Background

Air pollution, classified as carcinogenic to humans, is a major public health concern. Studies on breast cancer are scarce and remain inconsistent. We studied the association between breast cancer risk and long-term exposure to particulate matters (PM_2.5, PM₁₀) and nitrogen dioxide (NO₂) estimated at the womens' residential and workplace addresses.

Methods

We conducted a case-control study of 2419 cases and 2984 individually matched controls nested in the French prospective E3N cohort, over the period 1990-2011. Controls were matched to cases on department of residence, age (±1 year); date (±3 months), and menopausal status at blood collection. Annual mean PM_2.5, PM₁₀ and NO₂ concentration levels were estimated using a Land Use Regression (LUR) model (resolution 50m x 50m) and were assigned to women based on their geocoded residential and workplace addresses. The mean exposure was calculated for each woman from their inclusion into the E3N cohort to their index date (date of diagnosis of cases). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariate logistic regression models, for a 10 μg/m³ increase in PM_2.5, PM₁₀ and NO₂. Adjustment variables were selected from the literature, using a directed acyclic graph.

Results

The results showed a statistically significant linear increase in breast cancer risk related to mean exposure to PM_2.5 (adjusted OR 1.28; CI 1.00–1.63, for an increment of 10 μg/m³). A numerically increased risk was observed for PM₁₀ (adjusted OR1.09; CI 0.92–1.30) and NO₂ (adjusted OR 1.05; CI 0.97–1.13) for an increment of 10 μg/m³. No effect modification by menopausal status was observed (p interaction 0.99, 0.90, and 0.86 respectively for PM_2.5PM₁₀ and NO₂). Analyses by hormone receptor status showed a positive but not significant association for PM_2.5 for oestrogen receptor positive (ER+) breast cancer cases (adjusted OR 1.32; CI 0.97–1.79).

Conclusions

To our knowledge, this study is the first to investigate breast cancer risk associated with long term air pollution exposure at both, the subjects’ residence and workplace, estimated using a very fine spatial resolution LUR model. Future studies should consider exposure during commuting.

Legal entity responsible for the study

INSERM.

Funding

ARC Foundation for Cancer Research (CANCAIR201601245), ANSES, French League against Cancer, Fondation de France.

Disclosure

All authors have declared no conflicts of interest.

Background

Despite benefits of physical activity (PA) during breast cancer (BC) treatments, successful exercise strategies in routine BC care remain to be determined. The primary objective was to assess the efficacy of two 6-month PA interventions: connected PA program and therapeutic patient education (TPE), concomitant to adjuvant treatments.

Methods

DISCO was a 2x2 factorial, multicenter, phase III, randomized controlled trial. Women with a localized invasive BC and eligible for any adjuvant treatment, were randomized in 1 of the 4 groups: web-based connected device (adaptative program of 2 walking and 1 muscle strengthening sessions/week in autonomy + a connected activity wristband); TPE (2 sessions); combination of both interventions; usual care. All patients received PA recommendations. Assessments (baseline, 6&12 months) included physical fitness, body composition and questionnaires. The primary endpoint was the proportion of patients who reached PA recommendations at 6 months based on the Recent Physical Activity Questionnaire, in each intervention compared to patients who did not receive it. Statistical analyses were performed in the ITT population.

Results

From 2018 to 2021, 436 patients were randomized: 108 patients received the connected device, 108 the TPE program, 110 both interventions, and 110 usual care. At baseline, 66% of patients reached PA recommendations. During the 6-month intervention, 96% of patients wore the connected device, the median number of PA sessions was 45 and 80% of patients attended the TPE program. Overall, 89,3% of patients who received the connected device reached PA recommendations at 6 months vs. 89,4% of patients without the device and 91,9% of patients who benefits from TPE reached PA recommendations vs. 87% of patients without TPE. For the primary endpoint, no statistically significant difference was found for both interventions.

Conclusions

The findings provide new information on the efficacy of innovative interventions to practice PA during routine BC treatment. The 6-month major increase of PA, independently of patient group allocation, highlights the importance of providing PA recommendations and PA assessment to BC patients.

Clinical trial identification

NCT03529383; release date: 05/17/2018.

Legal entity responsible for the study

Centre Léon Bérard.

Funding

Fondation ARC and the French National Cancer Institute (grant no. PREV201601260); Foundation for Medical Research (grant no. DOC20161136212); “Métropole de Lyon / Cancéropôle Lyon Auvergne Rhône-Alpes” (grant no. 2016 Projet Structurant) and AG2R La Mondiale.

