2727 - Clinical Outcomes in Breast Cancer Patients with Underlying Germline PALB2 Mutations Treated with Radiation .

A. Shalaby¹, I. Jan¹, N. Ohri¹, Z. Abou Yehia², D. Toppmeyer³, and B. G. Haffty¹; ¹Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ, ²Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, ³Rutgers Cancer Institute of New Jersey, Department of Medical Oncology, New Brunswick, NJ

Purpose/Objective(s): The Partner and localizer of BRCA2 (PALB2) gene has crucial role in DNA double-strand break repair, upkeep of genome integrity, and suppression of cancer development. PALB2-deficient cells are known to be hypersensitive to ionizing radiation. Multigene panel testing has increasingly identified patients with PALB2 variants raising the question if those patients with heterozygous PALB2 variants have compromised outcomes or are at increased risk of radiation toxicity. We hypothesize that outcomes with radiation are acceptable with moderately hypofractionated (Hypo-RT) or conventionally fractionated (CRT) radiation after breast conserving surgery (BCS) or mastectomy in patients with heterozygous germline PALB2 pathogenic variants or variants of uncertain significance (VUS). Materials/

Methods: Between 2005 and 2023, breast cancer patients treated with radiation were consented for peripheral blood sequencing (PBS) on an institutionally approved IRB protocol. PALB2 variants detected by high-throughput PBS were designated benign, pathogenic, VUS, or with conflicting interpretations of pathogenicity using the ClinVar database. Variants designated benign or likely benign were excluded and those with conflicting interpretations of pathogenicity or variants of uncertain significance were classified as VUS. Toxicities were abstracted from medical records and were graded per Common Terminology Criteria for Adverse Events v5. Additional clinicopathologic information was abstracted from the medical records.
Results: A total of 583 patients were sequenced. After excluding benign PALB2 variants, 14 were included in this analysis: 5(36%) were pathogenic and 9(64%) were VUS. Median tumor size was 2 cm and median age at diagnosis was 51.5 years (range: 42–69). Among these patients 12(86%) had invasive disease, 10(71%) were ER+, and 9(64%) received chemotherapy; 11(79%) had BCS with 7(50%) undergoing sentinel lymph node dissection. All patients received photon based external beam radiation, 3 (21%) were treated with Hypo-RT, 11 (79%) with CRT, and 7(50%) received nodal irradiation. Median follow up was 69 months. Grade 2 acute radiation dermatitis (ARD) was noted in 8(57%) patients, and grade 3 in 2(14%) patients. For patients with grade 3 ARD, one had a pathogenic variant of PALB2, the other had a VUS. Late grade 2 fibrosis was recorded in 1(7%) patient. There were no grade 4 or 5 toxicities. Contralateral breast cancer did not occur in any patients. One patient (7%) had chest wall recurrence 4 months after finishing radiation.
Conclusion: This represents the first report on clinical outcomes in breast cancer patients with PALB2 undergoing radiation. We concluded that radiation therapy in individuals with heterozygous PALB2 germline pathogenic variants or variants of uncertain significance (VUS) appears to be well-tolerated with acceptable clinical outcomes.