Breast Cancer-free Interval Research Articles

GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.

A phase 3, randomized, open-label study of the anti-Globo H vaccine adagloxad simolenin/obi-821 in the adjuvant treatment of high-risk, early-stage, Globo H-positive triple-negative breast cancer.

TPS611 Background: Adagloxad simolenin (A-S) is an anti-Globo H immunogen comprised of the carbohydrate tumor antigen Globo H, covalently linked to keyhole limpet hemocyanin, a carrier protein that deploys T cells to enhance the humoral response. Administration of A-S in combination with the immune adjuvant OBI-821 serves as an anti-tumor associated carbohydrate antigen vaccine intended to generate anti-Globo H humoral responses in patients with Globo H-expressing tumors. Methods: Study OBI-822-011, a phase 3 study, was initiated in 2018. Following feedback from investigators and advisors the study design was changed from a double-blind, placebo-controlled study to an open-label, standard of care (SOC) study. The revised protocol includes patients who have recovered from surgery and completed all planned neoadjuvant and/or adjuvant multiagent chemotherapy and/or radiation therapy. SOC in the A-S/OBI-821 arm is concomitant therapy of capecitabine or immune checkpoint inhibitor. In the SOC arm patients will receive SOC therapy consisting of observation alone, or adjuvant capecitabine alone, or immune checkpoint inhibitor alone. The key protocol changes included a change from open-label to standard of care, providing unblinding and reconsent guidelines for patients enrolled into the study prior to the protocol amendment, allowing concurrent adjuvant single agent chemotherapy, revising the stratification algorithm from a non-hierarchical to a hierarchical structure and aligning the stratification factors with prognostic factors more representative of the study population, revising the eligibility criteria, number and frequency of assessments to reduce patient burden, revising the interim analysis timepoints for futility, and removed an interim analysis for superiority. Study Objectives: Primary Objective: To determine the effect of A-S/OBI-821 treatment on improving IDFS in the study population. Secondary Objectives: To determine the impact of A-S/OBI-821 treatment on Overall survival (OS), Quality of life (QoL), Breast cancer-free interval (BCFI), Distant disease-free survival (DDFS) in the study population; To determine the safety and tolerability of A-S/OBI-821 in the study population. Key Exploratory Objectives: Beyond the safety, efficacy, and QoL endpoints of this trial, exploratory endpoints will evaluate the relationship between aberrant Globo H expression and baseline characteristics, including tumor pathology and immune factors. Conclusion: An estimated 668 subjects will be enrolled, treated for up to 2 years, and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last subject randomized. Survival follow-up is for 5 years from randomization of last subject. Clinical trial information: NCT03562637.

Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer

Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. ClinicalTrials.gov Identifier: NCT01101438.

Use of a convolutional neural network-based mammographic evaluation to predict breast cancer recurrence among women with hormone receptor-positive operable breast cancer.

We evaluated whether a novel, fully automated convolutional neural network (CNN)-based mammographic evaluation can predict breast cancer relapse among women with operable hormone receptor (HR)-positive breast cancer. We conducted a retrospective cohort study among women with stage I-III, HR-positive unilateral breast cancer diagnosed at Columbia University Medical Center from 2007 to 2017, who received adjuvant endocrine therapy and had at least two mammograms (baseline, annual follow-up) of the contralateral unaffected breast for CNN analysis. We extracted demographics, clinicopathologic characteristics, breast cancer treatments, and relapse status from the electronic health record. Our primary endpoint was change in CNN risk score (range, 0-1). We used two-samplet-tests to assess for difference in mean CNN scores between patients who relapsed vs. remained in remission, and conducted Cox regression analyses to assess for association between change in CNN score and breast cancer-free interval (BCFI), adjusting for known prognostic factors. Among 848 women followed for a median of 59months, there were 67 (7.9%) breast cancer relapses (36 distant, 25 local, 6 new primaries). There was a significant difference in mean absolute change in CNN risk score from baseline to 1-year follow-up between those who relapsed vs. remained in remission (0.001 vs. -0.022, p = 0.030). After adjustment for prognostic factors, a 0.01 absolute increase in CNN score at 1-year was significantly associated with BCFI, hazard ratio = 1.05 (95% Confidence Interval 1.01-1.09, p = 0.011). Short-term change in the CNN-based breast cancer risk model on adjuvant endocrine therapy predicts breast cancer relapse, and warrants further evaluation in prospective studies.

PAM50 subtyping and ROR score add long-term prognostic information in premenopausal breast cancer patients

PAM50 intrinsic subtyping and risk of recurrence (ROR) score are approved for risk profiling in postmenopausal women. We aimed to examine their long-term prognostic value in terms of breast cancer-free interval (BCFi) and overall survival (OS) (n = 437) in premenopausal women randomised to 2 years of tamoxifen versus no systemic treatment irrespective of hormone-receptor status. Intrinsic subtyping added independent prognostic information in patients with oestrogen receptor-positive/human epidermal growth factor 2-negative tumours for BCFi and OS after maximum follow-up (overall P-value 0.02 and 0.006, respectively) and those with high versus low ROR had worse prognosis (maximum follow-up: hazard ratio (HR)BCFi: 1.70, P = 0.04). The prognostic information by ROR was similar regarding OS and in multivariable analysis. These results support that PAM50 subtyping and ROR score provide long-term prognostic information in premenopausal women. Moreover, tamoxifen reduced the incidence of breast cancer events only in patients with Luminal APAM50 tumours (0–10 years: HRBCFi(Luminal A): 0.41, HRBCFi(Luminal B): 1.19, Pinteraction = 0.02).Trial registration: This trial is registered in the ISRCTN database, trial ID: ISRCTN12474687.

