Frequency of germline mutations in women’s cancer susceptibility genes in a large cohort of Chinese breast cancer patients

abstracts

Annals of Oncology 244P

Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)1/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial

Background: In HRþ/HER2- early BC, high tumour infiltrating lymphocytes (TIL) levels predict higher pathological complete response to neoadjuvant chemotherapy, but are associated with shorter overall survival (Denkert, Lancet Oncol 2018). HRþ/ HER2- BC is a biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes, with different clinical behaviour (Cejalvo, CTR 2018). Little is known concerning the distribution of TIL levels and immune infiltrate composition across intrinsic subtypes in HRþ/HER2- BC. Methods: Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 postmenopausal patients with HRþ/HER2- early BC from the LETLOB trial (neoadjuvant letrozoleþ/-lapatinib) (Guarneri, JCO 2014). Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. Relative leukocyte fractions were calculated using CIBERSORT (Newman, Nature Methods 2015), a deconvolution method based on RNA gene-expression signatures. Pre-treatment stromal TILs were assessed on centralized HES slides according to recommendations (Salgado, Ann Oncol 2015). Results: Intrinsic subtype distribution was as follows: basal 18% (N ¼ 12), HER2enriched 8% (N ¼ 5), Luminal A 39% (N ¼ 25), Luminal B 36% (N ¼ 24). Non-luminal subtypes (HER2-enriched and Basal) had significantly higher baseline TIL levels than luminal subtypes (median (range): 7 (0-100) and 2 (0-35), respectively; p ¼ 0.038). Non-luminal subtypes also presented higher fractions of CD4 memory activated T-cells (p ¼ 0.018), cd T-cells (p ¼ 0.010) and M1 macrophages (p ¼ 0.001) and lower fractions of T-regulatory cells (p ¼ 0.002) than luminal subtypes. Conclusions: In HRþ/HER2- early BC, non-luminal subtypes show higher TIL levels and a more pro-inflammatory anti-tumour immune infiltrate composition. This immune heterogeneity across intrinsic subtypes should be considered when analysing the complex prognostic role of TILs in HRþ/HER2- early BC. Clinical trial identification: NCT00422903. Legal entity responsible for the study: University of Padua. Funding: GlaxoSmithKline funded the clinical trial (LETLOB) including gene-expression analysis; DOR grants 1721185/17 and 1830512/18 from the University of Padua. Disclosure: M.V. Dieci: Advisory / Consultancy: EliLilly; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Celgene. A. Frassoldati: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Eisai. A. Prat: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: Puma; Advisory / Consultancy: Oncolytics Biotech; Honoraria (institution), Research grant / Funding (institution): Nanostring; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Lilly. P.F. Conte: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: EliLilly; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck-KGa. V. Guarneri: Advisory / Consultancy, Speaker Bureau / Expert testimony: EliLilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

245P

Frequency of germline mutations in women’s cancer susceptibility genes in a large cohort of Chinese breast cancer patients

N. Liao1, B. Chen1, G. Zhang1, C. Ren1, Y. Wang1, L. Guo1, L. Cao1, L. Wen1, K. Li1, M. Jia1, C. Li1, H. Mok1, X. Chen1, G. Wei1, J. Lin1, Z. Zhang2, T. Hou2, X. Shi2, H. HanZhang2, H. Liu2 1 Department of Breast Cancer, Guangdong General Hospital, Guangzhou, China, 2 Medical Department, Burning Rock Biotech, Guangzhou, China

246P

Triple blinded prospective study assessing the impact of genomics & artificial intelligence Watson for oncology (WFO) on MDT’s decision of adjuvant systemic therapy for hormone receptor positive early breast carcinoma

S. Sampige Prasannakumar1, Y. Ramya2, C.K. Rohit2, K. Ashwin1, P. Patil3, A. Rauthan3 Surgical Oncology, Manipal Comprehensive Cancer Centre, Bangalore, India, 2Surgical Oncology, Manipal Comprehensive Cancer Center Manipal Hospital, Bangalore, India, 3 Medical Oncology, Manipal Comprehensive Cancer Center Manipal Hospital, Bangalore, Karnataka, India,