Disclosure

T. Bachelot: Financial Interests, Personal, Financially compensated role: Seagen, Pfizer, AstraZeneca/Daiichi Sankyo, Novartis, Lilly; Financial Interests, Institutional, Research Grant: Seagen, Pfizer, AstraZeneca/Daiichi Sankyo, Novartis; Non-Financial Interests, Personal, Advisory Board: Pfizer. J. Blay: Financial Interests, Institutional, Coordinating PI: LYRICAN; Financial Interests, Institutional, Leadership Role: Institut Convergence, Euracan (european commission). All other authors have declared no conflicts of interest.

Background

The relationships between body mass index (BMI) and survival outcomes are complex, and have not been thoroughly investigated in breast cancer patients who received adjuvant chemotherapy.

Methods

We collected data on 2394 patients from two randomized, phase III clinical trials that investigated adjuvant chemotherapy in breast cancer identified in Project Data Sphere. The objective was to examine the effect of baseline BMI, BMI after adjuvant chemotherapy, and BMI change from baseline to post-adjuvant chemotherapy on disease-free survival (DFS) and overall survival (OS). Restricted cubic splines, adjusting for confounding factors, were used to examine potential non-linear associations between continuous BMI value and survival. Stratified analyses involved chemotherapy regimens used.

Results

On multivariate analysis, severe obesity (BMI≥40.0 kg/m²) at baseline was independently associated with worse DFS (HR=1.48, 95%CI 1.02-2.16, P=0.04) and OS (HR=1.79, 95%CI 1.17-2.74, P=0.007) compared with underweight/normal weight (BMI≤24.9 kg/m²). A BMI loss >10% was also an independent prognostic factor for adverse OS (HR=2.14, 95%CI 1.17-3.93, P=0.014). When stratified by chemotherapy regimens, the multivariate analysis revealed that severe obesity adversely affected DFS (HR=2.38, 95%CI 1.26-4.34, P=0.007) and OS (HR=2.90, 95%CI 1.46-5.76, P=0.002) in the docetaxel-based group, but not in the non-docetaxel-based group. Restricted cubic splines revealed a “J-shaped” association of baseline BMI with risk of recurrence (P for non-linearity=0.111) or all-cause death (P for non-linearity=0.008), and this relationship was more pronounced in the docetaxel-based group (DFS: P for non-linearity=0.011; OS: P for non-linearity <0.001).

Conclusions

In early breast cancer patients treated with adjuvant chemotherapy, baseline severe obesity was lined to worse DFS and OS, while a BMI loss over 10% from baseline to post-adjuvant chemotherapy also negatively affected OS. Moreover, the prognostic role of BMI might differ between docetaxel-based and non-docetaxel-based groups.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The monarchE trial demonstrated that the addition of abemaciclib to endocrine therapy (ET) significantly improved invasive disease-free survival (IDFS) and distant relapse-free survival in node-positive, high-risk EBC patients (pts) with benefit deepening beyond the 2-year (yr) treatment (tx) period. Ki-67 ≥20% was prognostic of breast cancer outcomes but not predictive of abemaciclib benefit. Here, we evaluate expression of ER, PR and Ki-67 to determine their prognostic and predictive impact, including analyses as continuous variables.

Methods

ER/PR and Ki-67 expression was determined by immunohistochemistry (IHC). The graphical Subpopulation (subp) Tx Effect Pattern Plot (STEPP) analysis was conducted for each biomarker to robustly assess the tx effect ensuring a balance between subp sample size and enough number of overlapping subp. Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ER/PR status subtypes (positive ≥1%).

Results

Each IHC cohort varied slightly in number of pts and the precise IDFS HR point estimate (abemacilib+ET vs ET), but STEPP analysis revealed consistent abemaciclib tx benefit regardless of ER, PR or Ki-67 expression (Table, A). The IDFS benefit of abemaciclib was also consistent in ER+/PR+ and ER+/PR- tumors (Table, B). The 3-yr IDFS rates of the control arm showed that pts with PR- tumors had a higher risk of recurrence. Pts with ER- tumors followed a similar trend, but the effect could not be robustly estimated due to small numbers. Table: 240MO

Summary of STEPP and IDFS analysis

Conclusions

Consistent IDFS benefit of adjuvant abemaciclib was observed regardless of the level of ER, PR or Ki-67 expression, as well as in ER+/PR+ and ER+/PR- tumors. Similar to Ki-67 ≥20%, PR- status was prognostic of worse outcomes with ET alone.

Clinical trial identification

NCT03155997.