Abstract PD9-05: Prognostic and tamoxifen-predictive effect of PAM50 and ROR score in premenopausal women included in the randomised SBII:2 trial

Abstract PD9-05: Prognostic and tamoxifen-predictive effect of PAM50 and ROR score in premenopausal women included in the randomised SBII:2 trial

Abstract GS2-05: Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials

Abstract Background The updated combined SOFT+TEXT analysis, after 9 years median follow-up (MFU), revealed that adjuvant E+OFS vs T+OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI) but not overall survival (OS) in premenopausal women with HR+ early BC (Francis et al NEJM 2018). Given the high rate of OS in both arms and the long-term risk of relapse in HR+ BC, continued follow-up is key to assessing treatment benefit. We report a planned update analysis including OS with database lock of May 2021, after 13 years MFU.. Methods TEXT and SOFT enrolled premenopausal women with HR+ early BC from November 2003 to April 2011 (2660 in TEXT, 3047 in SOFT intention-to-treat (ITT) populations). TEXT randomized women within 12 weeks of surgery to 5 years E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5 years E+OFS vs T+OFS vs T alone, within 12 weeks of surgery if no CT planned, or within 8 months of completing (neo)adjuvant CT. Both trials were stratified by CT use. For the combined analysis of E+OFS vs T+OFS, the primary endpoint was DFS defined as invasive local, regional, distant recurrence, contralateral BC, second malignancy, death. Secondary endpoints included invasive breast cancer-free interval (BCFI), DRFI and OS.. Results: At database lock there were 953 DFS events and 473 deaths among 4690 pts assigned to T+OFS or E+OFS. In the ITT population, DFS, BCFI and DRFI outcomes for pts assigned E+OFS (n=2346) continued to be significantly improved over T+OFS (n=2344). 12-yr DFS was 80.5% vs. 75.9% (4.6% absolute improvement; HR 0.79 95% CI 0.70-0.90), 12-yr BCFI was improved by 4.1% and 12-yr DRFI by 1.8%. At 12 years OS was excellent in both groups, 90.1% in pts assigned E+OFS vs 89.1% in pts assigned T+OFS (HR 0.93; 95% CI, 0.78-1.11). There was heterogeneity of relative treatment effect according to HER2 status. When enrollment commenced, anti-HER2 adjuvant therapy was not standard; 53% of 583 pts with HER2+ tumors received HER2-targeted therapy. Below are Kaplan-Meier 12-yr estimates for patients with HER2 negative tumors by trial and chemotherapy stratum and for those with high-grade tumours, as an example of high-risk feature (Table). There is an emerging OS benefit for E+OFS vs T+OFS in pts with HER2 negative tumors who received chemotherapy in both trials.In pts with HER2-negative tumors, clinically-relevant outcome benefits were also seen in other high-risk subgroups: 12-yr DFS and OS were improved by 7.4% and 2.7%, respectively, in pts with pN1a disease, and by 10.6% and 4.5%, respectively, in those with tumors >2cm. Conclusions After 13 years MFU, adjuvant E+OFS, as compared with T+OFS, shows a sustained reduction in the risk of recurrence, more consistent in HER2 negative patients and in those with high-risk disease features, e.g., indication for adjuvant chemotherapy and G3 tumors. Oncologists may use this information to discuss potential benefits of E+OFS with individual patients. Follow-up continues for 5 additional years. Chemotherapy HER2-negativeSOFTT+OFS (n=424)E+OFS (n=411)Absolute difference12-yr DFS67.4%74.1%6.7%12-yr OS81.1%84.4%3.3%TEXTT+OFS (n=656)E+OFS (n=661)Absolute difference12-yr DFS71.0%78.4%7.4%12-yr OS83.5%86.8%3.3%No chemotherapy HER2-negativeSOFTT+OFS (n=445)E+OFS (n=447)Absolute difference12-yr DFS82.9%88.2%5.3%12-yr OS96.1%96.9%0.9%TEXTT+OFS (n=499)E+OFS (n=492)Absolute difference12-yr DFS80.2%86.7%6.5%12-yr OS95.9%96.2%0.2%G3 HER2-negativeT+OFS (n=423)E+OFS (n=405)Absolute difference12-yr DFS62.7%73.0%10.3%12-yr OS78.1%83.6%5.5% Citation Format: Meredith M Regan, Barbara A Walley, Gini F Fleming, Prudence A Francis, Marco A Colleoni, István Láng, Henry L Gómez, Carlo A Tondini, Harold J Burstein, Matthew P Goetz, Eva M Ciruelos, Vered Stearns, Hervé R Bonnefoi, Silvana Martino, Charles E Geyer, Jr, Claudio Chini, Alessandro M Minisini, Simon Spazzapan, Thomas Ruhstaller, Eric P Winer, Barbara Ruepp, Sherene Loi, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-05.

Abstract GS1-08: CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438)

Abstract Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients < 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI < vs > 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-08.

