Search

Purpose: Elucidating the unique immunomodulatory mechanisms in breast cancer microenvironment should provide useful insights to aid the development of new therapeutic strategies for this disease. Some studies suggested the immune regulatory function of hormone receptor such as estrogen receptor-α (ER) and androgen receptor (AR), but their mechanism has not been fully understood because of the complexity of immune milieu in breast cancer microenvironment. In this study, we systematically analyzed the relationships between ER, progesterone receptor (PgR), and AR expression and the immunological profile in breast cancer tissue. Methods: Gene set enrichment analysis (GSEA) was used to screen the biological processes associated with the expression of human sex hormone receptor genes (ESR1, PGR, and AR), using a gene expression profile dataset of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Then, using METABRIC and a gene expression profile dataset of The Sweden Cancerome Analysis Network - Breast (SCAN-B), the correlation between the immune cell composition in breast cancer tissue (estimated with the CIBERSORTx) and hormone receptor expression was analyzed. In our previous study of 45 breast cancer tissues, we evaluated the level of human tumor infiltrating lymphocytes (hTILs), expression of human programmed death-ligand 1 (hPD-L1), and infiltration of 11 types of immune cells, using hematoxylin–eosin staining, immunohistochemistry (IHC), and multicolor flow cytometry, respectively. In this study, the levels of ER, PgR, and AR expression were further evaluated using IHC, and their relationship with the immunological profile of breast cancer tissues was analyzed. Results: GSEA showed that the expression levels of the ESR1, PGR, and AR genes were negatively correlated with multiple immunological processes, including “INFLAMMATORY RESPONSE.” Analysis of the correlations between the immune cell composition and hormone receptor gene expression showed that ESR1 expression was inversely correlated with Macrophage M1, CD4 memory activated T cells, Macrophage M0, CD8 T cells, and CD4 memory resting T cells; PGR expression was inversely correlated with Macrophage M1, CD4 memory activated T cells, and Macrophage M0; and AR expression was inversely correlated with Macrophage M0 and Macrophage M1. Immunohistochemical evaluation of ER and AR expression revealed both receptors to be inversely associated with hTIL, hPD-L1 expression, and leukocyte infiltration in breast cancer tissue. Analysis of the immune cell composition in these tissues revealed that ER expression was associated with the decreased infiltration of total T cells, CD4+ T cells, monocytes/macrophages, myeloid-derived suppressor cells, dendritic cells, and myeloid dendritic cells; PgR expression was associated with the decreased infiltration of dendritic cells; and AR expression was associated with the decreased infiltration of CD4+ T cells, monocytes/macrophages, nonclassical monocytes, myeloid-derived suppressor cells, dendritic cells, myeloid dendritic cells, and minor natural killer cells. Conclusion: The correlation of hormone receptor expression with specific immunological profiles in the breast cancer microenvironment both at the genetic and protein levels strongly suggests that hormonal signals may preferentially affect certain subsets of immune cells. Citation Format: Toru Hanamura, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Takuho Okamura, Nobue Kumaki, Katsuto Hozumi, Takayuki Iwamoto, Chikako Honda, Sasagu Kurozumi, Naoki Niikura. Hormone receptor expression is associated with specific immunological profiles in the breast cancer microenvironment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-16.

Background: Patients (pts) with human epidermal growth factor receptor 2–positive breast cancer (HER2+ BC) have a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in pts with HER2+ BC with BM, an unmet medical need remains. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM (n=24), with a confirmed objective response rate (ORR) of 61.4%, an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, and median progression-free survival (PFS) of 19.4 and 18.1 months, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). T-DXd also demonstrated preliminary efficacy in a subgroup of pts with BM in the DESTINY-Breast03 trial, with an extracranial ORR of 67.4%, intracranial ORR of 63.9%, and median PFS of 15.0 months (Hurvitz S et al. SABCS 2021. Abst GS3-01). However, both trials excluded pts with active/progressive BM. Here we describe a trial evaluating T-DXd in a real-world setting in pts with stable or active BM and pts without BM with previously treated advanced/metastatic HER2+ BC. The data generated by this study will complement previous and ongoing studies, providing a more robust understanding of T-DXd treatment in patients with and without BM. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (91 sites in the US, Europe, Australia, Canada, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg every 3 weeks in pts with HER2+ BC ± BM. As part of prescreening, all pts will provide informed consent for tumor tissue samples (archival tumor tissue or fresh biopsy) to be collected and tested for HER2 status. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (no BM at baseline) and cohort 2 (BM at baseline). Pts must have previously treated HER2-positive BC that has progressed on or after ≥1 prior anti-HER2–based regimen (including disease progression ≤6 months after adjuvant treatment with HER2-targeted therapies) and received ≤2 lines of therapy in the metastatic setting (excluding pts with prior tucatinib). Cohort 1 will be limited to include ≤25% third-line pts. Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 per ICR). Secondary endpoints in both cohorts are overall survival, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and quality of life. Incidence of new symptomatic central nervous system (CNS) metastasis is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNS metastasis are secondary endpoints in cohort 2. Citation Format: Nancy U. Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Manoj Prahladan, Nadia Harbeck. Open-label, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with advanced/metastatic human epidermal growth factor receptor 2–positive breast cancer: DESTINY-Breast12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-02.

