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PURPOSE We aimed to characterize long-term quality of life (QOL) trajectories among patients with breast cancer treated with adjuvant chemotherapy and to identify related patterns of health behaviors. METHODS Female stage I-III breast cancer patients receiving chemotherapy in CANTO (CANcer TOxicity; ClinicalTrials.gov identifier: NCT01993498 ) were included. Trajectories of QOL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–C30 Summary Score) and associations with trajectory group membership were identified by iterative estimations of group-based trajectory models and multivariable multinomial logistic regression, respectively. RESULTS Four trajectory groups were identified (N = 4,131): excellent (51.7%), very good (31.7%), deteriorating (10.0%), and poor (6.6%) QOL. The deteriorating trajectory group reported fairly good baseline QOL (mean [95% CI], 78.3/100 [76.2 to 80.5]), which significantly worsened at year-1 (58.1/100 [56.4 to 59.9]) and never recovered to pretreatment values through year-4 (61.1/100 [59.0 to 63.3]) postdiagnosis. Healthy behaviors were associated with better performing trajectory groups. Obesity (adjusted odds ratio [aOR] v lean, 1.51 [95% CI, 1.28 to 1.79]; P < .0001) and current smoking (aOR v never, 1.52 [95% CI, 1.27 to 1.82]; P < .0001) at diagnosis were associated with membership to the deteriorating group, which was also characterized by a higher prevalence of patients with excess body weight and insufficient physical activity through year-4 and by frequent exposure to tobacco smoking during chemotherapy. Additional factors associated with membership to the deteriorating group included younger age (aOR, 1-year decrement 1.01 [95% CI, 1.01 to 1.02]; P = .043), comorbidities (aOR v no, 1.22 [95% CI, 1.06 to 1.40]; P = .005), lower income (aOR v wealthier households, 1.21 [95% CI, 1.07 to 1.37]; P = .002), and endocrine therapy (aOR v no, 1.14 [95% CI, 1.01 to 1.30]; P = .047). CONCLUSION This latent-class analysis identified some patients with upfront poor QOL and a high-risk cluster with severe, persistent postchemotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of chemotherapy and preserve QOL, including early addressal of behavioral concerns and provision of healthy lifestyle support programs.

BACKGROUND: Regular physical activity is associated with improved symptom control in patients with breast cancer but its association with chemotherapy completion or response is unclear. METHODS: Using a prospective design, 1075 breast cancer patients receiving neoadjuvant chemotherapy between March 2012 and February 2017 were studied. Physical activity was assessed using the Global Physical Activity Questionnaire [GPAQ-16], quantified in standardised MET-h/wk. Chemotherapy completion was defined as the proportion of patients completing planned treatment course, requiring dose reduction, or requiring dose delay. Response was evaluated by pathologic complete response (pCR). Associations between physical activity and primary outcomes were assessed using multivariable logistic regression models. RESULTS: There was no differences between any chemotherapy completion outcome on the basis of physical activity classification. The percent of patients not completing planned treatment was 5.7% for ≦0.33 MET-h/wk, compared with 6.8% for 0.34–16.65 MET-h/wk, and 4.6% for ≥16.6 MET-h/wk (p = 0.52). No significant relationships were observed between physical activity dose classification and pCR for the overall cohort or upon stratification by clinical subtype. CONCLUSION: Future studies are required to further investigate the relationship between pre-treatment levels of physical activity and function on treatment completion and response in breast and other cancer populations. CLINICAL TRIAL REGISTRATION: NCT01993498.

Introduction: In HR+, HER2- ABC, activating PIK3CA mutations occur in ~40% of tumors and confer worse prognosis, including endocrine therapy (ET) resistance. BYLieve (NCT03056755) is an ongoing Phase II, open-label, 3-cohort noncomparative study, evaluating the PI3Kα inhibitor and degrader alpelisib (ALP) + ET (fulvestrant [FUL] or letrozole) in patients (pts) with PIK3CA-mutated, HR+, HER2- ABC progressing on/after prior treatment, including CDK4/6i + ET. This study is of high clinical relevance as ET + CDK4/6i is the recommended standard of care for first-line treatment of pts with HR+, HER2- ABC. In Cohort A, pts received CDK4/6i + AI as immediate prior therapy and received ALP + FUL as study treatment. In the primary analysis, the primary endpoint was met with 50.4% (95% confidence interval [CI], 41.2%-59.6%) of the 121 pts in the Cohort A modified full analysis set (mFAS) alive and without disease progression at 6 mo. Median progression-free survival (mPFS) and overall survival (mOS) were 7.3 mo (95% CI, 5.6-8.3) and 17.3 mo (95% CI, 17.2-20.7), respectively. The most frequent grade ≥3 adverse events (AEs) in the 127 pts in the Cohort A safety set were hyperglycemia (28%), rash (9%), and rash maculopapular (9%). This analysis focuses on updated efficacy and safety endpoints reflective of all pts achieving ~18-mo follow-up. Methods: Pts in Cohort A received ≥1 dose of ALP 300 mg orally QD + FUL 500 mg intramuscular Q28D + C1D15. For the 18-mo follow-up, efficacy endpoints, including PFS, OS, overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR) in pts with complete or partial response, and PFS on next line of treatment (PFS2), will be analyzed on the mFAS, which includes pts with a centrally confirmed PIK3CA mutation in tumor tissue. Safety of ALP + FUL, including AEs and laboratory toxicities, will be evaluated in the safety set, which includes all pts who received ≥1 dose of study treatment. Results: Of the 127 pts enrolled in Cohort A and part of the safety set, 121 were included in the mFAS. We will present efficacy endpoint results from the pts in Cohort A along with the long-term safety profile of the ALP + FUL combination. Conclusion: These data will provide insights on the long-term efficacy and safety of ALP + FUL. This combination is currently approved and used, in the clinical setting, for the treatment of pts with HR+, HER2- PIK3CA-mutated ABC. Citation Format: Eva M Ciruelos, Florence Lerebours, Hope S Rugo, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Patrick Neven, Yeon Hee Park, Nicholas Turner, Dejan Juric, Ennan Gu, Christina H Arce, Murat Akdere, Stephen Chia. Alpelisib + fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + aromatase inhibitor (AI): 18-month follow-up of BYLieve Cohort A [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 P1-18-03.