Abstract OT2-05-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information that may guide subsequent adjuvant treatment for the individual patient. Pathological complete response (pCR) following neoSACT identifies a population with excellent outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to the absolute clinical benefit. Aims HER2-RADiCAL seeks to reduce the burden of toxicity and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less intensive therapy, including avoiding anthracyclines, with minimal or no loss of efficacy in the population. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort (single-arm) study embedded within a real-world data driven clinical pathway model. Participants will be registered within 6 weeks of completion of breast cancer surgery. The main eligibility criteria include clinical stage T1N1 or T2N0-1 at diagnosis and locally-determined pCR (ypT0/Tis ypN0) after standard of care taxane-based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab. After registration participants will continue to receive trastuzumab to complete a total of 9 cycles including those (neo-)adjuvant cycles administered prior to study entry. Participants will receive no further pertuzumab nor any adjuvant chemotherapy. Statistical methods The primary clinical endpoint is relapse free interval. Recruitment of 720 participants over 3 years will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, treatment pathway adherence and cost-effectiveness. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway taken from 4-nation UK National Health Service data at the beginning and end of the study. Patient and public involvement Patient advocates have shaped the research by confirming that the main outcomes being evaluated are important to patients and that the interventional cohort design, with power to exclude an absolute risk of recurrence outwith a 2-3% margin of historical control data, is acceptable and preferable to a randomised controlled trial, which would take longer to get answers and need many more patients to be included. They have been involved in protocol design, including methodology, sample collection and patient follow-up, and their input has shaped the patient information materials and consent forms. Patient advocates will have an ongoing key role in overseeing the progress of the study as members of the Trial Management Group, and they will also have an important role in communicating the study results to patients and the public. Current status HER2-RADiCAL is planned to open at ~40 UK sites commencing in September 2021. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Sarah Kernaghan, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Charlotte Coles, Cliona Kirwan, Mairead Mackenzie, Ciara O’Brien, Alistair Ring, Claire Snowdon, Hilary Stobart, Duncan Wheatley, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-05-01.

Breast Cancer Index (BCI) and prediction of benefit from extended aromatase inhibitor (AI) therapy (tx) in HR+ breast cancer: NRG oncology/NSABP B-42.

501 Background: The BCI HOXB13/IL17BR ratio (BCI-H/I) has been shown to predict endocrine tx (ET) and extended ET (EET) benefit. We examined the effect of BCI-H/I for EET benefit prediction in NSABP B-42, evaluating extended letrozole tx (ELT) in HR+ breast cancer patients (pts) who completed 5 yrs of ET. Methods: All pts with available primary tumor tissue were eligible. Primary endpoint was recurrence-free interval (RFI). Secondary endpoints were distant recurrence (DR), breast cancer-free interval (BCFI), and disease-free survival (DFS). Stratified Cox proportional hazards model was used. Due to a non-proportional effect of ELT on DR, time-dependent secondary analyses (≤4y, >4y) were performed. Likelihood ratio test evaluated treatment by BCI-H/I interaction. Results: In 2,179 pts analyzed (60% N0; 62% AI only; 80% HER2-), 45% were BCI-H/I-High and 55% BCI-H/I-Low. ELT showed an absolute 10y benefit of 1.6% for RFI (HR=0.77, 95% CI 0.57-1.05, p=0.10) (BCI-H/I-Low: 1.1% [HR=0.69, 0.43-1.11, p=0.13]; BCI-H/I-High: 2.4% [HR=0.83, 0.55-1.26, p=0.38]; interaction p=0.55). There was no statistically significant ELT by BCI-H/I interaction for BCFI (BCI-H/I-Low: HR=0.53, 0.36-0.78, p=0.001; BCI-H/I-High: HR=0.85, 0.60-1.21, p=0.36; interaction p=0.07) or for DFS (BCI-H/I-Low: HR=0.75, 0.58-0.95, p=0.017; BCI-H/I-High: HR=0.81, 0.64-1.04, p=0.09; interaction p=0.62). Before 4y, there was no statistically significant ELT benefit on DR in either BCI-H/I group. After 4y, BCI-H/I-High pts had statistically significant ELT benefit on DR (HR: 0.29, 0.12-0.69, p=0.003), while BCI-H/I-Low pts were less likely to benefit (HR: 0.68, 0.33-1.39, p=0.28) (interaction p=0.14). Conclusions: BCI-H/I prediction of ELT benefit on RFI was not confirmed. In time-dependent DR analyses, BCI-H/I-High pts had statistically significant benefit from ELT after 4y, while BCI-H/I-Low pts did not. Observed ELT benefit on BCFI in BCI-H/I-Low pts was primarily driven by second primary breast cancers. Additional follow-up is needed to further characterize BCI-H/I predictive ability in this study. Support: U10CA180868, -180822, U24CA196067; Novartis; Biotheranostics. Clinical trial information: NCT00382070. [Table: see text]

Utility of the 70-gene MammaPrint assay for prediction of benefit from extended letrozole therapy (ELT) in the NRG Oncology/NSABP B-42 trial.

