Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR
Abstract Background 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 neoadjuva...
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-022-02332-1 |
| _version_ | 1818263883187486720 |
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| author | Takayuki Ueno Shigehisa Kitano Norikazu Masuda Daiki Ikarashi Makiko Yamashita Tomohiro Chiba Takayuki Kadoya Hiroko Bando Takashi Yamanaka Shoichiro Ohtani Shigenori Nagai Takahiro Nakayama Masato Takahashi Shigehira Saji Kenjiro Aogi Ravi Velaga Kosuke Kawaguchi Satoshi Morita Hironori Haga Shinji Ohno Masakazu Toi |
| author_facet | Takayuki Ueno Shigehisa Kitano Norikazu Masuda Daiki Ikarashi Makiko Yamashita Tomohiro Chiba Takayuki Kadoya Hiroko Bando Takashi Yamanaka Shoichiro Ohtani Shigenori Nagai Takahiro Nakayama Masato Takahashi Shigehira Saji Kenjiro Aogi Ravi Velaga Kosuke Kawaguchi Satoshi Morita Hironori Haga Shinji Ohno Masakazu Toi |
| author_sort | Takayuki Ueno |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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 mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. Results 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). Conclusions 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. Trial registration UMIN000023162 |
| first_indexed | 2024-12-12T19:26:05Z |
| format | Article |
| id | doaj.art-5711388d449949039bda369d7ffea37a |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-12T19:26:05Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-5711388d449949039bda369d7ffea37a2022-12-22T00:14:30ZengBMCBMC Medicine1741-70152022-04-0120111010.1186/s12916-022-02332-1Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TRTakayuki Ueno0Shigehisa Kitano1Norikazu Masuda2Daiki Ikarashi3Makiko Yamashita4Tomohiro Chiba5Takayuki Kadoya6Hiroko Bando7Takashi Yamanaka8Shoichiro Ohtani9Shigenori Nagai10Takahiro Nakayama11Masato Takahashi12Shigehira Saji13Kenjiro Aogi14Ravi Velaga15Kosuke Kawaguchi16Satoshi Morita17Hironori Haga18Shinji Ohno19Masakazu Toi20Breast Surgical Oncology, The Cancer Institute Hospital of JFCRDivision of Cancer Immunotherapy Development, Advanced Medical Development Center, The Cancer Institute Hospital of JFCRDepartment of Breast and Endocrine Surgery, Nagoya University Graduate School of MedicineDivision of Cancer Immunotherapy Development, Advanced Medical Development Center, The Cancer Institute Hospital of JFCRDivision of Cancer Immunotherapy Development, Advanced Medical Development Center, The Cancer Institute Hospital of JFCRDivision of Pathology, The Cancer Institute Hospital of JFCRDepartment of Breast Surgery, Hiroshima University Hospital, Hiroshima UniversityBreast and Endocrine Surgery, Faculty of Medicine, University of TsukubaDepartment of Breast and Endocrine Surgery, Kanagawa Cancer CenterDepartment of Breast Surgery, Hiroshima City Hiroshima Citizens HospitalDivision of Breast Oncology, Saitama Cancer CenterDepartment of Breast and Endocrine Surgery, Osaka International Cancer InstituteDepartment of Breast Surgery, NHO Hokkaido Cancer CenterDepartment of Medical Oncology, Fukushima Medical University HospitalDepartment of Breast Oncology, National Hospital Organization Shikoku Cancer CenterDepartment of Breast Surgery, Kyoto University HospitalDepartment of Breast Surgery, Kyoto University HospitalDepartment of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of MedicineDepartment of Diagnostic Pathology, Kyoto University HospitalBreast Oncology Center, The Cancer Institute Hospital of JFCRDepartment of Breast Surgery, Kyoto University Graduate School of MedicineAbstract Background 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. Methods 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 mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. Results 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). Conclusions 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. Trial registration UMIN000023162https://doi.org/10.1186/s12916-022-02332-1Triple-negative breast cancerHomologous recombination deficiency (HRD)BRCA1/2Immune microenvironmentNeoadjuvant chemotherapyPlatinum |
| spellingShingle | Takayuki Ueno Shigehisa Kitano Norikazu Masuda Daiki Ikarashi Makiko Yamashita Tomohiro Chiba Takayuki Kadoya Hiroko Bando Takashi Yamanaka Shoichiro Ohtani Shigenori Nagai Takahiro Nakayama Masato Takahashi Shigehira Saji Kenjiro Aogi Ravi Velaga Kosuke Kawaguchi Satoshi Morita Hironori Haga Shinji Ohno Masakazu Toi Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR BMC Medicine Triple-negative breast cancer Homologous recombination deficiency (HRD) BRCA1/2 Immune microenvironment Neoadjuvant chemotherapy Platinum |
| title | Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR |
| title_full | Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR |
| title_fullStr | Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR |
| title_full_unstemmed | Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR |
| title_short | Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR |
| title_sort | immune microenvironment homologous recombination deficiency and therapeutic response to neoadjuvant chemotherapy in triple negative breast cancer japan breast cancer research group jbcrg 22 tr |
| topic | Triple-negative breast cancer Homologous recombination deficiency (HRD) BRCA1/2 Immune microenvironment Neoadjuvant chemotherapy Platinum |
| url | https://doi.org/10.1186/s12916-022-02332-1 |
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