Introduction: PIK3CA (encoding phosphatidylinositol 3-kinase alpha [PI3Kα]) is a driver oncogene mutated (mut) in ~40% of HR+, HER2- ABCs, leading to endocrine therapy (ET) resistance and poor prognosis. Alpelisib (ALP) is the first oral α-selective PI3K inhibitor and degrader approved in this patient (pt) population. Primary analyses of Cohorts A and B from BYLieve, an ongoing Phase II noncomparative study, demonstrated efficacy and a consistent safety profile of ALP + ET (fulvestrant [FUL] or letrozole [LET]) in pts with PIK3CA-mut, HR+, HER2- ABC in the post CDK4/6i setting. Post hoc analyses of ALP benefit in pts with centrally confirmed PIK3CA mut, based on median duration of prior CDK4/6i, supported the efficacy of ALP + ET in CDK4/6i-resistant, HR+, HER2- ABC. Here we assessed whether those who achieved a short duration of disease control (6-month [mo] cutoff), with prior CDK4/6i + ET received clinical benefit with ALP + ET. Methods: In Cohorts A and B, pts with PIK3CA-mut, HR+, HER2- ABC had received CDK4/6i + aromatase inhibitor (AI) or FUL, respectively, as immediate prior therapy (majority in first line). Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided based on duration of prior CDK4/6i therapy (≤6 mo or >6 mo), and the association of progression-free survival (PFS) with this covariate was analyzed using a stratified log-rank test and Cox Proportional Hazards model. A 6-mo cutoff was selected based on the ESO-ESMO ABC5 cutoff for primary ET resistance, as current guidelines do not specify cutoffs for CDK4/6i resistance. This analysis is based on the PFS endpoint and included pts for whom duration of prior CDK4/6i therapy was known. Results: Of the 121 pts in Cohort A with centrally confirmed PIK3CA-mut disease (modified full analysis set, mFAS), 120 had duration of prior CDK4/6i available; 26 had CDK4/6i for ≤6 mo and 94 for >6 mo, with similar demographics/disease characteristics between subgroups. The hazard ratio (HR) of median PFS (mPFS) between the ≤6-mo group and >6-mo group was 0.50 (95% confidence interval [CI], 0.27-0.94), indicating a lower risk of progression in the ≤6-mo group, with mPFS 10.0 mo (95% CI, 5.55-not estimable) and 6.0 mo (95% CI, 5.16-8.31), respectively. Grade ≥3 adverse events (AEs) were experienced by 67.5% (n=85) of all pts (safety set) in Cohort A and by 76.9% (n=20)/65.0% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Of the 115 pts in Cohort B with centrally confirmed PIK3CA-mut disease (mFAS), 113 had duration of prior CDK4/6i available; 31 had CDK4/6i for ≤6 mo and 82 for >6 mo, with similar demographics/disease characteristics between subgroups. The HR of mPFS between the ≤6-mo and >6-mo groups was 0.76 (95% CI, 0.47-1.23), with the wide CI indicating no difference in risk of progression between subgroups, and mPFS was 5.9 mo (95% CI, 3.55-10.97) and 5.6 mo (95% CI, 3.68-7.10), respectively. Grade ≥3 AEs were experienced by 69.9% (n=86) of all pts (safety set) in Cohort B and by 63.6% (n=21)/72.2% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Conclusions: This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with >6-mo duration of disease control, with a comparable safety profile. This confirms targeting PI3Kα with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy. Citation Format: Stephen Chia, Eva M Ciruelos, Hope S Rugo, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Nicholas Turner, Ennan Gu, Christina Arce, Murat Akdere, Dejan Juric. Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or >6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve [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 P1-18-08.