502 Background: The 70-gene MammaPrint (MP) assay predicts risk of distant recurrence (DR) in hormone-receptor positive early-stage breast cancer and classifies cancers as Low Risk or High Risk. NSABP B-42 evaluated ELT in patients (pts) who had completed 5 yrs of adjuvant endocrine therapy (tx). The primary objective was to determine the utility of MP to identify pts enrolled in NSABP B-42 who are likely to benefit from ELT. Methods: A total of 1,866 pts from B-42 had available MP results. Primary endpoint is DR. Secondary endpoints are disease-free survival (DFS) and breast cancer-free interval (BCFI). For the primary analysis, pts were classified as High Risk (MP-H) (MP score ≤0.000) or Low Risk (MP-L) (MP score > 0.000). Exploratory analyses were performed for MP-L subcategories: MP Ultralow Risk (MP-UL) (MP score > 0.355) and MP-L but not MP-UL (MP-LNUL) (MP score > 0.000, ≤0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model was used for treatment by risk group interaction. Stratified log-rank test was used to compare treatment groups. Hazard ratios and 95% CI were computed based on the stratified Cox PH model. Results: Among 1,866 pts, 706 (38%) were MP-H and 1,160 (62%) were MP-L. Of the MP-L, 252 (22%) were MP-UL. There were no significant differences in the distribution of patient and tumor characteristics between the MP group and the rest of the B-42 cohort, except for HER2 status. ELT effect was more pronounced in the MP cohort than in the overall B-42 population. For DR, there was statistically significant ELT benefit in MP-L (HR = 0.43, 95% CI 0.25-0.74, p = 0.002), but not MP-H (HR = 0.65, 0.34-1.24, p = 0.19) (interaction p = 0.38). For DFS, there was statistically significant ELT benefit in MP-L, but not MP-H (interaction p = 0.015). Similar findings were observed for BCFI (interaction p = 0.006). Within subcategories of MP-L, there was statistically significant ELT benefit in MP-LNUL, but not in MP-UL for all three endpoints, however the power in MP-UL was limited due to low number of pts (Table). Clinical trial information: 00382070. Conclusions: Statistically significant ELT benefit was observed for MP-L, but not MP-H. The treatment by risk group interaction was not statistically significant for DR, but it was for DFS and BCFI. The benefit appears to be stronger in MP-LNUL than in MP-UL. NCT: 00382070. Support: U10CA180868, -180822, U24CA196067; Novartis; Agendia.[Table: see text]

Abstract PS9-10: Can composite risk model help clinicians make adjuvant ovary function suppression dicision for breast cancer patients

Abstract Background: Composite measure of recurrence risk with certain clinicopathologic characteristics provided prognostic and adjuvant ovarian function suppression (OFS) therapeutic effect information for patients in the TEXT and SOFT trials, but the role of this composite risk score (CRS) in OFS treatment decision-making has not been established. We carry out this study to evaluate the association of CRS with OFS treatment recommendation in our multidisciplinary team (MDT) treated patient cohort.Methods: Premenopausal patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer who received surgery between April 2013 and December 2018 and had OFS decision-making made by MDT were included. The association of CRS with OFS recommendation and survival outcome were analyzed.Results: Totally 887 patients were identified, amongst which 239 (26.94%) were recommended to receive OFS. The median CRS was 1.92, 455 (51.3%) patients were categorized as low-risk and 432 (48.7%) as high-risk. Age < 35 years (OR = 24.68, 95% CI 12.97-46.95, P < 0.001), ≥ 4 ALNs metastasis (OR = 3.95, 95% CI 2.08-7.48, P < 0.001), ER ≥ 50% (OR = 5.45, 95% CI 2.16-13.75, P < 0.001) and CRS high-risk (OR = 2.82, 95% CI 1.62-4.91, P < 0.001) were independently predictive of OFS recommendation. CRS also served as an effective predictor of OFS recommendation in receiver operating characteristics (ROC) curve analysis (AUC = 0.775, P < 0.001). CRS high-risk was related to worse breast cancer-free interval (BCFI) (89% vs. 97.6%, HR 8.98, 95% CI 2.73-29.51, P < 0.001), no significant differences in overall survival (OS) were found between patients with CRS high and low-risk (96.5% vs. 99.8%, HR 5.5, 95% CI 0.66-45.73, P = 0.076).Conclusions: CRS was associated with OFS recommendation and BCFI in premenopausal patients with HR positive/HER2 negative breast cancer, which may be integral to their individualized OFS treatment decision-making. Table 1. Clinicopathologic characteristics, CRS and OFS recommendationUnivariate analysisMultivariate analysischaracteristicsNo-OFS N = (%)OFS N = (%)P valueOR95% CIP valueAge (years)< 0.001< 0.001< 3521 (23.33)69 (76.67)24.6812.97-46.95< 0.00135-3940 (30.77)90 (69.23)22.8713.59-38.48< 0.001≥ 40587 (88.01)80 (11.99)1Histologic grade< 0.0010.054I84 (94.38)5 (5.62)1II409 (73.96)144 (26.04)3.691.28-10.650.016III155 (63.27)90 (36.73)3.481.11-10.860.032Tumor size0.0120.172≤ 2cm428 (75.89)136 (24.11)1> 2cm220 (68.11)103 (31.89)0.720.45-1.15ALN status< 0.001< 0.0010421 (80.04)105 (19.96)11-3171 (68.95)77 (31.05)1.91.14-3.170.014≥ 456 (49.56)57 (50.44)3.952.08-7.48< 0.001ER0.022< 0.001< 50%53 (85.48)9 (14.52)1> 50%595 (72.12)230 (27.88)5.452.16-13.75PR0.052< 50%202 (68.94)91 (31.06)≥ 50%446 (75.08)148 (24.92)Ki67< 0.0010.466< 14%270 (84.38)50 (15.63)114%-19%48 (70.59)20 (29.41)1.650.77-3.530.20220%-25%127 (73.84)45 (26.16)1.110.6-2.060.747≥ 26%203 (62.08)124 (37.92)1.430.8-2.560.231CRS< 0.001< 0.001≤ 1.92405 (89.01)50 (10.99)1> 1.92243 (56.25)189 (43.75)2.821.62-4.91 Table 2. ROC analysis for prediction of OFS recommendationcharacteristicsAUCP valueAge (years)0.109<0.001Histologic grade0.601<0.001Tumor size0.596<0.001ALN status0.624<0.001ER0.5140.53PR0.4420.008Ki670.622<0.001CRS0.775<0.001 Citation Format: Yue Liang, Xiaosong Chen, Weiqi Gao, Siji Zhu, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Li Zhu, Yafen Li, Weiguo Chen, Kunwei Shen. Can composite risk model help clinicians make adjuvant ovary function suppression dicision for breast cancer patients [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 PS9-10.

