Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne ® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2‐negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing‐negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple‐negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

Purpose T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells. Methods This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10 −3 mm 2 . Results Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression ( p < 0.0001). Patients with T-bet + tumors had longer overall survival (OS) compared with patients with T-bet − tumors ( p = 0.047). The combination of CD8 + and T-bet + was associated with a better recurrence-free survival (RFS) and OS compared to CD8 + /T-bet − tumors ( p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet + tumors ( p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12–0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07–0.95, p = 0.039 for OS). Conclusions OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC. Electronic supplementary material The online version of this article (10.1007/s10549-019-05256-2) contains supplementary material, which is available to authorized users.

Background It is important to identify biomarkers for triple-negative breast cancers (TNBCs). Recently, pembrolizumab, an immune checkpoint inhibitor (ICI) for programmed cell death 1 (PD-1), was approved as a treatment strategy for unresectable or metastatic tumor with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency, such as malignant melanoma, non-small cell lung cancer, renal cell cancer and urothelial cancer. In addition, results from clinical trials suggested that ICI was a promising treatment for TNBCs with accumulated mutations. However, the frequency of MSI in Japanese TNBCs still remains unclear. We aimed to analyze the presence of MSI-H in TNBCs as a biomarker for ICI therapy. Methods In this study, we retrospectively evaluated the MSI of 228 TNBCs using an innovative method, MSI Analysis System Version 1.2 (Promega), consisting of 5 microsatellite markers: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 without a normal tissue control. Results Among 228 tumors, 222 (97.4%) were microsatellite stable, 4 (1.7%) low-frequency MSI and 2 (0.9%) MSI-H, respectively. Two MSI-H tumors were potentially aggressive pathologically as indicated by nuclear grade 3 and high Ki-67 (> 30%), and were classified as basal-like and non-BRCA-like, but were not consistent regarding tumor-infiltrating lymphocytes, CD8 and PD-L1 expression. Conclusions Although we found that MSI-H was uncommon (0.9%) in TNBCs, potential targets for ICIs exist in TNBCs. Therefore, MSI-H breast cancer patients should be picked up using not only conventional methods but also platforms for comprehensive genomic profiling.

Background:Microsatellite instability (MSI) is a phenotype resulting from defect in mismatch repair genes. The Food and Drug Administration approved anti-programmed death 1 (PD-1) immune checkpoint inhibitor for any solid tumor with MSI-high (MSI-H). Some tumors had good response to PD-1 blockade and it is a promising treatment for a part of refractory breast cancers. Our goal was to determine the frequency of MSI in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes. Patients and Methods:This study included 228 patients with primary TNBC underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue. Tumor and control DNA were amplified by polymerase chain reaction at the following 5 microsatellite markers: NR-21, BAT-26, BAT-25, NR-24, MONO-27. We classified the tumors as microsatellite stable(MSS), MSI-low or MSI-H. Results: The mean age of patients was 59 years (range: 30-89) and all were women. T1 tumors were 57.9% and N0 were 67.5%. Meanwhile, the tumors with nuclear grade 3 were 66.2% and high Ki-67 (&gt; 30%) were 66.7%. Among the 228 tumors, 222 tumors (97.4%) revealed MSS, of which 6 (2.6%) revealed MSI and 2 (0.9%) were MSI-H. Among the MSI tumors, T and N factor were showed as follows: T1: 2 tumors, T2: 3 tumors, T3: 1 tumor, N0: 5 tumors and N1: 1 tumor. Of two MSI-H tumors, one showed T1N0 and another showed T2N0. The both of them showed nuclear grade 3, high Ki-67 (&gt; 30%) and had common following instable markers: NR-21, BAT-26 and BAT-25. Conclusions: Our results demonstrated that the frequency of MSI-H was 0.9% (2/228). MSI might not be useful as a biomarker for immune check point inhibitors. MSI should be combined with another biomarker such as tumor mutational burden in TNBC. Citation Format: Kurata K, Kubo M, Mori H, Kawaji H, Motoyama Y, Kuroki L, Yamada M, Kaneshiro K, Kai M, Nakamura M. Microsatellite instability in triple negative breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-11.

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The role of the resection of primary tumour in stage IV breast cancer is unclear. Systemic therapy is recommended to prolong the survival and improve the quality of life (QOL). However, even if the systemic therapy is effective to control distant metastasis, sometimes the local lesion worsens, especially in the aggressive subtypes such as HER2-positive breast cancer. In uncontrollable tumours, the wound bed can bleed, weep and get infected, leading to dismal QOL. Our study describes two cases of patients with HER2-positive stage IV breast cancer who underwent palliative mastectomy which resulted in improvement of QOL. Local tumour control through palliative mastectomy can be beneficial for symptomatic aggressive patients with HER2-positive breast cancer to improve their QOL.

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Background/Aim: With advances in anti-HER2 treatment and improved prognoses of HER2-positive breast cancer, the American Society of Clinical Oncology and the American Society of Pathologists (ASCO/CAP) have revised the HER2 diagnostic guidelines several times. We examined how to respond clinically to the revisions of the interpretation of the immunohistochemistry (IHC) method. Patients and Methods: We re-evaluated 254 patients diagnosed as HER2 IHC equivocal, who underwent fluorescence in situ hybridization (FISH) before and after the IHC diagnostic criteria update in 2013. Results: Twenty of 131 (15.3%) IHC equivocal cases by the ASCO/CAP 2007 guideline were IHC score 3+ and one of 20 (0.76%) was negative for FISH. Five of 123 (4.1%) IHC equivocal cases by the ASCO/CAP 2013 guideline were negative for IHC as per the 2007 guideline and four were positive for FISH. Conclusion: After revision of the ASCO/CAP 2013 guideline, 3.3% of HER2-negative cases before the revision should have received anti-HER2 treatment.