Introduction: Alpelisib (ALP, a PI3Kα inhibitor and degrader) + ET has demonstrated efficacy in patients (pts) with HR+, HER2-, PIK3CA-mutated ABC progressing on/after CDK4/6i + ET in the ongoing Phase II BYLieve study (NCT03056755). The primary endpoint, in pts with centrally confirmed PIK3CA mutation in tumor tissue (modified full analysis set [mFAS]), was met in Cohorts A (ALP + fulvestrant [FUL]) and B (ALP + letrozole [LET]) with 50.4% (95% CI, 41.2%-59.6%) of 121 pts and 46.1% (36.8%-55.6%) of 115 pts alive and without disease progression at 6 mo, respectively. Activating PIK3CA mutations, occurring in ~40% of tumors, confer worse prognosis in the advanced setting. Here, we assess the correlation between progression-free survival (PFS) and other baseline biomarkers among pts in BYLieve Cohorts A and B. Methods: Enrolled pre-/postmenopausal women with HR+, HER2-, PIK3CA-mutated ABC received CDK4/6i + aromatase inhibitor (Cohort A) or FUL (Cohort B), as immediate prior treatment (Tx). Pts received ALP 300 mg PO QD + FUL 500 mg IM Q28D and C1D15 (Cohort A) or ALP 300 mg PO QD + LET 2.5 mg PO QD (Cohort B) as study Tx. This exploratory analysis of baseline biomarkers identified gene alterations using an error-connected sequencing ctDNA assay (Novartis PanCancer gene-panel) in plasma samples from pts with a centrally confirmed PIK3CA mutation in tumor tissue from Cohorts A and B. PFS was estimated using the Kaplan-Meier method in subgroups of pts based on high (≥10%) or low ( Table 1.mPFS in pts from BYLieve Cohorts A and B based on baseline biomarker statusCohort A (ALP + FUL)Cohort B (ALP + LET)nmPFS, mo (95% CI) nmPFS, mo (95% CI)Overall (mFASa)1,21217.3 (5.6-8.3)1155.7 (4.5-7.2)Patients with available plasma sample for the biomarker analysisb1027.37 (5.60-8.67)975.70 (3.77-7.33)ctDNA fractionHigh (≥10%)655.60 (4.00-7.37)685.43 (3.70-7.20)Low ( Citation Format: Dejan Juric, Nicholas Turner, Aleix Prat, Stephen Chia, Eva M Ciruelos, Manuel Ruiz-Borrego, Pamela Drullinsky, Florence Lerebours, Thomas Bachelot, O. Alejandro Balbin, Mukta Joshi, Estelle Roux, Christina H Arce, Murat Akdere, Hope S Rugo. Alpelisib + endocrine therapy (ET) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i): Biomarker analyses from the Phase II BYLieve study [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 P5-13-03.

BACKGROUND: With an increased lifespan, survivorship has become a crucial component of breast cancer (BC) care. Among survivorship concerns, adequate contraception counseling is needed in premenopausal patients (pts) not seeking to become pregnant. However, very limited evidence exists on attitudes and factors influencing contraception use over time in premenopausal women with early BC. METHODS: CANTO is a multicenter, prospective cohort study of 12,012 pts with stage I-III BC (NCT01993498). This analysis included women aged ≤50 years with known premenopausal status at BC diagnosis. Contraception use and type were longitudinally evaluated at diagnosis, year-1 (T1) and 2 (T2) after diagnosis. Multivariable logistic regression models assessed associations between clinical, socio-economic, treatment, toxicity (CTCAE) and pts-reported outcome (PROs, EORTC QLQ-C30/BR23) variables, with contraception use after diagnosis. RESULTS: Among 2,900 pts included, mean age at diagnosis was 43.1 (SD 5.6) years, 96.0% of pts already had children at BC diagnosis, 70.8% and 80.0% received chemotherapy and endocrine therapy (ET), respectively. Among patients treated with ET, 80.2% received tamoxifen alone and 19.8% other therapies (either tamoxifen or an aromatase inhibitor or a combination) plus ovarian function suppression (OFS). Following diagnosis, 45.0% of pts at T1 and 65.7% at T2 reported consulting a gynecologist. At diagnosis, 54.2% of pts reported contraception use, with the majority (62.6%) using hormonal methods. Prevalence of contraception use significantly decreased at T1 and T2 (38.9% and 41.2%, respectively; ptrend Citation Format: Matteo Lambertini, Claudia Massarotti, Julie Havas, Barbara Pistilli, Anne-Laure Martin, Alexandra Jacquet, Charles Coutant, Florence Coussy, Asma Dhaini Merimeche, Florence Lerebours, Olivier Tredan, Christelle Jouannaud, Olivier Rigal, Marion Fournier, Patrick Soulie, Maria Alice Franzoi, Lucia Del Mastro, Ann H. Partridge, Fabrice Andre, Ines Vaz-Luis, Antonio Di Meglio. Attitudes and factors influencing contraception use over time in premenopausal women with early breast cancer in the prospective CANTO study [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 P4-11-20.