Editorial acknowledgement

Monique Mendonca, employee of Eli Lilly and Company, provided medical writing support and editorial assistance.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

M.P. Goetz: Financial Interests, Institutional, Advisory Board: ARC Therapeutics, Biotheranostics, Blueprint Medicines, Rna Diagnostics, Sanofi Genzyme; Financial Interests, Institutional, Other, Consulting: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Other, General Consulting: Lilly; Financial Interests, Personal, Invited Speaker, CME Activity: Research to Practice, Clinical Education Alliance, Medscape, MJH Life Sciences; Financial Interests, Personal, Invited Speaker, CME Panel Discussant: Total Health Conferencing; Financial Interests, Personal, Other, Moderator for CME Activity: Curio Science; Financial Interests, Institutional, Local PI: Lilly, Pfizer, LOXO, ATOSSA Therapeutics, AstraZeneca, Sermonix. N. Turner: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Novartis, Pfizer, Roche/Genentech, GSK, Zentalis pharmaceuticals, Repare therapeutics, GSK, Relay therapeutics, Gilead, Inivata, Guardant, Exact Sciences; Financial Interests, Institutional, Funding: AstraZeneca, Pfizer, Roche/Genentech, Merck Sharpe and Dohme, Invitae, Inivata, Personalis, Natera; Financial Interests, Institutional, Other, provision of materials: BioRad; Financial Interests, Institutional, Other, Provision of assays: Guardant Health. H. Sasano: Financial Interests, Personal, Full or part-time Employment: Tohoku University . C. Arteaga: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Eli Lilly, Merck, AstraZeneca, Daiichi Sankyo, TAIHO Oncology, PUMA Biotechnology, Immunomedics, OrigiMed, Sanofi; Financial Interests, Personal, Research Funding: Pfizer, Pfizer, Takeda. S. Chandarlapaty: Financial Interests, Personal, Advisory Board, Consultant: Novartis, Boxer Capital, Totus Medicines, Nuvalent, Inivata, Neogenomics; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Advisory Board, Consultant: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Officer: Odyssey Biosciences; Financial Interests, Personal, Stocks/Shares: Odyssey Biosciences. S. Loi: Financial Interests, Institutional, Advisory Board, Consultant: Aduro Biotech, Novartis, GSK, Roche Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Pfizer, Seattle Genetics; Financial Interests, Institutional, Advisory Board, COnsultant: PUMA Biotechnologies, BMS; Financial Interests, Institutional, Advisory Board, consultant: Gilead Therapeutics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly; Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, PUMA Biotechnology, Eli Lilly, Roche - Genentech, Nektar Therapeutics, AstraZeneca, Seattle Genetics; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Roche Genentech; Non-Financial Interests, Advisory Role, consultant (not compensated): Pfizer, Eli Lilly, Gilead Therapeutics. J.S. Reis-Filho: Financial Interests, Personal, Other, Consultant: Goldman Sachs, Eli Lilly, Saga Diagnostics; Financial Interests, Personal, Other, Member of the Scientific Advisory Board and Consultant: Repare Therapeutics, Paige.AI; Financial Interests, Personal, Advisory Board: Personalis, Roche Tissue Diagnostics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: Bain Capital; Financial Interests, Personal, Advisory Board, Ad hoc member of the Pathology Scientific Advisory Board: Daiichi Sankyo, Merck; Financial Interests, Personal, Advisory Board, Ad hoc member of the Oncology Scientific Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board, Member of the SAB: MultiplexDX; Financial Interests, Personal, Member of Board of Directors: Odyssey Bio, Grupo Oncoclinicas; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics; Financial Interests, Personal, Other, Stock options: Paige.AI. H. Kreipe: Financial Interests, Personal, Other, Payment or honoraria for lectures: Roche Pharma, Novartis, Genomic Health, AstraZeneca, Eli Lilly, Pfizer, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Roche Pharma, Genomic Health, AstraZeneca. N. Harbeck: Financial Interests, Personal, Speaker’s Bureau, Fees for Non-CME Services Received Directly from Commercial Interest or their Agents: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, MSD, Novartis, Pfizer, Pierre Fabre, Seagen; Financial Interests, Personal, Advisory Board, Consulting Fees: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Seagen; Financial Interests, Personal, Sponsor/Funding, Fees for Non-CME Services Received Directly from Commercial Interest or their Agents: Roche; Financial Interests, Personal, Research Funding, Contracted Research: Roche; Financial Interests, Personal, Writing Engagement, Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions: Roche; Financial Interests, Personal, Stocks or ownership: WSG. P. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Local PI: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. C.S. Rubenstein: Financial Interests, Institutional, Full or part-time Employment: Loxo at Lilly. S. Wijayawardana: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. M. Muñoz: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. L.M. Litchfield: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. S.R.D. Johnston: Financial Interests, Personal, Advisory Board, Consulting Fees: AstraZeneca, Eli Lilly and Company, Pfizer, Biotechnology, Novartis, Sanofi Genzyme, Puma Biotechnology; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Pfizer, Eisai, Roche/Genentech.

