Background

Limited data are available on predictive biomarkers for dual anti-HER2 blockade in HER2+/HR- early breast cancer (BC). The present analysis aimed to identify associations of biological signatures and stromal TILs (sTILs) with pCR and survival in phase II WSG-ADAPT HER2+/HR- trial (NCT01779206).

Methods

Patients (pts) with cT1-cT4c, cN0-3 HER2+/HR- BC were randomized to receive pertuzumab + trastuzumab (P+T) in Arm A (n=92) or P+T+paclitaxel in Arm B (n=42). Gene expression signatures were analyzed in baseline (BL) biopsies using NanoString Breast Cancer 360 panel (n=117); BL and on-treatment (week 3) sTIL levels were available in 119 and 76 pts, respectively. Impacts of standardized gene expression signatures on pCR (odds ratios, OR) and invasive disease-free survival (iDFS; hazard ratios, HR) were estimated by logistic and Cox regression, respectively; Spearman correlations were computed.

Results

In all pts, ERBB2 (OR 1.7; 95%CI 1.1-2.7) and estrogen receptor (ER) pathway signaling signatures (OR 1.7; 95%CI 1.1-2.6) were favorable, while PTEN signature (OR 0.6; 95%CI 0.4-0.9) was unfavorable for pCR. After 60 months median follow-up, 13 (A: 11, B: 2) invasive events occurred, none following pCR (ypT0 ypN0). Regarding iDFS, several gene signatures related to immune response (IR) as well as ER signaling were favorable, all with similar HR about 0.4 - 0.6. These patterns were even more prominent in the neoadjuvant chemotherapy-free Arm A, where additionally, BRCAness signature was unfavorable (HR 2.0; 95%CI 1.0-3.8). All significant IR signatures were strongly intercorrelated. sTILs (BL/week 3/change) were not significantly associated with pCR or iDFS, though BL-sTIL correlated positively with IR signatures.

Conclusions

The present translational analysis of the WSG-ADAPT HER2+/HR- trial suggests distinct (except for ER signaling) gene signatures associated with pCR vs iDFS. IR signatures can augment morphological data from sTILs; the potential role of IR in preventing recurrence suggests that pts with up-regulated IR signatures could be candidates for de-escalation concepts in HER2+ BC.

Clinical trial identification

EudraCT Number: 2011-001462-17.

Legal entity responsible for the study

Westdeutsche Studiengruppe GmbH.

Funding

Hoffmann la Roche.

Disclosure

All authors have declared no conflicts of interest.

Background

In estrogen receptor positive (ER⁺) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent and plastic cell types in breast cancer and harbor intriguing immunomodulatory and architectural capabilities. However, the clinical significance of the spatial patterns of tumor cells, TILs and fibroblasts is largely unknown. Here we evaluate the patterns and clinical impact of the proximity between cancer cells, TILs and fibroblast in ER⁺ breast cancer.

Methods

A deep neural network was used to locate and identify tumor cells, TILs and fibroblasts on hematoxylin and eosin (H&E) stained whole slides from 179 ER⁺ breast tumors (included in ICGC series) together with a new empirical density estimation analysis to measure the spatial patterns. To quantify the proximity of the pairs of cell distributions, we measured the Kullback-Leibler divergence between the cell types. Next, we hierarchically clustered the tumors based on their spatial profiles. Gene set enrichment analysis was performed for each spatial cluster to study specific molecular characteristic per cluster. We validated the spatial clusters in an independent cohort of ER⁺ breast cancer (n=756, included in METABRIC series) and in addition studied their prognostic value.

Results

The spatial integration of fibroblasts, TILs and tumor cells leads to a new reproducible classification of ER⁺ breast cancer, where the spatial composition of tumors was linked to inflammation, fibroblast meddling or immunosuppression. ER⁺ patients with high TIL and low fibroblasts had improved survival (HR=0.429, p=0.0024), whilst the patients with intermediate TIL, high fibroblasts and epithelial to mesenchymal transition did not (HR=1.5, p=0.052). Especially a high spatial overlap of fibroblasts and TILs was associated with a good prognosis (HR=0.668, p=0.027).

Conclusions

Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER⁺ breast cancer from H&E slides and suggest that the spatial interplay of fibroblasts and TILs potentially holds a decisive role in the ER⁺ breast cancer-immune response.

Legal entity responsible for the study

The authors.

Funding

Dutch Cancer Foundation (grant KWF-10510).

Disclosure

C. Desmedt: Research grant/Funding (institution): Belgian Cancer Foundation; Research grant/Funding (institution): Luxemburg Cancer Foundation. R.F. Salgado: Research grant/Funding (institution): Merck; Research grant/Funding (institution): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Bristol-Myers Squibb. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Daiichi Sankyo. Y. Yuan: Honoraria (institution): Roche; Advisory/Consultancy: Merck. H. Horlings: Advisory/Consultancy: slidescore.com; Advisory/Consultancy: ellogon.ai; Research grant/Funding (institution): Roche. All other authors have declared no conflicts of interest.