Background: DESTINY-Breast04 demonstrated that the HER2 targeting antibody–drug conjugate trastuzumab deruxtecan (T-DXd) significantly prolonged progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization negative) metastatic breast cancer (mBC) in pts in the hormone receptor−positive (HR+) cohort and all pts (HR+ and HR-; median PFS, 9.9 vs 5.1 months [mo], hazard ratio: 0.50; median OS, 23.4 vs 16.8 mo, hazard ratio: 0.64; both P < 0.0001; Modi et al. N Engl J Med 2022). Objective response rate (ORR) with T-DXd was ≥50% across cohorts. These subgroup analyses examine pt history and disease characteristics that may correlate with response to therapy. Methods: N = 557 pts with centrally confirmed HER2-low mBC were randomized 2:1 to T-DXd or TPC. Randomization was stratified by HER2 status (IHC 1+ vs 2+), 1 vs 2 prior lines of chemotherapy, and HR+ (with vs without prior treatment with cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) vs HR−. With the exception of the PFS and OS analyses by prior CDK4/6i use, all other described efficacy analyses were assessed post-hoc. Results: Benefit of T-DXd vs TPC was consistent in pts with or without prior CDK4/6i use (Table 1). Pts with high disease burden (ie, ≥3 metastatic sites) also benefited from T-DXd vs TPC (Table 2). There was a small subgroup (n = 22) among all pts (HR+ [n = 18] and HR− disease [n = 4]) with rapid progression prior to enrollment (disease progression within 6 mo of concluding a prior course of chemotherapy in early breast cancer). T-DXd showed responses in 7/14 (50%) pts in this subgroup vs 0/8 with TPC; this subgroup also had prolonged median PFS with T-DXd vs TPC (Table 3). Efficacy data for HER2 IHC 1+ vs 2+ and prior chemotherapy subgroups will be presented. Median OS was not reached for many subgroups (insufficient events in each group [data not shown]); however, subgroups in general showed OS benefit consistent with the primary analysis. With T-DXd, rates of interstitial lung disease/pneumonitis were similar in pts with/without prior CDK4/6i use. Conclusions: T-DXd treatment for HER2-low mBC in the phase 3 study DESTINY-Breast04 showed consistent efficacy independent of disease burden, prior CDK4/6i treatment, or rapid progression status. ILD is an important identified risk and requires proactive monitoring and management. These data continue to support the use of T-DXd as the new standard of care across subgroups of pts with HER2-low mBC. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table 1. Efficacy by Prior CDK4/6i Treatment in Pts With HER2-Low Breast Cancer, HR+ Cohort. Table 2. Efficacy by Disease Burdena in Pts With HER2-Low Breast Cancer, ITT. Table 3. Efficacy by Rapid Progressor Statusa in Pts With HER2-Low Breast Cancer, ITT. Citation Format: Nadia Harbeck, Shanu Modi, William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Naoki Niikura, Binghe Xu, Hope Rugo, Konstantinos Papazisis, Javier Cortés, Ian Krop, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, David Cameron. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-01.