Abstract LB-103: The interaction between SNP genotype and aromatase inhibitor treatment response in early breast cancer

Abstract Purpose: To determine genetic variants that could differentiate aromatase inhibitors (AIs) efficacy in early stage breast cancer. Experimental Design: We performed a stratified cox-proportional hazards analysis utilizing stratification factors and other covariates examining Breast Cancer Free Interval (BCFI) SNP-treatment interaction in Caucasian patients entered on the MA.27 trial. This analysis involved 4465 patients (2226 on anastrozole and 2239 on exemestane arm) including 245 (121 on anastrozole and 124 events on exemestane arm) with a breast event. Preclinical laboratory studies included luciferase activity, chromatin immunoprecipitation (ChIP) assay, and cell migration assays. Results: We identified 887 SNPs with a p-value <1E-4 that could differentiate anastrozole from exemestane efficacy. We next used GTEx databases to determine whether these SNPs might be cis-eQTLs with nearby genes, and found that 95 SNPs were eQTL with 14 genes. Functional validation of SNP effect in these 14 genes on response to anastrozole and exemestane revealed that 3 SNPs showed genotype-dependent differences between anastrozole and exemestane. Two of the three SNPs, rs1877193 and rs6735923 located upstream of LY75 gene, were associated with higher LY75 gene expression. Our drug-SNP interaction GWAS showed that both SNPs were associated with better BCFI for exemestane compared to anastrozole (HR= 0.447, 0.458). The SNP rs62293499 located downstream of the GPR160 gene was also associated with better BCFI for exemestane compared to anastrozole (HR=0.433). Interestingly, all 3 SNPs were associated with worse outcome (shorter BCFI) in anastrozole treated patients (HR=1.39~1.58), but with longer BCFI in the exemestane treated patients (HR=0.58~0.71) based on our GWAS results in MA.27 trial. However, all 3 SNPs showed no association with BCFI if the two treatment arms, anastrozole and exemestane, were combined (HR=0.92~1.08). Consistently, cells with Ly75 or GPR160 SNP variant genotypes were more sensitive to exemestane compared to anastrozole. Mechanistically, the 3 SNPs regulated estrogen receptor-dependant LY75 and GPR160 expression. LY75 suppression induced epithelial-to-mesenchymal transition (EMT) in breast cancer cell lines, accompanied by increased migratory capacity in vitro. LY75 knockdown also resulted in predominant downregulation of functional pathways such as cell proliferation, while pathways associated with mesenchymal stimulation were generally increased. GPR160 knockdown also resulted in downregulation of cell proliferation pathways. Conclusions: This SNP genotype and AI treatment interaction clinical study revealed unique genetic variants that differentiate anastrozole and exemestane efficacy. The signals were lost in the GWAS analysis when anastrozole and exemestane were combined. Preclinical laboratory studies revealed novel functions of LY75 and GPR160 in breast cancer. These findings represent potential steps towards individualized AI therapy. Citation Format: Junmei Cairns, James N. Ingle, Krishna R. Kalari, Lois E. Shepherd, Matthew J. Ellis, Paul E. Goss, Poulami Barman, Erin E. Carlson, Matthew P. Goetz, Richard M. Weinshilboum, Liewei Wang. The interaction between SNP genotype and aromatase inhibitor treatment response in early breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-103.

Estimation of historical control rate for a single arm de-escalation study – Application to the POSITIVE trial

BackgroundAlthough randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context.MethodsPOSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants.ResultsCompared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed.ConclusionExternal control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.

Abstract B121: Pathologic characteristics of African American women with breast cancer treated at the DoD’s Murtha Cancer Center: Why survival cancer is not disparate to European American women when treated within the US military healthcare system

Abstract (AAW) are significantly higher than in European American women (EAW), including a 42% higher mortality detected in AAW in the SEER database and a worse breast cancer-free interval for AAW in The Cancer Genome Atlas. In contrast, survival analysis from women treated within the Department of Defense Military Healthcare System (DoD MHS) healthcare system found that AAW and EAW with early-stage breast cancer had similar survival rates. In this study, we evaluated pathological factors of AAW treated within the Murtha Cancer Center at Walter Reed National Military Medical Center to identify factors associated with this lack of disparate outcomes within the DoD MHS. Methods: Between 2001-2018, 346 AAW and 746 EAW treated at MCC/WRNMMC enrolled in the Clinical Breast Care Project(CBCP). All diagnoses were performed by a single breast pathologist and pathological characteristics including stage (AJCC Cancer Staging Manual seventh edition), grade, size, lymph node, hormone receptor and HER2 status were recorded. Data were analyzed using chi-square and log-rank analyses and Student t-tests with a P-value <0.05 used to define significance. Results: African American women comprised 29% of the women with invasive breast cancer in the CBCP. The average age at diagnosis was 56.1 years in AAW and 58 years in EAW and the frequency of women diagnosed <40 years of age did not differ significantly (9% AAW, 7% EAW). Tumor stage (P=0.004), grade (P<0.001), size (P<0.001), subtype (P<0.001) and lymph node status (P=0.028) all differed significantly between populations. Breast tumors from AAW were significantly less likely to be diagnosed at stage I compared toEAW (43% AAW, 55% EAW), and more likely to be lymph node positive (40% AAW, 33% EAW) and size T2 (34% AAW, 26% EAW). Biologically, AAW were more likely to have poorly differentiated (43% AAW, 28% EAW) and triple negative (24% AAW, 14% EAW) tumors. Seven percent of AAW and 6% of EAW died of disease with no significant difference in time to death (4.22 years AAW, 4.67 EAW). Neither 5-year nor 10-year survival differed significantly between populations. Conclusion: These data across all stages of breast cancer diagnosis support an earlier finding in early-stage patients that survival disparities, common in the general population, are not detected for AAW treated within the DoD MHS. Critically, this survival advantage for AAW treated at MCC/WRNMMC exists against a background of AAW having tumors with less favorable pathological characteristics, as seen in the US general population. Evaluation of pre- and post-diagnostic care within DoD MHS should be performed to determine how breast care within an equal-access healthcare setting is received by AAW patients and the DoD MHS can be used as a model of care to reduce breast cancer disparities within the US general population. Citation Format: Leann A Lovejoy, Craig D Shriver, Rachel E Ellsworth. Pathologic characteristics of African American women with breast cancer treated at the DoD’s Murtha Cancer Center: Why survival cancer is not disparate to European American women when treated within the US military healthcare system [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B121.

Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence.

TPS599 Background: Adagloxad simolenin (AS) is a therapeutic vaccine comprising the tumor-associated antigen Globo H linked to the carrier protein keyhole limpet hemocyanin (KLH). The KLH provides antigenic immune recognition and T-cell responses. AS is co-administered with a saponin-based adjuvant OBI-821 to induce a humoral response. A phase 2 trial showed that AS/OBI-821 exhibited a trend for superior progression-free survival vs placebo in patients whose breast cancers have higher Globo H expression. Methods: Patients with TNBC (ER/PR < 5%, and HER2-negative) with nonmetastatic disease and either 1) residual invasive disease of ≥1 cm in the breast or ≥1 positive axillary node following neoadjuvant chemotherapy or 2) ≥4 axillary lymph nodes with invasive carcinoma treated with adjuvant chemotherapy are included. Patients are prescreened for Globo H expression using a validated IHC assay (H-score of ≥15). Patients will receive either AS (30 μg) with OBI-821 (100 μg) or volume-matched placebo (1:1), administered as SC injections. Up to 21 SC injections of study treatment (or placebo), will be administered over 100 weeks, given on the following schedule: weekly for 4 doses; every 2 weeks for 4 doses; every 4 weeks for 4 doses; and then every 8 weeks for 9 doses. Patients may terminate treatment due to disease recurrence or unacceptable toxicity, withdrawal of consent, protocol violation, loss to follow-up or death. The primary objective is to determine the effect of AS/OBI-821 treatment on invasive disease-free survival in patients with TNBC at high risk for recurrence. Secondary objectives are to determine the impact of AS/OBI-821 treatment on overall survival, quality of life (QoL), breast cancer-free interval, distant disease-free survival, safety, and tolerability. Imaging and clinical examination will be performed regularly for 5 years. QoL will be assessed using the EORTC Core Quality of Life Questionnaire (QLQ)-C30 plus the EORTC Breast Cancer-specific QLQ-BR23 questionnaire and the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire. Adverse events will be graded/recorded as per National Cancer Institute CTCAE v5.0. An estimated 668 subjects will be enrolled, treated for up to 2 years and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last subject randomized. Survival follow-up is for 5 years from randomization of last subject. Clinical trial information: NTC03562637 .

Abstract GS4-01: Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole (L) in postmenopausal women with hormone-receptor+ breast cancer (BC) who have completed previous adjuvant therapy with an aromatase inhibitor (AI)