BACKGROUND: The use of two anti-HER2 monoclonal antibodies (mAbs) (pertuzumab and trastuzumab) combined with taxanes is the standard of care for first line treatment in HER2-positive metastatic breast cancer (mBC). Infusion related reactions (IRR) during first administration of anti-HER2 mAb have been reported. Reintroduction of the causal drugs is often possible, but there is no data to identify patients at highest risk of developing IRR and modalities of safe reintroduction. The aim of this study was to report patients who experienced IRR during anti-HER2 mAbs infusions at Institut Curie Hospitals (ICH) and to describe these reactions. METHODS: All IRR cases must be reported to the ICH pharmacies. We retrospectively inspected the electronic record of patients who experienced an IRR during pertuzumab (Pmab) and trastuzumab (Tmab). We collected patients’ characteristics, grade of IRR and outcomes. RESULTS: From January 2013 to December 2020, a total of 223 patients had at least one Pmab+Tmab infusion as part of their BC treatment. Among them, 28 patients (8%) with anti-HER2 mAb IRR were identified. All patients but one had an HER2-positive BC; the HER2-negative case was a HER3-mutant mBC. Twelve patients (43%) had de novo mBC. Twenty-six patients (93%) received Pmab+Tmab as first line treatment for mBC. Ten patients were previously exposed to Tmab and three to Pmab+Tmab for (neo)adjuvant treatment. At IRR onset, 21 patients (75%) had liver metastasis, with more than five liver metastases for 19 of them. Fifteen patients (55%) had liver enzymes upper normal limit. IRR occurred during first anti-HER2-mAb infusion in 22 patients (79%) despite pre-treatment with antihistaminic and/or glucosteroids for taxanes. The other IRR were reported at the 2nd, 5th, 6th, 8th and > 10th cycle of Pmab+Tmab. Sixteen IRR (57%) were attributed to Pmab infusion, 9 (32%) to Tmab infusion and 3 (11%) to Tmab and/or Pmab. Al IRR were declared to the pharmacovigilance agency. Majority of reactions were mild to moderate (54% of grade 2). Most frequent symptoms associated with IRR were: thrills (68%), hyperthermia (64%); low oxygen saturation (36%), pain (25%), hypotension (21%), cutaneous (18%) and digestive (18%) reaction. Three patients were transferred to ICU. One death was attributed to anti-HER2 mAb IRR (death was attributed to respiratory distress during the first Tmab infusion). Reintroduction off Pmab+Tmab was performed in 18 patients, after pre-treatment with antihistaminic and/or glucosteroids and with vital function monitoring in conventional hospitalization. No recurrence of IRR was observed in 15/18 patients. For the 3 patients with recurrent IRR, symptoms were mild to moderate. Objective response to anti-HER2 treatments was observed in twenty three patients (82%; 8 complete responses; 15 partial responses). Median PFS was 16 months. CONCLUSIONS: Most anti-Her2-mAb IRR occurs during first infusion, are mild to moderate and do not require a transfer in ICU. Our study suggests that patients with high liver burden might be over-represented among those experiencing an IRR. Reintroduction of Pmab+Tmab was safe in most patients, allowing the continuation of the anti-HER2 dual blockade. Citation Format: Delphine Loirat, Juliette Logeart, Pauline Vaflard, Aurélien Noret, Mathilde Saint-Ghislain, Edith Borcoman, Audrey Hurgon, Cyrille Cros, Thomas Genevee, Audrey Bellesoeur, Francesco Ricci, Florence Lerebours, Laurence Escalup, Marie-Paule Sablin, François-Clément Bidard, Paul H. Cottu, Jean-Yves Pierga. Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective study [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 P2-13-27.