Background: About 60% of breast cancers (BCs) traditionally categorized as HER2 negative (HER2-neg; immunohistochemistry [IHC] 0, IHC 1+ or IHC 2+/in situ hybridization [ISH]–) express low levels of HER2 (HER2-low; IHC 1+ or IHC 2+/ISH–; Schettini, NPJ Breast Cancer 2021). In the phase 3 DESTINY-Breast04 trial (NCT03734029), trastuzumab deruxtecan (T-DXd) showed significantly longer progression-free survival and overall survival (OS) vs physician’s choice of chemotherapy in patients (pts) with HER2-low metastatic BC (mBC) who previously received chemotherapy (Modi, NEJM 2022). As HER2-low becomes a clinically relevant HER2 status among pts with BC, greater understanding of pts with HER2-low disease is needed, including identification of these pts using conventional IHC assays. Our objectives were to assess the prevalence of HER2-low among HER2-neg mBC based on rescored HER2 IHC slides, to describe characteristics of pts with HER2-low mBC, and to characterize concordance between historical HER2 scores and rescores. Methods: This global, multicenter, retrospective study (NCT04807595) included pts with confirmed HER2-neg (HER2 IHC 0, 1+, or 2+/ISH−) unresectable/mBC diagnosed from 2014 through 2017. HER2 IHC-stained slides were rescored after training on low-end expression scoring using Ventana 4B5 and other assays by local laboratories at 13 sites in 10 countries blinded to historical HER2 scores. BCs were categorized as HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2 IHC 0 (IHC 0 or >0< 1+). Prevalence of HER2-low and concordance between historical HER2 scores and rescores were assessed. Demographics, clinicopathological characteristics, treatment patterns, and outcomes were examined via data from medical charts/health records. Results: HER2 rescores were obtained for 781 pts with HER2-neg mBC. HER2-low prevalence was 67.1% overall; 71.1% in hormone receptor (HR)–positive (HR+) and 52.5% in HR–negative (HR−) subgroups. There were no notable differences in characteristics (Table) or treatment patterns between pts with HER2-low and HER2 IHC 0. The most frequent therapies used in the first treatment in the metastatic setting were endocrine therapy (64.1%) for pts with HR+ mBC and chemotherapy (94.4%) for pts with HR− mBC. Among pts with HR+ mBC, 10.2% received cyclin-dependent kinase 4/6 inhibitors as part of their first treatment. There were no statistically significant differences in clinical outcomes between the HER2-low and HER2 IHC 0 groups within each HR subgroup. For pts with HR+ mBC, median time to first subsequent treatment was 10 and 8 months for the HER2-low and HER2 IHC 0 groups, respectively. Overall, concordance was 81.2% (kappa=0.582). Concordance between historical HER2 scores and rescores was 87.3% for HER2-low and 70.1% for HER2 IHC 0 samples. Conclusions: The prevalence of HER2-low (67.1%) among pts previously categorized as HER2-neg mBC in this study was similar to that of an earlier study (≈60%). No obvious differences in patient characteristics or clinical presentation were seen between pts with HER2-low and HER2 IHC 0 mBC. Overall percentage agreement between rescored and historical HER2 scores was 81.2%; agreement was numerically greater for HER2-low than HER2 IHC 0. As HER2-targeted therapies such as T-DXd for the treatment of pts with HER2-low BC are emerging, a greater understanding of pts with HER2-low expression who may benefit from these therapies is important. Citation Format: Giuseppe Viale, Mark Basik, Naoki Niikura, Eriko Tokunaga, Sara Brucker, Frédérique Penault-Llorca, Naoki Hayashi, Joo Hyuk Sohn, Rita Teixeira de Sousa, Adam M. Brufsky, Ciara S. O’Brien, Fernando Schmitt, Gavin Higgins, Della Varghese, Gareth D. James, Akira Moh, Andrew Livingston, Victoria de Giorgio-Miller. HER2-15 Retrospective Study to Estimate the Prevalence and Describe the Clinicopathological Characteristics, Treatment Patterns, and Outcomes of HER2-Low Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-15.

Information regarding patients who were treated for breast cancer in 2018 was extracted from the National Clinical Database (NCD), which is run by Japanese physicians. This database continues from 1975, created by the Japanese Breast Cancer Society (JBCS). A total of 95,620 breast cancer cases were registered. The demographics, clinical characteristics, pathology, surgical treatment, adjuvant chemotherapy, adjuvant endocrine therapy, and radiation therapy of Japanese breast cancer patients were summarized. We made comparisons with other reports to reveal the characteristics of our database. We also described some features in Japanese breast cancer that changed over time. The unique characteristics of breast cancer patients in Japan may provide guidance for future research and improvement in healthcare services.

Purpose Many studies have shown that the prognosis of invasive lobular carcinoma (ILC) is better than that of invasive ductal carcinoma (IDC). However, both disorders exhibit different prognoses according to molecular subtype, and the prognosis of ILC subtypes might depend on their hormone receptor positivity rate. This study clarified the prognosis of ILC and IDC in each subtype and examined the effectiveness of adjuvant chemotherapy (CT) in luminal ILC.Methods We planned the analysis using data from the Breast Cancer Registry in Japan. Because it was presumed that there are differences in characteristics between ILC and IDC, we created matched cohorts using exact matching to compare their prognoses. We compared the prognosis of ILC and IDC for each subtype. We also compared the prognosis of luminal ILC between the CT and non-CT groups.Results For all subtypes, the disease-free survival (DFS) and overall survival (OS) of ILC were poorer than those of IDC. In the analysis by each subtype, no statistically significant difference was found in DFS and OS in luminal human epidermal growth factor 2 (HER2), HER2, and triple-negative cohorts; however, luminal ILC had significantly poorer DFS and OS than luminal IDC. The CT effects on the prognosis of luminal ILC were greater in more advanced cases.Conclusion Luminal ILC had a poorer prognosis than luminal IDC, contributing to the worse prognosis of ILC than that of IDC in the overall cohort. Different therapeutic approaches from luminal IDC are essential for a better prognosis of luminal ILC.

