International Breast Cancer Study Group Research Articles

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Bayesian joint modeling of multivariate longitudinal and survival outcomes using Gaussian copulas.

There is an increasing interest in the use of joint models for the analysis of longitudinal and survival data. While random effects models have been extensively studied, these models can be hard to implement and the fixed effect regression parameters must be interpreted conditional on the random effects. Copulas provide a useful alternative framework for joint modeling. One advantage of using copulas is that practitioners can directly specify marginal models for the outcomes of interest. We develop a joint model using a Gaussian copula to characterize the association between multivariate longitudinal and survival outcomes. Rather than using an unstructured correlation matrix in the copula model to characterize dependence structure as is common, we propose a novel decomposition that allows practitioners to impose structure (e.g., auto-regressive) which provides efficiency gains in small to moderate sample sizes and reduces computational complexity. We develop a Markov chain Monte Carlo model fitting procedure for estimation. We illustrate the method's value using a simulation study and present a real data analysis of longitudinal quality of life and disease-free survival data from an International Breast Cancer Study Group trial.

Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role. Patients and methods: The International Breast Cancer Study Group (IBCSG) Trial 22–00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 ResultsWe confirmed that high immune CD3+ T cells as well as stromal and intra-epithelial Tregs (CD4+Foxp3+ T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients. Conclusionsimmune spatial classification on immune cells infiltrates seems crucial and could help patients’ selection in clinical trial and greatly improve responses to specific therapies.

Semiparametric normal transformation joint model of multivariate longitudinal and bivariate time-to-event data.

Joint models for longitudinal and survival data (JMLSs) are widely used to investigate the relationship between longitudinal and survival data in clinical trials in recent years. But, the existing studies mainly focus on independent survival data. In many clinical trials, survival data may be bivariately correlated. To this end, this paper proposes a novel JMLS accommodating multivariate longitudinal and bivariate correlated time-to-event data. Nonparametric marginal survival hazard functions are transformed to bivariate normal random variables. Bayesian penalized splines are employed to approximate unknown baseline hazard functions. Incorporating the Metropolis-Hastings algorithm into the Gibbs sampler, we develop a Bayesian adaptive Lasso method to simultaneously estimate parameters and baseline hazard functions, and select important predictors in the considered JMLS. Simulation studies and an example taken from the International Breast Cancer Study Group are used to illustrate the proposed methodologies.

Bayesian semiparametric joint model of multivariate longitudinal and survival data with dependent censoring.

We consider a novel class of semiparametric joint models for multivariate longitudinal and survival data with dependent censoring. In these models, unknown-fashion cumulative baseline hazard functions are fitted by a novel class of penalized-splines (P-splines) with linear constraints. The dependence between the failure time of interest and censoring time is accommodated by a normal transformation model, where both nonparametric marginal survival function and censoring function are transformed to standard normal random variables with bivariate normal joint distribution. Based on a hybrid algorithm together with the Metropolis-Hastings algorithm within the Gibbs sampler, we propose a feasible Bayesian method to simultaneously estimate unknown parameters of interest, and to fit baseline survival and censoring functions. Intensive simulation studies are conducted to assess the performance of the proposed method. The use of the proposed method is also illustrated in the analysis of a data set from the International Breast Cancer Study Group.

Proceedings of the 3rd Indian Cancer Genome Atlas Conference 2022: Biobanking to Omics: Collecting the Global Experience.

On January 13th and 14th 2022, the Center for Translational Cancer Research organized the virtual third Indian Cancer Genome Atlas (ICGA) Conference 2022 "Biobanking to Omics - Collecting the Global Experience." This conference was planned as the steppingstone to help ICGA understand the road ahead and the probable roadblocks in its preparatory phase as ICGA begins to streamline the tumor tissue biobanking and multi-omics efforts in the Indian subcontinent. The first day of the conference was dedicated to updates on the current status of ICGA, the future prospect, and the global understanding of multi-omics efforts. The key highlights included two keynote speeches by Dr Wui Jin Koh, Senior Vice President and Chief Medical Office, National Comprehensive Cancer Network, and by Dr Christina Curtis, Associate Professor, Stanford University School of Medicine. The first day ended with an intriguing panel discussion on "ICGA updates and Future Steps." The second day focused on biobanking practices across the globe and several aspects of biobank setup such as infrastructure, maintenance, quality control, patient consent, and lessons learned from established biobanking setups. The talk by Rosita Kammler, Head, Translational Research Coordination, International Breast Cancer Study Group, Switzerland, and Ruhul Amin, Director, Bangladesh Medical Research Council were the key highlights. The second day also ended with an engaging panel discussion on "Tumor tissue biobanking - national and international perspectives." Overall, the conference was well received and had good attendance from national and international students, researchers, and faculty from academia as well as industry.