Abstract Background: In the NSABP B-42 trial we aimed to determine whether 5 yrs of letrozole (L) v placebo (P) improves DFS in patients (pts) who have completed 5 yrs of hormonal therapy (tx). 3966 postmenopausal pts with stage I-III, hormone-receptor+ BC, disease-free after 5 yrs of an AI or tamoxifen (TAM) for ≤3 years → AI for the remainder of 5 yrs, were randomized to L 2.5 mg or P daily for an additional 5 yrs. In the primary analyses the beneficial effect of extended tx with 5 yrs of L did not reach statistical significance on disease-free survival (DFS). There was no significant improvement in overall survival (OS) with L, but L did provide a significant improvement in breast-cancer-free interval (BCFI) and distant recurrence (DR). The updated results based on the data received as of April 30, 2019, are presented here. Methods: Stratification was by pathological nodal status, prior adjuvant TAM or not, and baseline dexa T scores (>-2.0, ≤-2.0 SD). Primary endpoint was DFS including local, regional, distant recurrence, second primary cancers, and deaths from any cause as first event. Secondary endpoints included OS, BCFI (including recurrence or contralateral BC as first event), DR, osteoporotic fractures (OF), and arterial thrombotic (AT) events. Differences in DFS, OS, BCFI, DR, OF, and AT between L and P were assessed by the stratified log-rank tests and Cox proportional hazards models. Statistical significance level was set at 0.05. Results: Median follow-up for 3923 pts included in the current analyses was 9.3 yrs. As of 4/30/19, 890 DFS events had occurred (L=411, P=479); L resulted in a statistically significant increase in DFS v P (HR=0.84; 95% CI 0.74, 0.96; p=0.011); 10-yr DFS was L=76.1% and P=72.1%. The effect of L was statistically significantly different for pts with baseline T score ≤-2.0 (HR=0.63; 95% CI 0.49, 0.82) v those with a score >-2.0 (HR=0.93; 95% CI 0.80, 1.09) (interaction p=0.013). 495 deaths occurred (L=243, P=252); there was no statistically significant difference in OS with L v P (HR=0.97, 95% CI 0.82, 1.16; p=0.77); 10-yr OS was L=86.1% and P=85.5%. 413 BCFI events occurred (L=178, P=235); L v P resulted in a statistically significant 26% decrease in BCFI events (HR=0.74, 95% CI 0.61, 0.91; p=0.003); 10-yr cumulative incidence (Cum In) of BCFI was L=10.3% v P=13.3%. 229 DRs occurred (L=96, P=133); L v P resulted in a statistically significant 29% reduction in DR (HR=0.71, 95% CI 0.55, 0.93; p=0.01); 10-yr Cum In of DR was L=5.7% v P=7.5%. There were 209 OF (L=109, P=100). There were no significant differences in time to OF with L v P (P=0.46). Cum In of OF through 10 yrs was L=6.5% v P=6.4%. There were 154 AT events (L=82, P=72). Treatment with L did not result in an overall statistically significant increase in AT events compared to P (p=0.38). Cum In of AT through 10 yrs was L=4.7% v P=4.1%. Conclusions: The effect of extended tx with 5 yrs of L on DFS persisted in the updated analyses and reached statistical significance. There was no significant improvement in OS with L, but L continued to provide a significant improvement in BCFI and DR. Support: U10CA180868, -180822; UG1CA189867; Korea Health Technology R&D Project; Novartis. Citation Format: Eleftherios P Mamounas, Hanna Bandos, Barry C Lembersky, Jeon Hyeon Jeong, Charles E Geyer, Jr, Priya Rastogi, Louis Fehrenbacher, Mark L Graham, Stephen K Chia, Adam M Brufsky, Janice M Walshe, Gamini S Soori, Shaker R Dakhil, Thomas E Seay, James L Wade, III, Edward C McCarron, Soonmyung Paik, Sandra M Swain, D Lawerence Wickerham, Norman Wolmark. Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole (L) in postmenopausal women with hormone-receptor+ breast cancer (BC) who have completed previous adjuvant therapy with an aromatase inhibitor (AI) [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 GS4-01.

Abstract P5-12-01: SOLE (study of letrozole extension), a phase 3 randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC): Final analysis and sole estrogen substudy (SOLE-EST)

Abstract Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. We hypothesized that the rise in estrogen levels during short treatment interruptions would resensitize breast cancer cells to letrozole and improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). We previously reported the primary endpoint after 60 mos median follow-up: extended intermittent letrozole did not improve DFS vs extended continuous letrozole. However, only 9% of pts had breast cancer events, justifying updating the analysis with longer follow-up. The dynamic of recovery of estrogen levels after stopping letrozole therapy has not been previously reported. Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomized to an additional 5 yrs continuous letrozole (2.5 mg daily; n=2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n=2443). We report the final analysis of the SOLE trial after 84 mos median follow-up. In SOLE-EST, levels of estradiol (E2), estrone (E1) and estrone sulphate (E1S) at 0, 9, 10.5 and 12 mos after randomization were determined using a highly sensitive assay in a subgroup of 90 evaluable patients (21 in the continuous and 69 in the intermittent group). Results: There were 923 DFS events. 7 yr DFS was 81.5% in both groups. More pts had distant metastases in the continuous group (8.7% vs 7.5%) while second (non-breast) malignancies were more frequent in the intermittent group (5.5% vs 4.7%). Similar outcomes were observed for breast cancer-free interval (BCFI) (88.6% vs 88.0%), distant recurrence-free interval (DRFI) (91.6% vs 90.4%), and overall survival (OS) (90.6% vs 89.6%) for pts assigned intermittent vs continuous letrozole. In the intermittent group, median E2, E1 and E1S levels more than doubled compared with levels at 9 mos after randomization in the first 6 weeks after stopping letrozole during the treatment free interval while levels were stable for the 21 pts tested in the continuous group. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. Similar outcome was consistently observed for BCFI, DRFI and OS. The SOLE-EST substudy indicates an important increase in estrogen levels as soon as 6 weeks after stopping letrozole therapy in the intermittent group. Further investigation of prior exposure to aromatase inhibitors in relation with outcome and with E2, E1 and E1S levels in SOLE-EST are underway. Citation Format: Guy Jerusalem, Subrina Farah, Jacquie Chirgwin, Stefan Aebi, Per Karlsson, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Seamus O'Reilly, Andrea Gombos, Thomas Ruhstaller, Harold Burstein, Manuela Rabaglio, Barbara Ruepp, Giuseppe Viale, Richard D Gelber, Alan S Coates, Angelo Di Leo, Aron Goldhirsch, Meredith Regan, Marco Colleoni. SOLE (study of letrozole extension), a phase 3 randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC): Final analysis and sole estrogen substudy (SOLE-EST) [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 P5-12-01.