Background: HER2+ BC is associated with a high incidence (up to 50%) of brain metastasis (BM) despite advances in treatment (Zimmer AS et al. Cancer Rep (Hoboken). 2020;e1274; Hurvitz SA et al. Clin Cancer Res. 2019;25:2433-2441). Although several agents have been studied in patients (pts) with HER2+ BC with BM, an unmet medical need remains due to the poor prognosis in this pt population. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a pt subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, respectively, median progression-free survival (PFS) of 19.4 and 18.1 mo, respectively, and median duration of response (DOR) of 20.8 and 16.9 mo, respectively (Modi S et al. Cancer Res. 2021. Abst PD3-06; Jerusalem G et al. Ann Oncol. 2020. Abst 138O). Here we describe a trial evaluating T-DXd in pts ± BM with previously treated advanced/metastatic HER2+ BC. Trial design: DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing the efficacy and safety of T-DXd 5.4 mg/kg q3w in pts with HER2+ BC ± BM. Pts will be enrolled in 1 of 2 cohorts (250 pts each): cohort 1 (−BM at baseline) and cohort 2 (+BM at baseline). Pts must have previously treated advanced/metastatic HER2+ BC that has progressed with ≥1 prior anti-HER2-based regimen and received ≤2 lines of therapy in the metastatic setting (excludes pts with prior tucatinib). Pts with BM must have untreated BM not needing immediate local therapy or previously treated stable or progressing BM. Primary endpoints are ORR in cohort 1 and PFS in cohort 2 (both by RECIST version 1.1 per ICR). Secondary endpoints in both cohorts are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL. Incidence of new symptomatic CNS metastasis (CNSM) is a secondary endpoint in cohort 1, and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM are secondary endpoints in cohort 2. Citation Format: Nancy U Lin, Eva Ciruelos, Guy Jerusalem, Volkmar Müller, Naoki Niikura, Giuseppe Viale, Emma Oscroft, Shawn Anand, Graham Walker, Nadia Harbeck. Open-label, multinational, multicenter, phase 3b/4 study of trastuzumab deruxtecan (T-DXd) in patients with or without baseline brain metastasis with previously treated advanced/metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC): DESTINY-Breast12 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-26-01.

Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-11.

Background Elucidating the unique immunoregulatory mechanisms in breast cancer microenvironment may help develop new therapeutic strategies. Some studies have suggested that hormone receptors also have immune regulatory functions, but their mechanisms are not fully understood. In this study, we have comprehensively analyzed the relationship between the expressions of estrogen (ER), progesterone (PgR), and androgen receptors (AR), and the immunological profile in breast cancer. Methods Using publicly available gene expression profile datasets, METABRIC and SCAN-B, the associations between the expressions of hormone receptors and the immune cell compositions in breast cancer tissue, estimated by CIBERSORTx algorithm, were analyzed. We histologically evaluated tumor-infiltrating lymphocytes (hTIL), PD-L1 (hPD-L1) expression, and the infiltration of 11 types of immune cells by flow cytometry (FCM) for 45 breast cancer tissue samples. The relationships between them and the expressions of ER, PgR, and AR of tumor tissues, evaluated immunohistochemically, were analyzed. Results Expressions of ESR1, PGR, and AR were negatively correlated with overall immune composition. Expressions of ER and AR, but not that of PgR, were inversely associated with hTIL and hPD-L1 expression. FCM analysis showed that the expressions of ER and AR, but not that of PgR, were associated with decreased total leukocyte infiltration. Both CIBERSORTx and FCM analysis showed that ER expression was associated with reduced infiltration of macrophages and CD4+ T cells and that of AR with reduced macrophage infiltration. Conclusion Hormone receptor expression correlates with specific immunological profiles in the breast cancer microenvironment both at the gene and protein expression levels.

Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P

Background: Brain metastases (BM) occur in 20%-50% of patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC), and their presence is a poor prognostic factor. Leptomeningeal carcinomatosis (LMC) occurs in 12%–43% of pts with MBC. Therapeutic options for BC pts with BM and/or LMC are limited. Results of the DESTINY-Breast01 and DESTINY-Breast03 studies have shown the clinical benefit of trastuzumab deruxtecan (T-DXd) in HER2+ MBC pts with stable BM; however, the study populations were small and did not include pts with active BM (untreated or progressive) and/or LMC. This data gap is addressed in the present study. Methods: ROSET-BM (UMIN000044995) is a multicenter, retrospective chart review study of pts who received T-DXd for HER2+ MBC with BM and LMC between May 25, 2020, and April 30, 2021, in a standard-of-care setting. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Additionally, in the pts with brain imaging data, intracranial (IC)-ORR and IC-PFS were evaluated by independent radiologists to provide central review according to RECIST v1.1. Active BM were determined by independent central review (ICR). Pts whose baseline and pre-baseline brain imaging data were compared and confirmed increased tumor size, or pts with new lesions were classified as active BM. LMC was determined by ICR using brain imaging. Results: In the study period, 62 sites participated, enrolling 113 pts with HER2+ MBC and BM were treated with T-DXd. After exclusion of data from 9 who did not meet the criteria for inclusion, 104 pts were included in the analysis. In the 104 pts, 70.2% (n=73) were active BM, 16.3% (n=17) were active BM with LMC, 5.8% (n=6) were stable BM, 1.9% (n=2) were only LMC, and 5.8% (n=6) were not classified. Symptomatic BM were observed in 30.8% (n=32). Median number of prior lines of therapy was 4 (range, 1–15). Median duration of follow up from first T-DXd treatment was 11.2 months. ORR assessed by investigator was 55.7% (complete response [CR], 5.2%) in all pts, 51.7% (CR, 6.9%) in symptomatic BM pts (n=29), and 57.4% (CR, 4.4%) in asymptomatic BM pts (n=68). Among all pts, median PFS was 16.1 months (95%CI, 12.0–n/a), and median OS was not reached (OS at 1 year was 74.9%). In the 19 pts with LMC, 1-year PFS and OS were 60.7% (95%CI, 34.5–79.1) and 87.1% (95%CI, 57.3–96.6), respectively (neither reached the median). Of the 89 pts with brain lesion imaging data (at both baseline and follow-up), IC-ORR was 62.7% (CR, 0.0%). IC-PD was observed in 5.9% (n=3) of pts. Median IC-PFS was 16.1 months (95%CI, 12.2–n/a). In all pts, the most common event and adverse event leading to discontinuation of T-DXd were PD (27 pts, 26.0%) and interstitial lung disease (19 pts,18.3%), respectively. Conclusion: The results of this retrospective chart review show that T-DXd has promising efficacy in HER2+ MBC pts with active BM and LMC. This study was funded by Daiichi Sankyo Co., Ltd. Citation Format: Takashi Yamanaka, Naoki Niikura, Hironori Nomura, Hiroki Kusama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Shosuke Kita, Miki Yamaguchi, Tomoyuki Aruga, Nobuhiro Shibata, Akihiko Shimomura, Yuri Ozaki, Kazuhiro Shiraishi, Shuji Sakai, Yoko Kiga, Tadahiro Izutani, Kazuhito Shiosakai, Junji Tsurutani. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: A multicenter retrospective study (ROSET-BM study) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-01.

Background We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS. Patients and methods We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records. Results We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2–2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2–2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2–2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2–2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm. Conclusion We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.

Background Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end‐of‐life (EOL) communication between oncologists and patients with metastatic breast cancer. Materials and Methods We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39‐item questionnaire that measured facility type and function; physicians’ background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions. Results Ninety‐eight responses concerning physicians’ engagement in ACP with patients were obtained. Seventy‐one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians’ engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1–7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients’ life expectancy was less frequent compared with other topics. Conclusion The opportunity to improve EOL communication skills promoted physicians’ engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists. Implications for Practice This study found that the opportunity to improve end‐of‐life (EOL) communication skills promoted physicians’ engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment., The purpose of advance care planning is to enable individuals to make plans about their future health care and improve discussions about end‐of‐life care and treatment. This article examines the current status of advance care planning for patients with advanced metastatic breast cancer to determine factors associated with physician engagement in institutions that specialize in oncology.

Background Male breast cancer (MBC) is rare; however, its incidence is increasing. There have been no large-scale reports on the clinicopathological characteristics of MBC in Japan. Methods We investigated patients diagnosed with breast cancer in the Japanese National Clinical Database (NCD) between January 2012 and December 2018. Results A total of 594,316 cases of breast cancer, including 3780 MBC (0.6%) and 590,536 female breast cancer (FBC) (99.4%), were evaluated. The median age at MBC and FBC diagnosis was 71 (45–86, 5–95%) and 60 years (39–83) (p p p = 0.02). Axillary lymph node dissection was more frequent in MBC cases (32.9 vs. 25.2%, p p p p Conclusion Japanese MBC had an older age of onset, were more likely to be hormone receptor-positive disease, and received less perioperative chemotherapy than FBC.