Background

The NATALEE trial demonstrated a statistically significant iDFS benefit with RIB + NSAI vs NSAI alone in a broad population of pts with stage II or III HR+/HER2− EBC at risk of recurrence (Slamon D, et al. ASCO 2023. Oral LBA500). Evaluating iDFS outcomes in clinically relevant subgroups is important for understanding treatment (tx) benefit in specific pts. Here we present a prespecified exploratory subgroup analysis of iDFS in pts enrolled in NATALEE.

Methods

Pts with HR+/HER2− EBC were randomized 1:1 to RIB for 3 y (400 mg/d for 3 wk on/1 wk off) + NSAI for ≥5 y (letrozole 2.5 mg/d or anastrozole 1 mg/d) or NSAI alone. Premenopausal women and men received goserelin every 28 d. NATALEE included pts with anatomical stage IIA (N0 requiring additional risk factors or N1 [1-3 axillary lymph nodes]) and all pts with stage IIB or III disease per AJCC’s Cancer Staging Manual (8th ed). iDFS was evaluated by Kaplan-Meier methods. iDFS analysis was performed according to anatomical stage, menopausal status, nodal status, age, and Ki-67 score (locally tested). This prespecified analysis was not powered for statistical significance.

Results

A total of 5101 pts were included in this analysis (data cutoff: 11 Jan 2023; median follow-up for iDFS, 27.7 mo in both arms). Overall, the iDFS benefit with RIB + NSAI vs NSAI alone was consistent across all clinically relevant subgroups (Table), which in turn was consistent with that observed in the overall trial population.

Conclusions

The iDFS benefit with RIB + NSAI was generally consistent with that in the intent-to-treat population of NATALEE and was not driven by any particular subgroup. The results further support RIB + NSAI as a new tx of choice in a broad population of pts with HR+/HER2− EBC. Table: LBA23

Clinical trial identification

NCT03701334.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Casey Nielsen of MediTechMedia.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

A. Bardia: Financial Interests, Institutional, Research Grant: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Mersana, Innocrin; Financial Interests, Personal and Institutional, Advisory Board: Biothernostics Inc.; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Biothernostics Inc.; Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma, Puma; Financial Interests, Personal, Steering Committee Member: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics; Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma, Puma; Financial Interests, Personal, Other, Travel support: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho, Sanofi. G.N. Hortobagyi: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Steering Committee Member: Novartis. N.P. McAndrew: Financial Interests, Institutional, Funding: Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Daiichi Sankyo, AstraZeneca, GoodRx; Financial Interests, Personal, Advisory Board: Novartis, Daiichi Sankyo, Biotheranostics, Genomic Health; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Institutional, Funding, Contracted research funding paid to my institution: Daiichi Sanyko, Seattle Genetics, Dizal; Financial Interests, Personal, Other, Travel accommodation: TRIO, Daiichi Sankyo, Roche. J. Sohn: Financial Interests, Institutional, Research Grant: MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, GSK, Daiichi Sankyo, Sanofi, Boehringer Ingelheim; Financial Interests, Institutional, Funding: MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, GSK, Daiichi Sankyo, Sanofi, Boehringer Ingelheim; Other, Personal, Stocks/Shares, Stock/Immediate family member: Daiichi Sankyo. L. Hart: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Speaker’s Bureau: Novartis. S. Im: Financial Interests, Institutional, Research Grant: AstraZeneca, Daewoong Pharm; Financial Interests, Personal, Advisory Board: AstraZeneca, Hanmi, Pfizer; Financial Interests, Institutional, Advisory Board: Novartis; Non-Financial Interests, Personal, Other, Travel support: Novartis; Financial Interests, Personal, Advisory Role: Eisai, Amgen, Roche, Lilly, GSK, MSD. N. Harbeck: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Roche, Sandoz/Hexal, Gilead, Seagen; Financial Interests, Personal, Other, Lectures: Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, MSD, Pierre-Fabre, Roche, Gilead, Seagen; Non-Financial Interests, Personal, Leadership Role, Co-Director WSG: West German Study Group. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunome, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, Sanofi. B. Xu: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, Lectures: AstraZeneca, Pfizer, Roche, Eisai. C.H. Barrios: Financial Interests, Institutional, Research Grant: Pfizer, Pharma Mar, Polyphor, Henlius Biotech, Shanghai, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Squibb, BioMarin, Astellas Pharma, AbbVie, Merck (MSD), Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GSK, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, Amgen, Pfizer; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, MSD, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, GSK, Daiichi Sankyo; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, MSD, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, GSK, Daiichi Sankyo; Financial Interests, Personal, Stocks or ownership: MedSIR, Thummi. R. Moroose: Financial Interests, Personal, Speaker’s Bureau: Gilead, Lilly, Pfizer, Seattle Genentics, Genentech; Financial Interests, Personal, Speaker, Consultant, Advisor: J&J. V. Gonzalez: Other, Institutional, Other, Translational Research In Oncology is contracted by Novartis as CRO conducting the NATALEE trial.: Novartis. R. Fresco: Other, Institutional, Other, TRIO is contracted by Novartis as CRO conducting the NATALEE trial: Novartis. F. Ghaznawi: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks or ownership: Novartis. S. Waters: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. A. Chakravartty: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. D. Slamon: Financial Interests, Personal, Member of Board of Directors: Biomarin; Financial Interests, Personal, Stocks or ownership: Biomarin, Pfizer, Amgen, Seattle Genetics, 1200 Pharma, TORL BioTherapeutics; Financial Interests, Personal, Other, Travel expenses: Biomarin, Pfizer, Novartis; Financial Interests, Institutional, Research Funding: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Novartis; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: Eli Lilly; Financial Interests, Personal, Leadership Role, Founder: 1200 Pharma, TORL BioTherapeutics. All other authors have declared no conflicts of interest.

