% CI 1.94-8.08, P &amp;lt; 0.001) as compared to patients with Luminal A disease. No interaction between intrinsic luminal subtypes and treatment was observed (test for interaction: P = 0.42 for RFS; P = 0.32 for OS). Combination endocrine treatment with goserelin/tamoxifen tended to be more effective than CMF chemotherapy in both luminal A and luminal B subtypes. Conclusion: Intrinsic luminal subtype is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor positive breast cancer but is not predictive for outcome of adjuvant treatment with either goserelin/tamoxifen or chemotherapy with CMF. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-13.

Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: Design of the TEXT and SOFT trials

ObjectivesIn 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? MethodsTEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. ResultsTEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014. ConclusionsWe present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer.Trial RegistrationTEXT: Clinicaltrials.govNCT00066703SOFT: Clinicaltrials.govNCT00066690

Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial

Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures.In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1mg daily), calcium and vitamin D. ResultsAll osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm.At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate.There was a significant drop in lumbar spine (−5.4%) and hip (−4.5%) mean BMD, in the normal BMD group, none of whom received alendronate.Fracture data will be presented. ConclusionIn postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

Association of expression of aquaporin 5 (AQP5) with prognosis in hormone-responsive early breast cancer patients.

e11594 Background: Our previous study showed the association of AQP5 up-regulation with cancer proliferation and migration in hormone-responsive breast cancer cell lines (MCF-7) and with unfavorable prognosis in a small number of patients with breast cancer. Accordingly, we analyzed the prognostic impact of AQP5 expression in a number of patients with early breast cancer (EBC). Methods: We enrolled 447 patients who underwent operation for EBC between June 2003 and August 2008 and performed immunohistochemical (IHC) stain for AQP5 expression in tissue microarray (TMA) collected from tumor tissue. Two pathologists independently scored staining intensity (IS, 0 through3) and percentage of positive tumor cells (PC, 0 through 4) and categorized as negative (0 through 2), weak (3 through 5), and strong (6 or more) according to the sum. Results: The median age of patients was 49 years (range 23-82). 80 (17.9%) patients underwent breast conserving surgery and adjuvant chemotherapy was given to 406 (90.8%) patients. Among enrolled subjects, 298 (66.7%) were hormone-responsive, 64 (14.3%) for HER2 overexpressed, and 79 (17.7%) for triple negative EBC by ER, PgR, and HER2 expression. AQP5 expression (staining score &gt;2) was observed in 267 (59.7%) patients including 123 (27.5%) overexpression (stating score &gt;5). In univariate analysis, AQP5 overexpression was associated with survival in patients with hormone-responsive and HER2 overexpressed EBC. Moreover, multivariate survival analysis revealed that AQP5 overexpression was an independent prognostic marker for survival in patients EBC, which was prominent in patients with ER/PgR-positive tumor type. However, no difference in AQP5 expression was observed based on patient and tumor characteristics. Conclusions: Consistent with our previous study with breast cancer cell lines, AQP5 expression in tumor tissue can be considered as a prognostic marker in patients with EBC after curative operation.

Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities

Bisphosphonates are approved for treating malignant bone disease from advanced cancer because they are effective inhibitors of osteoclast-mediated bone resorption. However, there may be a greater role for the use of bisphosphonates than has previously been considered. There is a large body of preclinical evidence showing that bisphosphonates exert a variety of direct and indirect anticancer activities that affect both tumor cells and the surrounding microenvironment, and that stimulate immune reactions. Recent data from clinical trials have shown that adding the bisphosphonate zoledronate to endocrine therapy or chemotherapy improves disease-free survival of patients with endocrine-responsive early breast cancer in a low estrogen environment (that is, following ovarian suppression therapy or in women with established menopause at diagnosis). Adjuvant treatment with the bisphosphonate clodronate also improves disease-free survival in postmenopausal breast cancer. Additionally, zoledronate was found to prolong survival in patients with symptomatic multiple myeloma or other advanced cancers. Here, we present an overview of preclinical and clinical studies that demonstrate anticancer benefits of bisphosphonates, and we discuss potential mechanisms of action that might be responsible for the anticancer activity of bisphosphonates in the clinic.