A Selection Model for Longitudinal Data with Non-Ignorable Non-Monotone Missing Values

Missing values are not uncommon in longitudinal data studies. Missingness could be due to withdrawal from the study (dropout) or intermittent. The missing data mechanism is termed non-ignorable if the probability of missingness depends on the unobserved (missing) observations. This paper presents a model for continuous longitudinal data with non-ignorable non-monotone missing values. Two separate models, for the response and missingness, are assumed. The response is modeled as multivariate nor mal whereas the binomial model for missingness process. Parameters in the adopted model are estimated using the stochastic EM algorithm. The proposed model (approach) is then applied to an example from the International Breast Cancer Study Group.

Abstract GS2-04: A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01)

Abstract Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age <50 years orage ≥50 years plus at least one of the risk factors for local recurrence (palpable tumor,multifocal disease, tumor size ≥ 1.5cm, intermediate or high nuclear grade, central necrosis, comedo histologyand/or surgical margin <10 mm). Patients were randomized to have tumor bedboost (16 Gy in 8 daily fractions) or no boost following conventional WBI (50Gy in 25 daily fractions) or hypofractionated WBI (42.5 Gy in 16 dailyfractions) in one of three randomization categories selected by centers priorto study activation. Randomization A was a 4-arm randomization of no boost vs. boostfollowing conventional WBI vs. hypofractionated WBI. Patients in RandomizationB and Randomization C were assigned no boost or boost following conventional WBIand hypofractionated WBI, respectively. The primary endpoint was time to localrecurrence, analyzed by intention to treat. The trial was designed to detect a3% difference in 5-year free-from- local recurrence rates between the no boostand boost groups (93% vs 96%; hazard ratio, 0.56) with 90% power and 2-sidedalpha level of 5%. The primary effect of boost was assessed on all randomizedpatients. The secondary effect of WBI dose-fractionation and the interactionbetween boost and WBI dose-fractionation were assessed on patients in RandomizationA and additionally on all patients. Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P<0.001). Forty-four percent and 45% of LRs were invasive in the no boostgroup and boost group, respectively. The effect of boost did not vary significantlyby age, tumor size, nuclear grade, surgical margin or endocrine therapy. Therewere no significant differences in the 5-year free-from- local recurrence ratesbetween the conventional WBI group and hypofractionated WBI group inRandomization A (94% vs. 94%, P=0.84) and in all randomized patients (95% vs.95%, P=0.89). The test for interaction between boost and dose-fractionation wasnot significant in Randomization A or in all randomized patients (both P=0.89).The rates of grade ≥2 breastpain (12% vs. 16%, P=0.84) and skin and subcutaneous tissue fibrosis (6% vs.15%, P=0.14) did not differ significantly between the groups. Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-04.

Breast Cancer Treatment in the Era of Precision Medicine

Breast cancer is the most common cancer in women in the Western world. Treatment decisions in the adjuvant and metastatic setting are based on three immunohistochemistry markers, namely estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Based on the St. Gallen consensus, four distinct subtypes are defined: luminal A, luminal B, HER2-enriched and basal-like subtype breast cancer. In the era of precision medicine, more accurate profiling of breast cancer is now possible. Highly specific methods, including, but not limited to, next-generation sequencing (NGS), proteomics, and immune profiling, help to identify the targets for the appropriate treatment. Several international consortia trials, e.g., AURORA from the International Breast Cancer Study Group (IBCSG), are on the way to standardize optimal molecular treatment for breast cancer patients. This review gives you a clinically oriented overview of treatments for all breast cancer subtypes and an insight into molecular techniques and profile-based decisions. It is an overview from clinicians for clinicians.