Abstract. Long-term adherence to adjuvant endocrine therapy (ET, tamoxifen and aromatase inhibitors) is paramount for patients with early-stage breast cancer. Adherence to adjuvant endocrine therapy is hampered by numerous side effects associated with sustained estrogen deprivation. We aimed to describe recent real-world patterns of therapy, patients’ discontinuations of ET, toxicities, quality of life (QoL) and to develop a predictive model of early ET discontinuation. Methods. We used the first 9595 patients of the French CANTO cohort (NCT01993498), to evaluate among 6238 premenopausal and postmenopausal patients with HR+/HER2- stage I-III BC, who were prescribed adjuvant ET: a. treatment patterns of adjuvant ET including change of ET prescription during the follow-up course b. ET-associated toxicities and c. impact on QoL. Independent variables included medical history and toxicities as measured by : Common Toxicity Criteria Adverse Events (CTCAE) v4, Patient-Reported Outcomes (PROs) including European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30) and Breast Cancer Module (BR23), and Hospital Anxiety and Depression Scale (HADS). Treatment discontinuation and treatment change were determined on the basis of patient’s declaration and medical decisions reported in the CANTO eCRF. We used patient data at 4 months from therapy initiation to train and evaluate on a held-out test set a machine-learning model (gradient-boosted trees) that is predictive of time to early discontinuation i.e. permanent discontinuation before four years of additional therapy. Results. 4052 post-menopausal patients and 2186 premenopausal patients were included in this analysis. Median follow-up after ET initiation is 3 years and 2 months. 86% of post-menopausal patients were prescribed a non-steroidal AI initially and 92% of premenopausal patients received tamoxifen first. Discontinuation rate of the first adjuvant endocrine therapy at 1 year was 14% and 10% in premenopausal and post-menopausal patients, respectively. Among 741 post-menopausal and 340 premenopausal patients who started a second ET, discontinuation of the second prescribed adjuvant ET at 1 additional year of therapy is 30% in both populations. Patients who switched from a first adjuvant ET to a second or further one continued to have more treatment-related toxicities and associated decrements in QoL. Exclusions due to data completeness and outcome definition led to 5331 patients being used for the model (4264 in the training set and 1067 in the validation set). In that population, the permanent discontinuation rate at 3 years is 6%. Our prediction model of time to early discontinuation obtains a C-index of 0.78 in the held-out validation set. Conclusion. Tolerability and continued adherence to ET remains a challenge for many patients. Early discontinuation models may assist in identifying patients who are likely to interrupt their adjuvant ET. Adapted clinical management, including robust support and management of toxicities, as well as new and more tolerable adjuvant endocrine therapies may improve the clinical outcomes of these patients. Citation Format: Felix Balazard, Aurélie Bertaut, Élise Bordet, Stéphane Mulard, Julie Blanc, Nathalie Briot, Gautier Paux, Asma Dhaini Merimeche, Olivier Rigal, Charles Coutant, Marion Fournier, Christelle Jouannaud, Patrick Soulie, Florence Lerebours, Paul-Henri Cottu, Olivier Tredan, Laurence Vanlemmens, Christelle Levy, Marie-Ange Mouret-Reynier, Mario Campone, Keri J. S. Brady, Medha Sasane, Megan Rice, Catherine Coulouvrat, Anne-Laure Martin, Alexandra Jacquet, Ines Vaz-Luis, Christina Herold, Barbara Pistilli. Patterns of adjuvant endocrine therapy, discontinuations, toxicities and quality of life: Development of a model for early discontinuation using the CANTO cohort [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 P1-13-08.

Supplementary Table 11

Table S6

Supplementary Table 1 from Molecular Profiling of Inflammatory Breast Cancer

Supplementary Data from DNA Methylation Markers Predict Outcome in Node-Positive, Estrogen Receptor-Positive Breast Cancer with Adjuvant Anthracycline-Based Chemotherapy

Purpose:High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.Experimental Design:We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.Results:Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (PInteraction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = −0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02–1.06; P = 0.001), but not in luminal tumors or TNBCs (PInteraction = 0.04).Conclusions:The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.

Purpose: Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. The molecular mechanisms responsible for IBC are largely unknown.Experimental Design: To obtain further insight into the molecular pathogenesis of IBC, we used real-time quantitative reverse transcription (RT)-PCR to quantify the mRNA expression of 538 selected genes in IBC relative to non-IBC.Results: Twenty-seven (5.0%) of the 538 genes were significantly up-regulated in IBC compared with non-IBC. None were down-regulated. The 27 up-regulated genes mainly encoded transcription factors (JUN, EGR1, JUNB, FOS, FOSB, MYCN, and SNAIL1), growth factors (VEGF, DTR/HB-EGF, IGFBP7, IL6, ANGPT2, EREG, CCL3/MIP1A, and CCL5/RANTES) and growth factor receptors (TBXA2R, TNFRSF10A/TRAILR1, and ROBO2). We also identified a gene expression profile, based on MYCN, EREG, and SHH, which discriminated subgroups of IBC patients with good, intermediate, and poor outcome.Conclusion: Our study has identified a limited number of signaling pathways that require inappropriate activation for IBC development. Some of the up-regulated genes identified here could offer useful diagnostic or prognostic markers and could form the basis of novel therapeutic strategies.

supplementary material

Background SOLAR-1 and BYLIEVE trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP). Patients and methods: The French EAP was opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant, managed per standard of care. Primary endpoint was PFS by local investigators using RECIST1.1. Results Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1–16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95%CI, 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95%CI, 37.8–52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age 5 lines of prior treatments (HR = 1.4, 95%CI = 1.0–2.0) and the C420R PI3KCA mutation (HR = 4.1, 95%CI = 1.3–13.6). Most frequent grade 3/4 adverse events (AEs) were hyperglycemia, rash, fatigue and diarrhea occurring in 11.6, 9.9, 4.3 and 3% of patients, respectively. N = 91 (39.1%) patients discontinued alpelisib due to AEs. Discussion To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant. PFS was not overtly impaired by a prior use of either everolimus or fulvestrant. No new safety signal was found.