Background

Estrogen receptor-low (ER-low) Her2-negative breast cancer has similar pathological and molecular characteristics as triple-negative breast cancer (TNBC), and it is questionable whether it should be considered a separate entity. When the international guidelines lowered the cutoffs for ER to ≥1% in 2010, the ≥10% threshold was kept in Sweden. ER-low breast cancer (ER 1-9%) has thus in Sweden been treated as TNBC, which is interesting now that the international community recognize limited data for benefit of endocrine therapy in the ER-low group The benefit of endocrine therapy in these tumors is under debate and discussion. We aimed to describe real-world patient and tumor characteristics, treatment patterns and overall survival in a Swedish population-based cohort of patients with HER2 negative/ ER zero and ER low breast cancer treated as TNBC.

Methods

TNBC cases diagnosed in Sweden 2008-2020 were included in a population-based cohort study. Patient, tumour and treatment characteristics were analysed by ER status (ER-negative 0% vs ER-low 1-9%), and associations between subgroups compared using χ² test. Endpoints were overall survival (OS) and distant disease-free survival (DDFS). Kaplan-Meier curves were used to describe time-to-event endpoints and Cox proportional hazards models to estimate adjusted hazard ratios.

Results

Of the 5657 tumors, 90.1% were ER-negative and 9.9% ER-low. In the unadjusted analysis of OS, ER-low disease was associated with a borderline significantly better OS than ER-negative disease (n=3893, HR 0.83 (0.70-1.001), p=0.051), but this was restricted to patients not given chemotherapy (n=1764, HR 0.65 (0.50-0.88), p=0.002). ER-status 0% vs 1-9% did not affect OS in the multivariable analysis (HR 1.09, 95% CI 0.89-1.34). DDFS did not differ by ER-status 0% vs 1-9% (n=1299, HR 0.97 for ER-negative vs ER-low (0.62-1.53)). After preoperative treatment, the importance of pCR for OS did not significantly differ between ER-negative or ER-low disease.

Conclusions

ER-low breast cancer has characteristics and prognosis similar to ER-negative breast cancer when treated as TNBC. The use of ≥10% as threshold for ER positivity is supported by this study.

Legal entity responsible for the study

Karolinska Institutet.

Funding

MSD.

Disclosure

I. Fredriksson: Other, Institutional, Coordinating PI: MSD. J. Hartman: Financial Interests, Personal, Full or part-time Employment: Stratipath. D. Sönmez: Financial Interests, Personal, Full or part-time Employment: MSD. H. Lindman: Other, Institutional, Invited Speaker: MSD. All other authors have declared no conflicts of interest.

Background

Oncotype DX represents one of the genomic assays associated with the highest quality of evidence driving a strong recommendation for its use to guide decisions on adjuvant therapy for HR+/HER2- early BC patients. The clinical value of TILs in HR+/HER2- BC may be unearthed by focusing on patients whose tumors exhibit features of higher biological aggressiveness. Here we deepen and describe the correlation between RS and TILs, proposing an immuno-genomic model for HR+/HER2- BC.

Methods

We enrolled T1-T3, N0-N1 BC patients with available RS and TILs in the context of four multicenter, prospective studies primarily aimed at assessing the impact of the Oncotype DX® test on adjuvant treatment decisions in a clinical practice scenario. RS was categorized into: 0-10 (low risk), 11-25 (intermediate risk) and 26-100 (high risk); TILs were categorized into: low (0-10%), intermediate (11-59%) and high (60-100%).