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.

<p>Axillary management still needed for patients with sentinel node micrometastases</p>

More attention has been paid to the axillary management over the past 50 years, and clinical practice has been changed as results of the random controlled trials. The American College of Surgeons Oncology Group Z0011 and International Breast Cancer Study Group (IBCSG) 23-01 trials provided high-level evidence to support the omission of axillary lymph nodes dissection (ALND) in sentinel lymph node (SLN)-positive patients receiving breast-conserving surgery (BCS) and adjuvant systemic treatment. In patients treated with BCS, whole breast irradiation (WBI) with tangential fields could lead to substantial axillary irradiation and control the residual tumor burden in axilla, whereas (intraoperative) partial breast irradiation has no therapeutic effect on these residual axillary metastases. In the observation group of the IBCSG 23-01 trial, 425 patients received BCS and 80 (18.8%) of them just underwent intra-operative radiotherapy. While the 10-year axillary recurrence rate was acceptable low (1.7%, 8/467) in the no ALND group, it was 4.5% (6/134) in patients without axillary management, which was significantly higher than that of 0.6% (2/333) in patients with axillary management (P=0.0024). Should we accept an axillary recurrence rate as high as 4.5% in patients with only SLNs micrometastases? What is the best way to control the residual tumor burden in the axilla and decrease the recurrence rate if there is no ALND? The evidence showed that both WBI after BCS (Z0011, AATRM [Agència d’Avaluació de Tecnologia i Recerca Mèdiques]) and axillary regional nodal irradiation after mastectomy/BCS OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy), AMAROS (After Mapping of the Axilla: Radiotherapy Or Surgery) could control the regional residual tumor burden when the SLN is positive and an ALND is omitted. In the modern era, systemic therapy could further decrease the risk of local/regional recurrences. After the subanalysis of the POSNOC (POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy), SERC (Sentinelle Envahiet Randomisation du Curage), and Dutch BOOG (BOrstkanker Onderzoek Groep) trials, a prediction model might be established to identify those patients who could beneft from no axillary management as a guide to clinical practice. At present, axillary management should still be required for patients with SLN micrometastases.

Performance of standard imputation methods for missing quality of life data as covariate in survival analysis based on simulations from the International Breast Cancer Study Group Trials VI and VII*

Imputation methods for missing data on a time-dependent variable within time-dependent Cox models are investigated in a simulation study. Quality of life (QoL) assessments were removed from the complete simulated datasets, which have a positive relationship between QoL and disease-free survival (DFS) and delayed chemotherapy and DFS, by missing at random and missing not at random (MNAR) mechanisms. Standard imputation methods were applied before analysis. Method performance was influenced by missing data mechanism, with one exception for simple imputation. The greatest bias occurred under MNAR and large effect sizes. It is important to carefully investigate the missing data mechanism.

Imputing missing quality of life data as covariate in survival analysis of the International Breast Cancer Study Group Trials VI and VII

ABSTRACTQuality of life (QoL) was an important endpoint in the adjuvant breast cancer trials International Breast Cancer Study Group (IBCSG) Trial VI and VII. Here, QoL was considered as a time-dependent effect. The hypothesis explored is that poorer QoL throughout the trial is associated with poorer disease-free survival (DFS) and vice-versa. Potential bias in the parameter estimates is an important concern associated with missing observations. Standard simple and multiple imputation methods were applied to missing QoL assessments before analysis in a time-dependent Cox model. There was no evidence that the patient's QoL is related to the patient's DFS.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. Novartis and the International Breast Cancer Study Group.