Background

The phase (ph) II DESTINY-Breast01 trial showed strong efficacy of T-DXd (objective response rate, 61.4%; median progression-free survival, 19.4 mo) and manageable safety in pts with pretreated HER2+ mBC (Modi SABCS 2020), supporting approval for treatment (tx) of pts with HER2+ mBC that has progressed on ≥2 anti-HER2 therapies (US/EU) or after chemotherapy (Japan). ILD is an important identified risk with T-DXd. We characterized ILD in pts with HER2+ mBC treated with T-DXd across ph 1 and 2 trials.

Methods

Pts with HER2+ mBC who received the approved dose of T-DXd monotherapy (5.4 mg/kg every 3 wk) in 2 ph 1 studies (J101 [NCT02564900], A104 [NCT03383692]) and the ph 2 DESTINY-Breast01 (NCT03248492) trial between Aug 2015 and June 08, 2020 (data cutoff) were included. Imaging and clinical data (baseline through time of potential ILD case) were retrospectively reviewed by an independent adjudication committee. We report ILD events adjudicated as drug related.

Results

245 pts with heavily pretreated HER2+ mBC were included (ph 1, 61; ph 2, 184). Median T-DXd tx duration was 9.7 mo (range, 0.7-40.3 mo). 38 pts (15.5%) experienced an event adjudicated as drug related ILD; most were grade (G) 1/2 (30 [12.2%]). One pt each had G3 and G4 events (0.4%) and 6 had G5 ILD (2.4%). Median time to first ILD event was 5.6 mo (range, 1.1-20.8 mo) with 37/38 pts (97%) having first onset before 12 mo. 42% of pts were treated >12 mo and risk of new ILD (any grade) beyond 12 mo was low (conditional probability, 1.8%). For 27/44 events (61%), the adjudication committee assessed onset of ILD as being earlier than that reported by investigators (median difference, 52 d; range, 1-288 d). Data on use of steroids to manage ILD will be presented.

Conclusions

At the approved dose of T-DXd, most ILD events were low grade and occurred in the first 12 mo with an apparent decreased risk after 12 mo of tx; additional follow-up is needed to confirm. The adjudication committee assessed onset of ILD as being earlier than the investigators in the majority of cases, highlighting the need for close monitoring to allow for earlier identification and effective management of ILD using updated guidelines.

Clinical trial identification

NCT02564900, NCT03383692, NCT03248492.

Editorial acknowledgement

Medical editorial assistance was provided by Michael Demars, PhD (ArticulateScience LLC), and funded by AstraZeneca Pharmaceuticals LP.

Legal entity responsible for the study

Daiichi Sankyo, Inc. and Daiichi Sankyo Co., Ltd.

Funding

AstraZeneca Pharmaceuticals LP. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan.

Disclosure

C.A. Powell: Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Voluntis. S. Modi: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research support: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research support: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research support: AstraZeneca; Advisory/Consultancy: Macrogenics; Speaker Bureau/Expert testimony, Research grant/Funding (self), Research support: Seattle Genetics; Research grant/Funding (self), Research support: Novartis. H. Iwata: Non-remunerated activity/ies, Support of parent study and funding of editorial support: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly Japan; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Kyowa Hakko Kirin; Research grant/Funding (institution): MSD; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Nihonkayaku; Research grant/Funding (institution): Bayer. S. Takahashi: Research grant/Funding (self), Grant, personal fees: Daiichi Sankyo; Research grant/Funding (self), Grant, personal fees: Eisai; Research grant/Funding (self), Grant, personal fees: Novartis; Research grant/Funding (self), Grant, personal fees: Taiho; Research grant/Funding (self), Grant, personal fees: MSD; Research grant/Funding (self), Grant, personal fees: Chugai; Research grant/Funding (self), Grant, personal fees: Bayer; Research grant/Funding (self), Grant, personal fees: AstraZeneca. K. Nie: Full/Part-time employment: AstraZeneca. A. Qin: Full/Part-time employment: Daiichi Sankyo. J. Singh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo. C. Taitt: Full/Part-time employment: Daiichi Sankyo; Shareholder/Stockholder/Stock options, Full/Part-time employment, employment & stock ownership in past 2 years: BMS. S. Verma: Advisory/Consultancy: Amgen; Advisory/Consultancy, Full/Part-time employment: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Lilly; Advisory/Consultancy: Macrogenics; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Spectrum Pharmaceuticals; Full/Part-time employment: AstraZeneca. D.R. Camidge: Honoraria (self): Daiichi Sankyo.

Background

Venous thromboembolic events (VTE), elevated aminotransferases (EAT) and interstitial lung disease (ILD) are adverse events (AEs) for abemaciclib (oral CDK4 & 6 inhibitor). In monarchE, patients (pts) receiving abemaciclib+endocrine therapy (ET) as adjuvant treatment (txt) of HR+, HER2- high-risk early breast cancer (EBC) reported these AEs more frequently vs ET alone pts.