Metastatic breast cancer (MBC) is generally considered incurable. However, MBC which has limited number and sites of metastasis: oligometastatic breast cancer (OMBC) may have definitive remission with individualized, metastasis-directed ablative therapies and multidisciplinary management, such as surgery and radiotherapy. Earlier detection of primary metastatic breast cancer using accurate imaging technologies may allow the initiation of therapy for OMBC. In breast cancer, the lymph nodes, liver, bone, lung, and brain are common sites of metastasis. Additional studies are recommended if signs or symptoms indicate metastasis. The imaging modality should be selected for suspicious locations or original metastatic regions. The standard staging studies are ultrasonography for lymph node metastasis, abdominal and/or pelvic contrast-enhanced CT for liver metastasis, chest CT for pulmonary metastasis, and bone scan for bone metastasis. FDG-PET/CT may be helpful for bone or liver metastasis. MRI may be considered for liver, soft tissue, or brain metastasis.

Background In the global phase III IMpassion031 study, neoadjuvant atezolizumab plus nab-paclitaxel/anthracycline-based chemotherapy improved pathological complete response in patients with early stage triple-negative breast cancer. Here, we report primary analysis results from a subgroup of Japanese patients. Methods Patients with histologically documented, previously untreated, stage cT2–cT4, cN0–cN3, cM0 triple-negative breast cancer were randomized 1:1 to receive intravenous atezolizumab 840 mg or placebo every 2 weeks in combination with chemotherapy consisting of nab-paclitaxel intravenous 125 mg/m2 once a week, followed by doxorubicin intravenous 60 mg/m2 and cyclophosphamide intravenous 600 mg/m2 every 2 weeks. Patients then underwent surgery. Pathological complete response (ypT0/is ypN0) in the intention-to-treat and PD-L1-positive (≥1% PD-L1-expressing tumor-infiltrating immune cells) populations were co-primary endpoints. Results This subanalysis (data cutoff: 3 April 2020) included 36 patients from Japan (intention-to-treat; atezolizumab arm, n = 17; placebo arm, n = 19). Pathological complete response occurred in 41% (n = 7; 95% confidence interval, 18–67) of patients in the atezolizumab arm and 37% (n = 7; 95% confidence interval, 16–62) in the placebo arm. In the PD-L1-positive population, pathological complete response occurred in 50% (n = 5; 95% confidence interval, 19–81) of patients in the atezolizumab arm and 45% (n = 5; 95% confidence interval, 17–77) in the placebo arm. Treatment-related grade 3–4 adverse events occurred in 71% and 68% of patients in the respective arms. Conclusion Atezolizumab added to neoadjuvant chemotherapy numerically improved pathological complete response versus placebo in this small exploratory analysis of Japanese patients with early stage triple-negative breast cancer, a trend directionally consistent with the global study results. No new safety signals were identified.

Postmastectomy radiotherapy (PMRT) is the standard treatment for locally advanced breast cancer. However, the effectiveness of PMRT in patients with pT1-2 and N1 tumours remains controversial. Therefore, this study aimed to determine the prognostic impact of PMRT in patients with breast cancer and with pT1-2 and 1-3 lymph node metastases.Using data from the Japanese National Clinical Database from 2004 to 2012, we evaluated the association of PMRT with locoregional recurrence (LRR), any recurrence, and mortality. We enrolled patients who had undergone mastectomy and axillary node dissection and were diagnosed with pT1-2 and N1. We compared clinicopathological factors and prognosis between patients who received (PMRT group) and those who did not receive (No-PMRT group) PMRT.Among 8914 patients enrolled, 492 patients belonged to the PMRT group and 8422 to the No-PMRT group. The median observation time was 6.3 years. There was no significant difference in the incidences of LRR (4.0% versus 5.0%, P = 0.61), recurrence (13.8% versus 11.8%, P = 0.23) and breast cancer death (6.0% versus 4.3%, P = 0.08) at 5 years between the groups. Multivariable analysis revealed that LRR was significantly associated with tumour size, number of node metastases and triple-negative subtype but not with PMRT.The LRR rate in the No-PMRT group was 5.0% at 5 years among patients with T1-2 and N1. PMRT did not significantly influence LRR in patients with T1-2 and N1. However, PMRT administration should be tailored considering the individual risks of tumour size, 3 node metastases and triple-negative subtype.

