Management of PALB2-associated breast cancer: A literature review and case report

Abstract

Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2-associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple-negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD-L1 positive triple-negative BC, who progressed after an immune checkpoint inhibitor (ICI)-containing regimen and then experienced a pathologic complete response after platinum-based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD-L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2-associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms.

Keywords: PALB2; PARP inhibitor; breast cancer; immunotherapy.

FIGURE 1

(A) Patient's breast at diagnosis. (B) Partial response after 3 cycles of nab‐paclitaxel and atezolizumab. (C) Clinical progression after 4 cycles of nab‐paclitaxel and atezolizumab. (D) Clinical response after 1 cycle of carboplatin and gemcitabine. (E) Disappearance of the ulcerated lesion after 6 cycles of carboplatin and gemcitabine.

FIGURE 2

PALB2 protein structure. The coiled‐coil domain is responsible for its interaction with BRCA1; the WD40 domain is involved in the interaction with BRCA2, DNA polymerase η (DNApolη), RAD51, and RNF168; the ChAM domain binds to nucleosome and participates to the formation of PALB2‐BRCA2‐RAD51 complex; two DNA‐binding domains enhance the RAD51‐mediated ssDNA invasion.