Introduction: Alpelisib (ALP), an inhibitor and degrader of phosphatidylinositol-3-kinase α (PI3Kα), + fulvestrant (FUL) demonstrated efficacy in PIK3CA-mutated, HR+, HER2- ABC in the phase 3 SOLAR-1 trial, which included only 20 patients (pts) with prior CDK4/6 inhibitor (CDKi) in the PIK3CA-mutated cohort. BYLieve (NCT03056755), a phase 2, open-label, 3-cohort noncomparative study, evaluates ALP + endocrine therapy (ET; FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC, progressing on/after prior therapies, including CDKi + ET. Cohorts A and B were restricted to pts receiving CDKi + (aromatase inhibitor [AI] or FUL), respectively, as immediate prior therapy, but Cohort C included pts whose cancer progressed on/after AI (in adjuvant or metastatic setting), and who received chemotherapy (CT; any line), or ET (FUL or LET monotherapy or with targeted therapy, including CDKi + FUL, but not CDKi + AI) as immediate prior treatment. Cohorts A and B demonstrated efficacy and safety of ALP + ET after prior CDKi. Here, we report primary results and biomarker analyses from Cohort C.. Methods: Pts in Cohort C received ALP 300 mg orally QD + FUL 500 mg intramuscular Q28D + C1D15. The primary endpoint was assessed in each cohort separately and is the proportion of pts with centrally confirmed PIK3CA mutation alive and without disease progression at 6 mo per local assessment; 95% CIs are calculated using Clopper and Pearson (1934) exact method. The 95% CI lower bound of the primary endpoint >30% is clinically meaningful evidence of treatment effect. In an exploratory analysis of baseline biomarkers using ctDNA, progression-free survival (PFS) was estimated in pt subgroups per high (≥10%) or low ( Citation Format: Hope S Rugo, Patrick Neven, Isabel Saffie, Yeon Hee Park, Michelino De Laurentiis, Florence Lerebours, Eva Maria Ciruelos, Nicholas Turner, Dejan Juric, Ennan Gu, Christina H Arce, Mukta Joshi, Estelle Roux, Murat Akdere, Stephen Chia. Alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+, HER2— advanced breast cancer (ABC) who received chemotherapy or endocrine therapy (ET) as immediate prior treatment: BYLieve Cohort C primary results and exploratory biomarker analyses [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 PD13-05.

BackgroundUsing the large nationwide French, national, multicenter, prospective cancer and toxicities (CANTO) cohort, we assessed cognitive functioning change after cancer treatments in a subgroup of breast cancer (BC) patients.MethodsWe included patients with newly diagnosed invasive stage I-III BC enrolled in the CANTO substudy focused on cognitive evaluation and healthy control women matched for age and education. Episodic and working memory, executive functions, processing speed, attention, self-report cognitive difficulties (SRCD), fatigue, anxiety and depression were assessed with neuropsychological tests and self-report questionnaires before treatment (baseline) and approximately 1 (year 1) and 2 years (year 2) after diagnosis. We used linear mixed models to study changes in cognition and tested the effect of adjuvant chemotherapy.ResultsWe studied 276 localized BC patients (62% chemotherapy) compared with 135 healthy controls (HC). After adjustment, patients had lower baseline working memory, processing speed, and attention scores than HC (P ≤ .001), and the difference remained statistically significant over follow-up for working memory and processing speed. Executive function scores were similar between groups at baseline but decreased at year 1 among patients compared with HC (Pchange = .006). This decrease in chemotherapy patients was statistically significant compared with HC scores (Pchange ConclusionsCognitive difficulties are an important concern in BC patients, starting at diagnosis. Cancer treatments induce executive function decline and SRCD, which decrease over follow-up.

We assessed long-term associations of Granulocyte-Colony Stimulating Factors (G-CSF) use with patient-reported outcomes (PROs) and hematologic toxicity among chemotherapy-treated, early-stage breast cancer patients in CANTO (NCT01993498). Among 2920 patients longitudinally followed-up until year-4 after diagnosis, 49% used G-CSF. In multivariable-adjusted mixed-models, EORTC QLQ-C30 pain and summary score were not substantially different between groups (overall adjusted mean difference, use vs no-use [95%CI]: +1.27 [-0.33 to +2.87] and −1.01 [-1.98 to −0.04], respectively). PROs were slightly worse at year-4 among patients receiving G-CSF, although differences were of trivial clinical significance. No major differences were observed in leukocyte or platelet count over time., Highlights • Studies on long-term side effects of G-CSF, including on quality of life, are lacking. • We evaluated PROs and hematological values until year-4 after diagnosis among women with early breast cancer receiving G-CSF. • 49% women treated with adjuvant chemotherapy in CANTO (N = 2920) used G-CSF. • Long-term PROs and hematological values were not substantially different in women using G-CSF or not. • There were slightly worse outcomes at year-4 in patients using G-CSF, although of trivial clinical significance.