Methods

The safety population (pop) comprised 5591 treated (tx) pts (median duration of abemaciclib: 17 months). The protocol included management guidance for AEs. Pts with history of VTE were not eligible. Risk factors for VTE (Khorana risk score) and adjuvant radiotherapy (95.4% pts) were well balanced across arms.

Results

In abemaciclib tx pts: Most VTEs were G≥3 (1.3%), primarily pulmonary embolism (0.9%) (Table). Of pts experiencing VTE, 94% received anti-coagulants and 19.4% discontinued abemaciclib or all txt due to VTE. VTEs were increased with tamoxifen txt; G≥3 VTEs were higher in pts with body mass index (BMI)> 25 (1.8%) vs BMI<25 (0.6%). 85% of G≥3 EAT were single occurrences; incidence was highest early on txt (∼3 months). Of pts experiencing G≥3 EAT, 71% had dose hold/reduction and 16% discontinued due to EAT. All G≥3 alanine aminotransferase (ALT) increases, per central lab, were reversible with dose modification or discontinuation. No pts had drug-induced liver injury (no Hy’s law cases). Most ILD events were G1 (1.4%). Of pts experiencing ILD, 52% were tx with steroids/antibiotics and 23% discontinued abemaciclib or all txt due to ILD. ILD was higher in Asians (6.6%; G1: 4.9%; G≥3: 0.3%; 13% of Asian pts with ILD discontinued (0.9% of pop)). Table: 44O

Characteristics of VTEs, EAT and ILD

Conclusions

VTE, EAT and ILD were manageable with dose adjustments and comedications in pts with EBC; results were consistent with the known safety profile of abemaciclib. Although ILD was higher in Asian pop, G≥3 AEs and discontinuations were similar. Most pts experiencing these AEs could continue abemaciclib.

Clinical trial identification

NCT03155997.

Editorial acknowledgement

Eglantine Julle-Daniere.

Legal entity responsible for the study

Eli Lilly.

Funding

Eli Lilly.

Disclosure

M. Toi: Honoraria (self), Research grant/Funding (self), Research grant, Lecture honoraria: Chugai, Takeda, Pfizer, Taiho, Eisai, AstraZeneca, Shimadzu, Yakult; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant, Lecture honoraria, Advisory role for a drug development: Kyowa-Kirin, Daiichi Sankyo; Research grant/Funding (self): JBCRG association, Astellas; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Honoraria (self), Lecture Honoraria: MSD, Exact Science, Novartis; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting: Konica Minolta, BMS; Honoraria (self), Research grant/Funding (self), Research Fund and Honoraria for lecture: Nippon Kayaku; Research grant/Funding (self): AFI Technologies; Advisory/Consultancy: Athenex Oncology, Bertis, Terumo, Kansai Medical Net; Advisory/Consultancy, Research grant/Funding (self): Luxonus; Research grant/Funding (self): Shionogi, GL Science; Officer/Board of Directors: JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast Cancer Research Network. N. Harbeck: Shareholder/Stockholder/Stock options: West German Study Group; Honoraria (self): Roche, Novartis, Amgen, Pfizer, Genomic Health, AstraZeneca, Zodiac Pharma, Pierre Fabre; Advisory/Consultancy: Roche/Genentech, Novartis, Celgene, Pfizer, Eli Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohme, Odonate Therapeutics, Seattle Genetics, West German Study Group, Pierre Fabre; Research grant/Funding (institution): Roche/Genentech (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Merck Sharp & Dohme (Inst). J.M. Puig: Honoraria (self), Personal fees: Protocol JPCF. J. Cruz: Honoraria (self), Advisory/Consultancy, Lectures, Travel, Advisory: PharmaMar, Roche, Novartis, Pfizer; Honoraria (self), Advisory/Consultancy, Lectures, Advisory: Eli Lilly, AstraZeneca; Advisory/Consultancy: Daiichi, Seagen, Glaxo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Lectures: Bayer. M. Takahashi: Honoraria (self): Eli Lilly; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Eisai; Research grant/Funding (self): Kyowa Kirin; Research grant/Funding (self): Taiho. M. Hulstijn, E.A. Twum, A. Regev, B. San Antonio: Full/Part-time employment: Eli Lilly. D.M. Median: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Institutional research funding, Honoraria, Lecture fee, Consulting/Advisory role: Eli Lilly; Advisory/Consultancy, Non-remunerated activity/ies, Educational, Lecture fee, Consulting/Advisory role: AstraZeneca; Research grant/Funding (self), Lecture fee: A&D Pharma; Honoraria (self): Clovis; Advisory/Consultancy, Travel/Accommodation/Expenses: Genekor; Honoraria (self), Advisory/Consultancy, Lecture fee, Honoraria, Advisory role: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Lecture fee, Advisory, Travel, Educational: Pfizer; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses, Lecture fee, Honoraria, Travel, Educational: Roche; Honoraria (self): Samsung Bioepis. M. Campone: Honoraria (institution), Advisory/Consultancy, Consulting/advisory/fees to the Institution: AstraZeneca, Sanofi, Servier, AbbVie, Accord, Pfizer, Seagen; Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GT1. All other authors have declared no conflicts of interest.