1

Background: Decision on adjuvant systemic therapy in hormone positive early breast carcinoma is the only grey area in breast carcinoma management. This study was done to investigate the concordance between the results of genomic test(Endopredict), artificial intelligence(Watson For Oncology,WFO) and tumor board decision and implications of the same in clinical practice. Methods: This was a triple blinded, prospective study. Decision regarding the adjuvant systemic therapy was done by the multidisciplinary tumor board (MDT)after reviewing the pathology reports & the results correlated with Endopredict test reports & artificial intelligence(Watson for Oncology). Results: Total of 42 patients included. Mean age was 58.3 years, 71.4% were post-menopausal. Breast conservation was done in 47.6%. 64.2% were T1-2N0 stage. Infiltrating ductal carcinoma was major type (83.3%). Decision by MDT to give adjuvant chemotherapy was for 25 patients (59.5%) & hormonal therapy for rest. Recommendation by Watson for oncology was to give adjuvant chemotherapy in 50%. Endopredict score (EPclin) resulted in a low-risk group of 22 patients (52.3%), while 15(47.6%) had a high risk EPclin score. Discordance between the endopredict test, Watson & tumor board was for 11 patients (26.1%): 3 patients had high risk score, but the tumor board decision was to give hormonal therapy due to the age factor. 8 patients had low risk score, but tumor board decision was to give adjuvant chemotherapy. Extremes of age, premenopausal status, intermediate grade & high Ki 67% values were the factors associated with discordance. The treatment decision changed for 4 patients (4/11, 36%) after reviewing the endopredict test and Watson recommendation. Conclusions: Tumor board decision can be more scientific & evidence based with the help of genomics & a learnt colleague in the form of Watson for Oncology. Even though the clinical experience is the important determinant of adjuvant therapy, genomic test with artificial intelligence, which includes the scientific evidence, will guide in decision making. Long term follow up is needed for the validation in our clinical setting. Legal entity responsible for the study: Manipal Hospital Ethical Committee. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: The prevalence of cancer related germline mutations in unselected Chinese breast cancer (BC) patients is unknown. Our study aims to examine the

Volume 30 | Supplement 5 | October 2019

doi:10.1093/annonc/mdz240 | v81

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G. Griguolo1, M.V. Dieci2, L. Pare´3, F. Miglietta2, D.G. Generali4, A. Frassoldati5, G. Bisagni6, F. Piacentini7, E. Tagliafico8, K. Cagossi9, G. Ficarra10, A. Prat3, P.F. Conte2, V. Guarneri2 1 Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy, 2Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy, 3Medical Oncology, Hospital Clinic de Barcelona/IDIBAPS - SOLTI Breast Cancer Research Group, Barcelona, Spain, 4U.O. Multidisciplinare di Patologia Mammaria, ASST O. Istituti Ospitalieri di Cremona, of Cremona/University of Trieste, Cremona, Italy, 5Clinical Oncology, Department of Morphology, Surgery and Experimental Medicine, S Anna University Hospital, Ferrara, Italy, 6Department of Oncology and Advanced Technologies, Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy, 7 Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy, 8Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy, 9Breast Unit Ausl Modena, Ramazzini Hospital, Carpi, Italy, 10Department of Pathology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy

germline mutations prevalence and to investigate the relationship among tumor characteristics, somatic mutations and germline mutations. Methods: Matched white blood cells and tumor tissue samples of 524 unselected Chinese BC patients (stage Tis to IV) were profiled using a panel consisting of 520 cancer-related genes. Germline mutations of 62 cancer susceptibility genes included all breast/ovarian cancer-related genes in the US genetic guidelines were assessed. Results: A total of 76 pathogenic or likely pathogenic (P/LP) germline variants spanning 15 genes were detected from 58 patients (11%), with 29 and 38 mutations detected in BRCA1/2 and other cancer susceptibility genes, respectively. Overall, mutations detected included 11 BRCA1, 18 BRCA2, 4 MUTYH, 4 PALB2, 3 ATM, 3 BRIP1, 3 CDH1, 3 RAD51C, 2 CHEK2, 2 FANCA, 2 PMS2, 2 TP53, 1 FANCI, 1 FANCL and 1 PTEN. We detected 1968 germline mutations classified as variants of uncertain significance spanning all 62 cancer susceptibility genes from 490 patients (93%). We revealed young age, premenopausal status, and family history of breast/ovarian cancer were associated with P/LP germline mutations. Interestingly, somatic TP53 mutations were detected in all patients with P/LP germline BRCA1 mutations (100%, 11/11) and a majority (67%, 2/3) of patients with likely pathogenic CDH1 mutations. No somatic TP53 mutation was detected in patients with germline ATM and TP53 mutations. Somatic PIK3CA mutations were more frequently seen in patients with germline CDH1 (3/3). A patient with pathogenic germline PALB2 mutation (p.Q921fs) also has somatic PALB2 mutation (p.D525fs). Conclusions: Our study derived the prevalence of P/LP germline mutation in 524 Chinese BC patients and 11% were found to have a germline mutation. We explored the characteristics of tumor somatic mutations in germline mutations carriers, which provided a better understanding of patients with germline mutations. Legal entity responsible for the study: Ning Liao. Funding: National Natural Science Foundation of China (Grant No. 81602645), Guangdong Provincial Natural Science Foundation (Grant No. 2016A030313768). Disclosure: All authors have declared no conflicts of interest.