Background and purpose The spread of COVID-19 has restricted the delivery of standard medical care to surgical patients dramatically. Surgical triage is performed by considering the type of disease, its severity, the urgency for surgery, and the condition of the patient, in addition to the scale of infectious outbreaks in the region. The purpose of this study was to evaluate the impact of the COVID-19 pandemic on the number of surgical procedures performed and whether the effects were more prominent during certain periods of widespread infection and in the affected regions. Methods We selected 20 of the most common procedures from each surgical field and compared the weekly numbers of each operation performed in 2020 with the respective numbers in 2018 and 2019, as recorded in the National Clinical Database (NCD). The surgical status during the COVID-19 pandemic as well as the relationship between surgical volume and the degree of regional infection were analyzed extensively. Results The rate of decline in surgery was at most 10–15%. Although the numbers of most oncological and cardiovascular procedures decreased in 2020, there was no significant change in the numbers of pancreaticoduodenectomy and aortic replacement procedures performed in the same period. Conclusion The numbers of most surgical procedures decreased in 2020 as a result of the COVID-19 pandemic; however, the precise impact of surgical triage on decrease in detection of disease warrants further investigation.

Background. A better understanding of tumor immunology can facilitate the development of new treatment strategies for various malignancies. Histologically assessed tumor-infiltrating lymphocytes (hTILs) and programmed cell death 1 ligand 1 (hPD-L1) have been established as prognostic or predictive biomarkers in certain subsets of breast cancer. However, the complexity of multiple types of immune cells is not fully understood. In this study, the immune cell fractions in breast cancer tissue and blood were evaluated to analyze their association with hTILs and hPD-L1. Methods. In total, 45 tumor and 18 blood samples were collected from breast cancer patients. The total leukocyte counts, proportions of 11 types of immune cells in the samples, and PD-L1 expression in each fraction were evaluated using multicolor flow cytometry for both the tumor and blood samples. The hTILs and hPD-L1 were evaluated with hematoxylin and eosin staining and immunohistochemistry respectively. Results. The immune cell composition of the blood showed a partial correlation with that of the tumor tissue; however, no significant association was found between the blood immune cell compositions and hTIL or hPD-L1 expression. A higher hTIL was associated with increased leukocyte infiltration as well as a higher proportion of CD4+ and CD8+ T cells and lower proportion of natural killer cells and natural killer T cells. PD-L1 was highly expressed in the monocyte/macrophage (Mo/Mφ), nonclassical monocyte (CD16+ Mo), myeloid-derived suppressor cell (MDSC), dendritic cell (DC), and myeloid dendritic cell (mDC) fractions in the tumor tissues. hPD-L1 positivity was associated with increased leukocyte infiltration in the tumor tissues and PD-L1 expression in Mo/Mφ, CD16+ Mo, MDSC, DC, and mDC fractions. Conclusion. There was a partial correlation in the composition of immune cells at the tumor site and that in the peripheral blood. A high proportion of hTILs reflects not only higher immune cell infiltration but also differences in the immune responses in the tumor microenvironment. Non-B-cell antigen-presenting cell fractions such as Mo/Mφ, CD16+ Mo, MDSC, DC, and mDC fractions are involved primarily in the PD-L1 pathway in the breast cancer microenvironments.

Background Preoperative chemotherapy in combination with trastuzumab and pertuzumab is a preferred regimen for treating patients (pts) with HER2-positive, invasive, early breast cancer (BC). Pts who have received such treatment but still have residual invasive disease in the breast or lymph nodes at surgery are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 is approved as a postneoadjuvant treatment for pts with residual invasive disease (in the breast and/or axillary nodes) after optimal neoadjuvant chemotherapy and trastuzumab (or trastuzumab with pertuzumab). T-DXd is a potent HER2-targeted ADC with a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of ≈8. T-DXd is approved globally for the treatment of adult pts with HER2-positive, unresectable or metastatic BC who have received ≥2 prior anti-HER2-based regimens in the metastatic setting or had prior chemotherapy and are refractory to or intolerant of standard treatments. These approvals have been supported by results from DESTINY-Breast01, an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2-positive metastatic BC. In an updated data cutoff (June 8, 2020), T-DXd demonstrated an objective response rate (ORR) of 61.4% (113/184 pts) and a duration of response of 20.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. Cancer Res. 2021;81[4 suppl]:PD3-06). Yet, further unmet need exists in patients who do not achieve pathologic complete response to neoadjuvant treatment, as these patients have increased risk of recurrence. Here, we describe a randomized phase 3 trial evaluating T-DXd vs T-DM1 as postneoadjuvant treatment for high-risk pts with HER2-positive primary BC who have residual invasive disease following neoadjuvant therapy. Study Description DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing the efficacy and safety of T-DXd with those of T-DM1 in pts with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with pathologic evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must have a higher residual risk for recurrence, following standard T-DM1, defined as either presenting with inoperable disease (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0) or operable BC at presentation (clinical stages T1-3, N0-1, M0) with axillary node-positive disease after neoadjuvant chemotherapy and anti-HER2 treatment. Approximately 1600 pts will be randomly assigned (1:1) to T-DXd or T-DM1 from ≈ 400 sites globally. Randomization is stratified by operative status at presentation, hormone receptor status, pathologic nodal status following neoadjuvant therapy, and type of HER2-targeted neoadjuvant therapy (single vs dual). T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg will be administered intravenously once every 3 weeks for 14 cycles. Invasive disease-free survival based on investigator assessment is the primary efficacy endpoint. Secondary endpoints are overall survival, disease-free survival, distant recurrence-free interval, and brain metastasis-free interval. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated (NCT04622319). Citation Format: Charles E Geyer, Jr, Michael Untch, Aleix Prat, Priya Rastogi, Naoki Niikura, Elton Mathias, Lee Anne McLean, Yibin Wang, Sibylle Loibl. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-03.