Results

811 patients were included. RS distribution was (n=810): low risk 22.0%, intermediate risk 61.2%, high risk 16.8%. TIL distribution was (n=455): low TILs 84.6%, intermediate TILs 13.6% and high TILs 1.8%. A significant, weak positive, linear correlation was found between continuous TILs and RS (Pearson coefficient=0.223, p<0.001). When considering RS and TILs categories, tumors with intermediate/high TIL levels significantly enriched the high RS subgroup (p=0.006). This was confirmed both within Luminal A (Ki67<20% and PgR ≥20%) and Luminal B cohorts (ki67≥20% and/or PgR <20%). Among high-RS patients, 16.7% of Luminal A and 26.7% of Luminal B tumors had intermediate/high TILs.

Conclusions

We observed that RS and TILs capture only slightly overlapping information on the biology of HR+/HER2- tumor microenvironment. We demonstrated the feasibility of combining RS and TILs into a composite immuno-genomic model, which may identify patients simultaneously showing features of high biological/clinical risk and enhanced immunogenicity and may serve the purpose of guiding and focalizing patient selection in the further development of immunotherapy strategies for Luminal-like disease.

Legal entity responsible for the study

The authors.

Funding

Fondazione AIRC under 5 per mille 2019 - ID. 22759 program to VG and IG20583 to EB; Institutional funds from UniPD (FM, MVD, VG).

Disclosure

F. Miglietta: Financial Interests, Personal, Speaker, Consultant, Advisor, outside the submitted work: Roche, Novartis, Gilead, Pfizer, Seagen. M.V. Dieci: Financial Interests, Personal, Invited Speaker: Eli Lilly, Exact sciences, Gilead, Seagen, Daiichi Sankyo, Novartis; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Exact Science, Daiichi Sankyo, Gilead; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Personal, Other, Consultancy on educational project: Roche. T. Giarratano: Financial Interests, Personal, Speaker, Consultant, Advisor, outside the submitted work: Roche. E. Bria: Financial Interests, Personal, Advisory Board: AZ, Roche, BMS, MSD, Eli-Lilly, Amgen, Pfizer, Novartis; Financial Interests, Personal, Invited Speaker: AZ, Roche, BMS, MSD, Eli-Lilly, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: AZ, Roche. A. Zambelli: Financial Interests, Personal, Advisory Board, outside the submitted work: Pfizer, Roche, Novartis, Lilly, Daiichi Sankyo, Seagen, AstraZeneca, MSD, ExactSciences. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. All other authors have declared no conflicts of interest.

Background

Several analyses have shown prognostic impact of clinical and IHC markers in addition to genomic signatures in HR+/HER2 EBC. However, it remains unclear whether histology (e.g. invasive lobular BC (ILC) or further factors provide additional information. We present outcome from the prospective WSG-ADAPT HR+/HER- trial combining both static and dynamic biomarkers to optimize adjuvant therapy in luminal EBC.

Methods

pN0-1 with clinically high-risk HR+/HER2- EBC pts with RS0-11 OR RS12-25/Ki67_{postendocrine}≤10% after 3 +/- of preoperative ET received ET alone; the remaining high-risk cohort was randomized to the CT trial. Prognostic scores containing clinical factors with and w/out mutational/copy number data were derived retrospectively after splitting the data into training- and validation sets. LASSO and cross validation methods were used to predict iDFS in therapy subgroups. Additionally, multivariate Cox models were adapted using a forward-backward selection approach to identify prognostic markers.

Results

4491 pts were included (n=2246 ET- and n=2245 CT-treated). In the whole set, tumor and nodal (T/N) stage, RS and PR expression were prognostic for iDFS (Cox model). In ET-treated pts, only T-stage, RS and ER expression by RT-pCR were significant by Cox analysis, but prognostic score could not be determined. In CT-treated patients, T/N stage, G2-3 vs. G1, RS, ILC, and PR expression, but not IHC4 entered the model. In the CT cohort, a prognostic score consisting of T/N stage, age (≤50, >50), RS, ILC, PR expression and baseline and post-ET Ki67 yields a ROC AUC of 66% in the validation set. ILC was associated with lower RS than IDC (RS>25: 5.62% vs. 19.37%).High-risk CT-treated ILC had more frequently ERBB2 (11.6% vs. 2.5%) and a lower frequency of CDH1 mutations (60.5% vs 70.7%). Only CCND1 amplification was associated with worse iDFS in the NGS sub-cohort (n=584).

Conclusions

Use of RS in combination with further clinical and genetic factors improves prognostic ability; however, there is no treatment-independent prognostic model for HR+ HER2- EBC pts. For the first time, we have shown worse prognosis of the ILC high-risk subgroup, associated with distinct biological features.

