Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR

• Published in: BMC medicine 2022-04, Vol.20 (1), p.136-136, Article 136
• Main Authors: Ueno, Takayuki, Kitano, Shigehisa, Masuda, Norikazu, Ikarashi, Daiki, Yamashita, Makiko, Chiba, Tomohiro, Kadoya, Takayuki, Bando, Hiroko, Yamanaka, Takashi, Ohtani, Shoichiro, Nagai, Shigenori, Nakayama, Takahiro, Takahashi, Masato, Saji, Shigehira, Aogi, Kenjiro, Velaga, Ravi, Kawaguchi, Kosuke, Morita, Satoshi, Haga, Hironori, Ohno, Shinji, Toi, Masakazu
• Format: Article
• Language: English
• Subjects: Adjuvant treatment; Anthracycline; Anthracyclines - therapeutic use; Antibodies; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biopsy; BRCA1 protein; BRCA1/2; Breast cancer; Cancer; Cancer research; Cancer therapies; Carboplatin; Care and treatment; CD3 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - pathology; Cell density; Chemotherapy; Cyclophosphamide; Cytokeratin; Density; Fluorescence; Foxp3 protein; Gene amplification; Genetic aspects; Genetic factors; Homologous Recombination; Homologous recombination deficiency (HRD); Homology; Humans; Immune microenvironment; Immune response; Immune system; Immunohistochemistry; Japan; Lymphocytes; Lymphocytes T; Medical research; Microenvironments; Multivariate analysis; Mutation; Neoadjuvant chemotherapy; Neoadjuvant Therapy - methods; Oncology; Oncology, Experimental; Paclitaxel; Patients; Phenotypes; Platinum; Point mutation; Risk factors; Subgroups; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer; Tumor Microenvironment; Tumors; Working groups
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-022-02332-1

Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8 T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4 T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4 T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4 T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). Intratumoral and stromal CD4 T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. UMIN000023162.