Editorial introductions

Editorial introductions

Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98

PurposeTo evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer.MethodAIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group’s trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs).ResultsForty-six percent of the tumors had a high AIB1 expression. In line with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80–100 vs. 1–79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival (univariable: hazard ratio 1.35, 95% confidence interval 1.12–1.63. Multivariable: hazard ratio 1.29, 95% confidence interval 1.06–1.58) and overall survival (univariable: hazard ratio 1.34, 95% confidence interval 1.07–1.68. Multivariable: hazard ratio 1.25, 95% confidence interval 0.99–1.60). HER2 did not seem to modify the prognostic effect of AIB1. No difference in treatment effect between tamoxifen and letrozole in relation to AIB1 was found.ConclusionsIn a subset of the large international randomized trial BIG 1-98, we confirm AIB1 to be a strong prognostic factor in early breast cancer. Hence, although tumor AIB1 expression does not seem to be useful for the choice of tamoxifen versus an aromatase inhibitor in postmenopausal endocrine-responsive breast cancer, AIB1 is an interesting target for new anti-cancer therapies and further investigations of this biomarker is warranted.

Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.

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 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 PD6-04: HOHO study: How European and US young women cope with breast cancer and fertility concerns

Abstract Background The International Breast Cancer Study Group (IBCSG), in collaboration with Dana-Farber Cancer Institute, conducts the European (EU) cohort of the Helping Ourselves Helping Others (HOHO) study. HOHO is a prospective longitudinal cohort study investigating short and long-term treatment and fertility concerns in young women with breast cancer (BC): most previous studies have been retrospective. Patients and methods From Aug 2009-Jan 2016, 300 patients aged 18-40 yrs with early/advanced BC were enrolled within 6 mos of diagnosis in 18 Centers in Italy and Switzerland. Patients are surveyed every 6 mos the first 3 yrs and yearly for additional 7 yrs. 297 baseline surveys were evaluable. The baseline survey includes sociodemographic and treatment data, and a modified Fertility Issues Survey (including fertility concerns, preservation, outcome and impact on treatment decisions). Clinical data are collected yearly. We qualitatively compare the EU baseline data with the published US data (Ruddy et al, JCO 32:1151, 2014). Results Almost two thirds of women in both cohorts discussed future fertility with their doctors at diagnosis. Fertility concerns, desire for future pregnancy (both before disease onset and at time of survey) and steps to reduce infertility were all more common in the EU cohort. EU women were also more concerned about fertility when discussing treatment and about a possible relapse affecting their ability to care for future children. Conclusion Many young women with newly diagnosed BC have concerns about fertility, which may affect their treatment decisions. In the EU cohort fewer women had a stable relationship and children before diagnosis, potentially influencing their treatment decisions and encouraging fertility preservation. Concerns about a possible relapse could partly explain the decrease in their pregnancy desire after the disease. Differences between EU and US women seem to emerge: continued data collection will determine if they persist over time. The POSITIVE Trial (IBCSG 48-14/ALLIANCE 221405) will address safety and outcome of pregnancy after BC. USEUN (%)N (%)620 (100)297 (100)Age &amp;lt;35 yrs229 (37)95 (32)Married or in a significant relationship474 (76)192 (65)Had children before BC diagnosis409 (66)160 (54)Never pregnant158 (25)119 (40)Before BC wished to have future children230 (37)161 (54)At time of survey wished to have future children160 (26)120 (40)If wanted more children, concerned about: (some women indicated more than one)n=160n=120Caring for them if BC recurred27 (17)45 (38)Children having increased risk of developing cancer70 (44)38 (32)Pregnancy would increase risk of recurrence-56 (47)Reason(s) for not wanting more children: (some women indicated more than one)n=460n=177Caring for them if BC recurred18 (4)28 (16)Children having increased risk of developing cancer33 (7)22 (12)Pregnancy would increase risk of recurrence59 (13)16 (9)Concerned about fertility at time of treatment decision-making (a little, somewhat or a lot)319 (51)189 (64)Fertility concerns affected treatment decision (a little, somewhat or a lot)160 (26)115 (39)Took special steps to decrease infertility65 (10)79 (27)Discussed fertility issues with physician before starting therapy424 (68)198 (67) Citation Format: Pagani O, Bagnardi V, Ruggeri M, Bianco N, Gallerani E, Buser K, Giordano M, Gianni L, Rabaglio M, Freschi A, Cretella E, Clerico M, Amadori D, Simoncini E, Ciccarese M, Rauch D, Glaus A, Berardi R, Franzetti A, Ruddy KJ, Gelber S, Partridge AH, Colleoni M. HOHO study: How European and US young women cope with breast cancer and fertility concerns [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 PD6-04.