2251P - The genomic landscape of radiotherapy-induced breast angiosarcoma: An alleanza contro il cancro (ACC) initiative for an unmet need in rare tumors

Background

Radiotherapy-induced breast angiosarcoma (RIBAS) is a very rare late complication of radiotherapy (RT) in breast cancer. The incidence of RIBAS is expected to increase in the next few years, following the widespread adoption of breast-sparing surgery in combination with adjuvant treatment. To date, no actionable gene mutations are described, and data availability is very limited. Leveraging a multicentric retrospective cohort, we assessed the genomic features of a collected case series of patients affected by both sporadic (sBAS) and RT-induced form of angiosarcoma.

Methods

We retrospectively collected FFPE tumor and germline samples, obtained by surgery or biopsy. Samples were subjected to whole exome sequencing (WES, NovaSeq 6000 Illumina). Raw data were analyzed using the open source nf-Sarek pipeline. Mutation calls were identified using Mutect2, Strelka2 and independently validated using the Dragen platform^TM. Variants were annotated using COSMIC, OncoKB, ClinVar in conjunction with functional predictors, such as FATHMM, SIFT and Polyphen. Copy number aberrations were assessed using CNVkit.

Results

We collected matched tumor-normal pairs from 43 cases (30 RIBAS, 8 sBAS, 5 with no clinical annotation). All the patients were female, the overall median age at diagnosis was 68.8 years (IQR: 52.1 – 75.1), 69.8 (IQR: 61.4 – 76) for RIBAS and 41.2 (IQR: 28.6 – 53.7) for sBAS patients. WES was performed on 18 cases, 12 RIBAS, and 6 sBAS. We identified two PIK3CA hotspot mutations (p.E542V, p.V344M) in RIBAS only, but not in sBAS. One TP53 mutation was identified in one sBAS sample. The most recurrent copy number aberration was MYC amplification (N = 5), exclusively found in RIBAS. Over-representation analysis showed enrichment in the NOTCH signaling, and E2F-targets pathways.

Conclusions

The genomic repertoire of RIBAS and sBAS is heterogenous, and we identified recurrent potential clinically actionable markers. We are currently expanding our analyses to 26 novel cases, including those reported in the Angiosarcoma Project. Germline calls are being assessed. To our knowledge, our study represents the largest effort to unveil the molecular landscape of RIBAS.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Alleanza Contro il Cancro - Ricerca Corrente Reti 2019, 2021 e 2022.

Disclosure

A. Vingiani: Financial Interests, Other, Honoraria: Roche, Lilly. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. G. Pruneri: Financial Interests, Other: Novartis, Roche, Lilly, Exact Science. L. Mazzarella: Financial Interests, Advisory Board: Thetis Inc. G. Zoppoli: Financial Interests, Stocks or ownership: Immnomica srl.; Financial Interests, Invited Speaker: Novartis; Non-Financial Interests, Product Samples: ThermoFisher Scientific; Non-Financial Interests, Personal, Other, Travel Grant: Novartis, Roche. All other authors have declared no conflicts of interest.