Abstract OT1-08-03: Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence

Abstract Background: Adagloxad simolenin (AS) is an investigational immune stimulant comprising the Globo H hexasaccharide epitope linked to the carrier protein keyhole limpet hemocyanin (KLH). KLH facilitates a more vigorous immune response given the weak antigen, Globo H. Furthermore, AS is co-administered with the potent saponin-based adjuvant OBI-821 to induce a humoral response. A phase 2 trial examining the correlation between Globo H expression and clinical outcomes showed that patients with metastatic breast cancer whose tumors had an H-score of ≥15 (validated immunohistochemical [IHC] assay to determine Globo H expression; range 0-300) treated with AS/OBI-821 had a trend for superior progression-free survival vs placebo. As previously reported, Globo H is expressed similarly among both hormone receptor-positive and triple-negative breast cancer tumor subtypes. In an effort to improve outcomes in TNBC, we are conducting a randomized phase 3 trial in this high-risk population. Study Aim: The primary objective is to determine the effect of AS/OBI-821 on invasive disease recurrence and disease-free survival in patients with TNBC at high risk for recurrence. Secondary objectives are to determine the impact of AS/OBI-821 on overall survival, quality of life (QoL), breast cancer-free interval, distant disease recurrence and disease-free survival, safety, and tolerability. Methods. Eligible patients will have TNBC (estrogen receptor/progesterone receptor <5%; HER2-negative) with nonmetastatic disease and 1) either residual invasive disease ≥1 cm in breast or ≥1 positive axillary node following neoadjuvant chemotherapy; or 2) ≥4 axillary lymph nodes with invasive carcinoma treated with adjuvant chemotherapy. Tumors must express Globo H (H-score ≥15 by central laboratory analysis using a validated IHC assay). Eligible patients will receive either AS/OBI-821 or placebo (randomized 1:1), administered as subcutaneous (SC) injections in a double-blind manner. Up to 21 SC injections of study treatment (AS/OBI-821 given as 30 μg AS [OBI-822] in combination with 100 μg OBI-821) or placebo (volume-matched placebo with sucrose and trehalose), with either AS/OBI-821 or placebo will be administered over 100 weeks: weekly for 4 doses, every 2 weeks for 4 doses, every 4 weeks for 4 doses, and then every 8 weeks for 9 doses. All patients will be followed for invasive disease recurrence and overall survival for a maximum of 5 years after randomization. Patients will be followed every 26 weeks for disease recurrence during the follow-up period until a total of 187 endpoint events (either disease recurrence or death) are reached or the last patient has been followed for 3 years after randomization. Enrolled patients will undergo imaging (baseline, weeks 28, 52, 76, 104, 130, 156, 208, 260) and clinical examination every 3 months for 2 years and every 6 months thereafter. QOL will be assessed (weeks 1, 28, 52, 76, 104, 130, 156, 208, 260) using the EORTC QLQ-C30 plus additional EORTC QLQ-BR23 for breast cancer and European Quality of Life 5 Dimensions 5 Levels questionnaire. Adverse events will be graded/recorded by investigators as per National Cancer Institute CTCAE v5.0. Blood/tumor tissue samples will be collected for exploratory assessments during/after end of trial. Present and target accrual: Approximately 110 study centers across Europe, North America, and Asia-Pacific will enroll an estimated 668 patients. Patients will be treated for up to 2 years and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last patient randomized. Survival follow-up is for 5 years from randomization of last patient. Citation Format: Hope S Rugo, Louis WC Chow, Javier Cortes, Peter A Fasching, Binghe Xu, Chiun-Sheng Huang, Sung-Bae Kim, Yen-Shen Lu, Rita Nanda, Priyanka Sharma, Richard B Schwab, Chen-En Tsai. Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence [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 OT1-08-03.

Ki-67 assessment in early breast cancer: SAKK28/12 validation study on the IBCSG VIII and IBCSG IX cohort

The assessment of Ki-67 in early-stage breast cancer has become an important diagnostic tool in planning adjuvant therapy, particularly for the administration of additional chemotherapy to hormone-responsive patients. An accurate determination of the Ki-67 index is of the utmost importance; however, the reproducibility is currently unsatisfactory. In this study, we addressed the predictive/prognostic value of Ki-67 index assessed by using the most reproducible methods, which were identified in the pilot phase. Paraffin blocks obtained from patients with moderately differentiated, estrogen receptor (ER)-positive early-stage breast cancer in Switzerland, who were originally randomized to the treatment arms with and without chemotherapy in the IBCSG VIII-IX trials, were retrieved. Of these 344 randomized patients, we identified 158 patients (82 treated with and 76 treated without chemotherapy) for whom sufficient tumour tissue was available. The presence of Ki-67 was assessed visually by counting 2000 cells at the periphery (A) and estimating the number of positive cells in five different peripheral regions (C), which was determined to be the most reproducible method identified the pilot phase. The prognostic and predictive value was assessed by calculating the breast cancer-free interval (BCFI) and overall survival (OS) rate. Ki-67 was considered a numerical and categorical variable when different cut-off values were used (10%, 14%, 20% and 30%). An mRNA-based subtyping by using the MammaTyper kit with the application of a 20% Ki-67 immunohistochemistry (IHC) cut-off equivalent was also performed. 158 of 344 randomized patients could be included in the Ki-67 analysis. The mean Ki-67 values obtained by using the two methods differed (A: 21.32% and C: 16.07%). Ki-67 assessed by using method A with a cut-off of 10% was a predictive marker for OS, as the hazard ratio (>10% vs. <=10%) in patients with chemotherapy was 0.48 with a 95% confidence interval of [0.19–1.19]. Further, the HR of patients treated without chemotherapy was 3.72 with a 95% confidence interval of [1.16–11.96] (pinteraction=0.007). Higher Ki-67 index was not associated with outcome and using the 10% Ki-67 cut-off there was an opposite association for patients with and without chemotherapy. Ki-67 assessments with IHC significantly correlated with MammaTyper results (p=0.002). The exact counting method (A) performed via a light-microscope revealed the predictive value of Ki-67 assessment with a 10% cut-off value. Further analyses employing image analyses and/or mRNA-based-assessments in larger populations are warranted.