Clinical trial identification

NCT01779206.

Legal entity responsible for the study

West German Study Group.

Funding

Exact Science.

Disclosure

O. Gluz: Financial Interests, Personal, Advisory Board: Roche, Lilly, Amgen, Novartis, Pierre Fabre, MSD, Celgene, Pfizer, Gilead, Molecular Health, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Science; Financial Interests, Institutional, Coordinating PI: Roche, LIlly; Non-Financial Interests, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Proprietary Information: West German Study Group. U.A. Nitz: Financial Interests, Personal, Advisory Board: Exact Science. S. Kummel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Seagen. Pfizer, pfm Medical, Roche, Somatex, Gilead. M. Braun: Financial Interests, Personal, Advisory Board: AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva. B. Aktas: Financial Interests, Personal, Advisory Board: Pfizer, Roche Pharma, Merck Sharp & Dohme, onkowissen.de, Novartis Pharma, AstraZeneca, PharmaMar, Lilly, promedicis. R.F.L. Baehner: Financial Interests, Personal, Full or part-time Employment: Exact Science. M. Graeser: Financial Interests, Personal, Advisory Board: AstraZeneca. R. Würstlein: Financial Interests, Personal, Advisory Board: Agendia, Amgen, Apogheva, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Nanostring, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sanofi Genzyme, Seagen, Stemline, Clinsol; Financial Interests, Personal, Invited Speaker: Aristo, Clovis Oncology, Eisai, Palleos, PINK, FOMF, Aurikamed, Pomme Med, medconcept, MCI; Financial Interests, Personal, Writing Engagement: Hexal; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Coordinating PI: WSG, PINK; Financial Interests, Institutional, Local PI: BKFZ; Non-Financial Interests, Advisory Role: PINK, Brustkrebs Deutschland e.V., Junge Erwachsene Mit Krebs, AGO Kommission Mamma, AGSMO, DKG, TZM, CCC München, Mammamia. H. Kreipe: Financial Interests, Personal, Advisory Board: Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, Pfizer. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. All other authors have declared no conflicts of interest.

Background

Neoadjuvant systemic therapy (NST) for triple-negative breast cancer (TNBC) and HER2+ breast cancer (HER2+BC) yields a pathol-ogic complete response (pCR) in approximately 60% of patients. A pCR to NST predicts an excellent prognosis and can be accurately determined by percutaneous image-guided vacuum-assisted core biopsy (VACB). Radiotherapy alone, without breast surgery after NST among patients who had a VACB–determined pCR was evaluated in the feasibility phase (Johnson et al. JACS 2023 ), 2-year pre-planned primary outcome (Kuerer et al Lancet Onc 2022 ), the 32.4 mo patient reported outcomes (Johnson et al SSO 2023 ) and now at the preplanned 3-year primary endpoint.

Methods

This multicentre phase II clinical trial enrolled women aged ≥40 years with unicentric cT1-2N0-1M0 TNBC or HER2+BC and a residual breast lesion <2 cm on imaging after NST. One biopsy was obtained by 9G image-guided VACB containing a minimum of 12 cores from the tumour bed. If no invasive/in situ disease was identified, breast surgery was omitted, and patients underwent whole-breast radiotherapy/boost. Primary outcome was ipsilateral breast tumour recurrence (IBTR) rate and secondary outcomes included evaluation of baseline and longitudinal obtained circulating tumor cells (CTCs) in a total of 33 blood samples and patient-reported outcomes.

Results

During 2017-2021 50 total patients were enrolled and underwent VACB following NST. The mean age was 60·4 years (SD 7·8); 21 patients had TNBC and 29 had HER2+BC. Mean imaging final tumour size after NST was 0·90 cm (SD 0·81), and 17 patients (34%) had a complete radiologic response. VACB identified a pCR in 31 patients (62%). Among these 31 patients, median follow-up was 38.4 months (IQR: 22.4-49·5) the 3-year IBTR rate was 0% (primary endpoint) and 3-year DFS and OS rates were 100%. Two patients were CTC-positive at baseline, 2 were positive at 6-months, and 1 at 12-months. No patients had CTCs detected at more than one timepoint.

Conclusions

Eliminating breast surgery in highly selected patients with an image-guided VACB–determined pCR following NST shows promising 3-year results and additional time and clinical trials evaluating this approach are indicated.

Clinical trial identification

NCT02945579; 20-1-2017 release date.

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

US National Cancer Institute (National Institutes of Health).

