Affiliations: [a] A.M. Rywlin, Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA | [b] Department of Radiation Oncology, Mount Sinai Medical Center, Miami Beach, FL, USA | [c] Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
Correspondence:
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Corresponding author: Christopher A. Febres-Aldana, Mount Sinai Medical Center, Department of Pathology and Laboratory Medicine, 4300 Alton Rd, Miami Beach, FL 33140, USA. Tel.: +1 (305) 674 2277; E-mail: christopher.febres@msmc.com
Abstract: BACKGROUND:Hormone-receptor-negative breast carcinoma (HRNBC), including triple-negative and HER-2 amplified tumors, can overexpress P16INK4a with substantial contribution to tumor progression. In nonneoplastic cells, P16INK4a mediates growth arrest and senescence secondary to cytotoxic compounds. OBJECTIVE:We assessed the impact of neoadjuvant chemotherapy (NAC) on P16INK4a expression in breast specimens. METHODS:P16INK4a and CD-44 were evaluated by immunohistochemistry in biopsies and subsequent post-NAC excision in a cohort of 27 women with HRNBC. Positivity was estimated on hotspots of tissue available by calculating cellular densities in nonneoplastic tissues with a low proliferation rate (Ki-67 < 1%) and tumor percentage using ImageJ 1.51t (National Institutes of Health, USA). RESULTS:Pre-NAC P16INK4a and CD-44 tumor expression were similar between the complete (n = 15) and incomplete (n = 12) response groups. Residual HRNBCs exhibited decreased immunoreactivity for P16INK4a, while the expression of CD-44 increased (n = 10, P < 0.05). The magnitude of change correlated with the baseline expression (r = 0.37, P16; r = −0.85, CD-44). Post-NAC nonneoplastic mammary duct and lobular epithelia, perilobular stroma, and adipose tissue, but not peritumoral stroma, accumulated P16INK4a(+) cells. The post-NAC cellular density change was more significant in epithelia of patients with high P16INK4a(+) baseline (r = 0.86, P < 0.0001) and those with a complete pathologic response (n = 14, P < 0.05). All tumors beds with complete treatment effect showed diffuse P16INK4a positivity. CONCLUSION:NAC induced the accumulation of P16INK4a(+)cells in nonneoplastic breast tissues more pronounced in patients with a complete pathologic response. Therapy-induced senescence is a potential marker of bystander damage due to NAC. P16INK4a loss and CD-44 gain may represent a phenotype of chemoresistance in residual HRNBCs.
Keywords: Breast cancer, chemotherapy, P16INK4a, CD-44, therapy-induced senescence
DOI: 10.3233/BD-190419
Journal: Breast Disease, vol. 39, no. 2, pp. 51-59, 2020