Genomic tests can guide the decision to administer adjuvant chemotherapy in women with hormone receptor (HR)-positive, Human Epidermal growth Factor 2 (HER2)-negative breast cancer (BC) at intermediate risk of recurrence. We assessed the decision-making and economic impact of the Prosigna test in a real-life setting. Retrospective cohort study of HR + , HER2- BC patients managed from 2016 to 2020, potential candidates for adjuvant chemotherapy, at intermediate risk of recurrence, in whom a Prosigna test was performed according to contemporary guidelines. The additional cost of chemotherapy over one year in terms of direct medical and non-medical costs was estimated in this study to be €9,737 (derived from a previous study, NCT02813317). The cost of the Prosigna test, as defined by the reimbursement system, was €1,849. Among the 809 patients included in this study, 2.3 Prosigna tests had to be performed to avoid adjuvant chemotherapy for one patient. The number of tests that had to be performed to avoid chemotherapy for one patient was higher for patients with grade 3 tumors and pN1mic axillary node involvement and lower for grade 1 tumors or in the absence of axillary node involvement (pN0), but did not vary according to the 10-year overall survival gain predicted by the Predict online test. The cost saving related to withholding of adjuvant chemotherapy for one patient on the basis of the Prosigna test results was €5,485. We present one of the largest cohorts of HR + , HER2- BC patients at intermediate risk of recurrence, in whom a Prosigna test was used to guide the adjuvant therapy decision in a real-life setting, resulting in a 44% decrease in the indication for chemotherapy.

Summary Background Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. Methods This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov , NCT03056755 . Findings Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5–15·9). 61 (50·4%; 95% CI 41·2–59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. Interpretation BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Funding Novartis Pharmaceuticals.

Background Current international expert guidelines in the 1st line setting for HR+/HER2- ABC recommend endocrine therapy plus a CDK4/6 inhibitor unless there is a visceral crisis. However, due to a lack of sequencing data, recommendations for further treatment lines are not clear-cut. In this context, treatment decisions are often based on response to first line treatment, aggressiveness of the disease and clinical expertise. Evidence-based medicine should inform decisions. This study aims to estimate the weight of beliefs and habits in therapeutic strategy choices. Methods This observational survey « Chemotherapy : beliefs and habits » was conducted among a representative sample of French oncologists with a breast cancer activity in private and public hospitals. The survey was conducted between November 2019 and January 2020. Oncologists were asked about their knowledge, perception and practice regarding the treatment of HR+/HER2- ABC patients. A focus was made on their perception of best available external clinical evidence leading to guidelines. Results 119 physicians answered the survey. They agreed that in absence of visceral crisis the first line treatment of HR+/HER2- metastatic breast cancer should be endocrine therapy plus a CDK4/6 inhibitor (98,3%). First line endocrine therapy was believed to be associated with a higher progression-free survival benefit (79%) and overall survival benefit (75%) compared to chemotherapy. Even in case of primary or secondary endocrine resistance, oncologists remained in favor of using an endocrine-based therapy at first line in 82% and 66% of cases respectively. The visceral crisis concept was presented through clinical cases. In a life-threatening situation, 10% of physicians maintained their choice of 1rst line endocrine therapy plus a CDK4/6 inhibitor. The oncologists were asked to choose the determinants of treatment choices (patient’s preferences, efficacy, safety, quality of life). Oncologists valued patients’ preference and quality of life with increasing treatment lines while clinical efficacy as measured by survival data were less and less guiding in their choice of treatment. Conclusion Evidence-based medicine is the integration of best research evidence with clinical expertise and patient values. It is a useful framework held as a standard in therapeutic strategy. However, beliefs and habits play an important role in the choice of treatment for HR+/HER2- ABC beyond the first treatment line. Clinical trials are needed in this setting to determine the best sequence of treatments. A comprehensive analysis of the survey results will be presented at the meeting. Citation Format: Julien Peron, Sylvie Giacchetti, Ophélie Cassuto, Tullia Deverge, Charlotte Bouyssou, Jean-Marc Ferrero, Elisabeth Luporsi, Florence Lerebours. Impact of oncologists’ beliefs and habits on treatment decisions in hormone receptor positive (HR+)/ HER2 negative advanced breast cancer (ABC) [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 PS13-48.