Disclosure

H.M. Kuerer: Financial Interests, Personal, Writing Engagements, Editor: NEJM Group; Financial Interests, Personal, Advisory Board: Merck Inc; Financial Interests, Personal, Invited Speaker: Physician Education Resources Inc; Financial Interests, Personal, Royalties, Textbook Editor: McGraw-Hill Professional, Inc; Financial Interests, Personal, Royalties: Elsevier Publishing, Inc; Financial Interests, Personal, Royalties, Editor: Up-To-Date, Inc; Other, Institutional, Invited Speaker, Breast Committee Leadership: NRG Oncology. G. Rauch: Financial Interests, Institutional, Research Grant: GE Healthcare, Inc. S. Krishnamurthy: Financial Interests, Personal, Advisory Board: AstraZeneca Inc; Financial Interests, Personal, Royalties: Elsevier Publishing, Inc. W. Yang: Financial Interests, Personal, Royalties: Elsevier Publishing, Inc. J.A. Mouabbi: Financial Interests, Personal, Advisory Board: GE Healthcare, Inc, Cardinal Health, Inc. J. Boughey: Financial Interests, Institutional, Research Grant: SymBioSis, Inc. S. Shaitelman: Financial Interests, Institutional, Research Grant: Alpha Tau, Exact Sciences, TAE Life Sciences, Artios Pharmaceuticals. K. Hunt: Financial Interests, Personal, Advisory Board: ArmadaHealth, AstraZeneca; Financial Interests, Institutional, Research Grant: Cairn Surgical, Eli Lilly and Company, Lumicell. M. Mitchell: Financial Interests, Institutional, Research Grant: Artidis. B. Smith: Financial Interests, Institutional, Research Grant: Artidis, Varian Medical Systems; Financial Interests, Personal, Stocks/Shares: Oncora Medical. V. Valero: Financial Interests, Personal, Invited Speaker: Roche. All other authors have declared no conflicts of interest.

Background

Breast cancer (BC) recurrence may follow a dormant phase in which quiescent cells reside in niches such as bone marrow (BM). Dormant BM disseminated tumor cells (DTCs) are independently associated with BC recurrence/death. We investigated whether targeting dormancy through autophagy inhibition (hydroxychloroquine (HCQ), and/or mTOR signaling (everolimus (EVE) in DTC+ BC survivors was feasible, reduced DTCs and/or prevented recurrence.

Methods

The CLEVER trial (NCT03032406) is a randomized, phase II trial in patients (pts) diagnosed within 5 years, with positive nodes, triple-negative disease, high-risk Oncotype/Mammaprint, and/or residual disease post-neoadjuvant therapy who completed all treatment except endocrine therapy. DTCs were detected in BM aspirate (BMA) by IHC with pan-CK antibody AE1/AE3. DTC+ pts were randomized to six 28-day cycles (C) of HCQ (600 mg BID), EVE (10 mg daily) or both (+/- 3-month (m0) observation period). If DTC+ persisted after C6, pts received another 6C HCQ+EVE. DTC assessment was done after C3, C6, C12 (if applicable) and 6-mo after end of treatment. Adverse events (AE) were assessed by CTCAEv4. Primary endpoint was feasibility, defined as >75% completion of C6C without G3/G4 AE. Secondary endpoints were safety, DTC response rate (RR) and 3-year RFS. DTC RR was analyzed with Bayesian Poisson regression models.

Results

184/197 eligible pts had baseline BMA, 55 (30%) were DTC+, 53 were randomized: HCQ (n=15), EVE (n=15), and HCQ+EVE (n=23). 13 patients had repeat after 3-mo observation. Feasibility endpoint was met. There were no G4/5 toxicities. At a median follow up of 42 mo (range 7-60), 1 pt recurred in lung (after 2 cycles EVE), 1 pt developed new contralateral breast cancer. The posterior probabilities that HCQ, EVE, and HCQ+EVE reduced DTCs by at least 80% after C3 vs observation alone are 99.1%, 98.2%, and 99.9%, respectively.

Conclusions

The CLEVER trial provides proof-of-principle that therapeutic targeting of dormant BC is feasible and active in eliminating DTCs by targeting dormancy-specific mechanisms. Follow up for recurrence and survival is ongoing.

Clinical trial identification

NCT03032406.

Legal entity responsible for the study

University of Pennsylvania.

Funding

National Cancer Institute R01CA208273, Novartis (Drug Only).

Disclosure

A. DeMichele: Financial Interests, Institutional, Research Funding: NOVARTIS, Neogenomics, Pfizer, Genentech, Calithera. I. Makhlin: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Gilead. L. Chodosh: Financial Interests, Personal, Expert Testimony: Teva Pharmaceuticals, Eisai, Sanofi, Lilly, Whittaker, Clark and Daniels, Imerys, Colgate, Sterigenics. All other authors have declared no conflicts of interest.