Background: Triple negative breast cancer (TNBC) is an heterogeneous disease and encompasses at least 4 subtypes. One of these expresses the androgen receptor (AR). Several prospective trials demonstrated antitumour efficacy with anti-androgen treatment in patients with advanced breast cancer. Darolutamide is an androgen-receptor antagonist with a potent anti-tumour efficacy in metastatic prostate cancer with a favorable safety profile. We conducted a randomized non-comparative phase II trial to study the efficacy and tolerability of darolutamide and capecitabine in AR-positive TNBC (NCT03383679). Material and methods: Patients (Pts) with a metastatic, centrally reviewed, AR-positive (≥ 10% by immunohistochemistry) and TNBC who have received a maximum of one line of chemotherapy for advanced disease were eligible. They were randomised in a 2:1 ratio to receive darolutamide (D arm) 600 mg twice daily or capecitabine (C arm) at 1000 mg/m² twice daily 2 weeks on and 1-week off, until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of pts presenting a complete response (CR), partial response (PR), or stable disease (SD) at 16 weeks. Main secondary endpoints included objective response rate, overall survival, progression-free survival and safety. An interim statistical analysis was planned when 19 assessable pts will be available in the D arm. According to an optimal 2-stage Simon’s design,if Results: Out of 133 pts screened and centrally analyzed, from 37 centres, 54% (72/133) were AR-positive. 45 pts were randomized (29 in D arm and 16 in C arm) from April 2018 to December 2019. In arm D, median age was 60 years (range 47-88). and 13.8 % received a first line of chemotherapy for metastatic disease. A total of 19 pts were eligible and assessable for the primary endpoint in D arm. 5 CBR were confirmed at 16 weeks (26.3%; 95% CI: 9.2%-51.2 %) including 1 confirmed PR and 4 SD. In arm D, fatigue (23.8%), ASAT increased (23.8%), and blood alkaline phosphatase increased (23.8%) were the most common drug-related adverse events; the majority of them being grade 1 or 2. 6 pts presented with drug-related serious adverse events: one in D arm and 5 in C arm. Conclusions: According to the planned interim analysis, the efficacy objective is met (5 CBR) in D arm. Moreover, darolutamide is well tolerated. Thus, patients are now recruited in the second stage. Keywords: Androgen receptor,triple-negative breast cancer, darolutamide, advanced breast cancer Citation Format: Hervé Bonnefoi, Florence Lerebours, Olivier Tredan, Florence Dalenc, Christelle Levy, Mahasti Saghatchian, Marie Ange Mouret Reynier, Delphine Mollon, Severine Guiu, Laurence Venat Bouvet, Elisabeth Carola, Geraldine Martineau, Marina Pulido, Gaetan MacGrogan, Anthony Goncalves. First efficacy results of a 2-stage Simon’s design randomised phase 2 of darolutamide or capecitabine in patients with triple-negative, androgen receptor positive advanced breast cancer (UCBG06-3) [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 PS12-05.

Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [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 PD2-07.

Graphical abstract, Introduction Inflammatory Breast Cancer (IBC) is the most aggressive form of breast carcinoma characterized by rapid onset of inflammatory signs and its molecular fingerprint has not yet been elucidated. Objectives The objective of this study was to detect both gene expression levels and alternate RNA splice variants specific for IBC. Methods W e performed splice-sensitive array profiling using Affymetrix Exon Array and quantitative RT-PCR analyses in 177 IBC compared to 183 non-IBC. We also assessed the prognostic value of the identified candidate genes and splice variants. Results A 5-splice signature (HSPA8, RPL10, RPL4, DIDO1 and EVL) was able to distinguish IBC from non-IBC tumors (p

International audience; Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expectancy.Objective: To identify and characterize distinct longitudinal patterns of depressive symptoms in patients with BC from diagnosis to 3 years after treatment.Design, settings, and participants: The CANTO-DEePRESS (Deeper in the Understanding and Prevention of Depression in Breast Cancer Patients) cohort study included women in the French multicenter CANTO (CANcer TOxicities) cohort study (conducted between March 20, 2012 and December 11, 2018), who were 18 years or older with invasive stage I to III BC and no previous BC treatment. The study aimed to characterize toxicities over a 5-year period following stage I to III primary BC treatment. Assessments of depressive symptoms were performed on a subset of patients with available data at diagnosis and at least 2 other time points. All data were extracted from the CANTO database on October 1, 2020.Main outcomes and measures: The primary outcome was the level of depressive symptoms at each assessment time point measured with the Hospital Anxiety and Depression Scale and depression subscale at BC diagnosis and at 3 to 6, 12, and 36 months after the end of treatment. The group-based trajectory modeling was used to identify trajectory groups, and multinomial logistic regression models were used to characterize the following factors associated with trajectory group affiliation: demographic, socioeconomic, clinical, lifestyle, and quality-of-life data.Results: A total of 4803 women (mean [SD] age, 56.2 [11.2] years; 2441 patients [50.8%] with stage I BC) were included in the study. Six trajectory groups that described the heterogeneity in the expression of depressive symptoms were identified: noncases with no expression of symptoms (n = 2634 [54.8%]), intermediate worsening (1076 [22.4%]), intermediate improvement (480 [10.0%]), remission (261 [5.4%]), delayed occurrence (200 [4.2%]), and stable depression (152 [3.2%]). HADS-D scores at diagnosis were consistently associated with the 5 depressive trajectory group affiliations, with an estimated higher probability per point increase of experiencing subthreshold or clinically significant depressive symptoms between diagnosis and the 3 years after the end of BC treatment. The higher probabilities ranged from 1.49 (95% CI, 1.43-1.54) for the intermediate worsening group to 10.53 (95% CI, 8.84-12.55) for the stable depression group. Trajectory groups with depressive symptoms differed from the noncases group without symptoms by demographic and clinical factors, such as having dependent children, lower household income, cancer stage, family history of BC, previous psychiatric hospitalizations, obesity, smoking status, higher levels of fatigue, and depression at diagnosis.Conclusions and relevance: In this cohort study, nearly a third of patients with BC experienced temporary or lasting significant depressive symptoms during and after treatment. Improving early identification of women at risk of developing long-term or delayed depression is therefore critical to increase quality of life and overall survival. Subjected to validation, this study is an important first step toward personalized care of patients with BC at risk of depression.