Background It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. Methods The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. Results Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). Conclusion TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD). We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS). There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p

Background: Lymphocyte predominant breast cancer subgroup, defined as ≥ 50% stromal tumor-infiltrating lymphocytes (sTILs), is associated with high pathological complete response (pCR) rate after neoadjuvant therapy (NAT) and favorable outcome. In a cohort of triple negative (TNBC) and HER2+ breast cancer (BC) patients treated with NAT, we aimed to assess the predictive and prognostic value of pre- and post-NAT sTILs and the information provided by the change in sTILs during NAT. Materials and methods: Two-hundred and nine consecutive patients (n=80 TNBC; and n=129 HER2+) who received NAT between 2001 and 2009 in our institution were evaluated. Pre-NAT sTILs were assessed on biopsy sample (baseline) and post-NAT sTILs on surgical specimens just for non-pCR patients. sTILs level was categorized as low 0-9%, intermediate 10-49%, and high ≥50%. The change in sTILs during NAT was calculated as the absolute difference between pre- and post-NAT sTILs. We evaluated the association of pre-NAT sTILs and pCR, and the association between pre- and post-NAT sTILs, and their change with relapse-free survival (RFS). Results: Overall pCR rate was 37.8% (31.3% for TNBC, 41.2% for ER+/HER2+BC, 42.3% for ER-/HER2+BC). In each subtype, pre-NAT low sTILs group was significantly associated with lower pCR rate. During the median follow-up period of 98 months, 44 recurrences (21.1%) were observed. For TNBC, low pre-NAT sTILs group was associated with higher recurrence risk compared with int/high sTILs (HR=4.675 [2.013-10.859], p Conclusion: In TN and HER2+ BCs, tumors with low pre-NAT sTILs have a low likelihood to achieve a pCR (predictive marker). In TNBC, low pre-NAT sTILs were associated with higher recurrence risk. In non-pCR TNBC patients, both low pre- and post-NAT sTILs were associated with shorter RFS. These results suggest that sTILs information should be taken into account when additional post-surgery treatments are considered in non-pCR patients. Citation Format: Ochi T, Giampaolo B, Murai M, Nozaki F, Kobayashi D, Iwamoto T, Niikura N, Suzuki K, Yamauchi H, Hayashi N. Predictive and prognostic value of stromal tumor-infiltrating lymphocytes before and after neoadjuvant therapy in triple negative and HER2-positive breast cancer [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 P2-08-31.

Introduction Oral mucositis is a clinically significant complication of mucotoxic cancer therapy. The incidence of oral mucositis (any grade) as an adverse drug reaction of everolimus is 58%, while an analysis of Asian people has reported its occurrence as 81%.This study hypothesizes that the occurrence of oral mucositis will reduce with professional oral care (POC) administered prior to everolimus treatment. Method: This was a randomized, multi-center, open-label, phase III study, to evaluate the efficacy of POC in preventing mucositis induced by everolimus in postmenopausal, estrogen receptor (ER)-positive, metastatic breast cancer patients. Patients were randomized into POC and control groups (1:1 ratio). All patients received everolimus with exemestane and continued the everolimus until disease progression. In the POC group, patients were subjected to teeth surface cleaning, scaling and tongue cleaning, before initiating everolimus, and continued to receive weekly POC from dentist or oral surgeons throughout the 8 weeks of treatment. In the control group, patients brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary end-point was to measure the incidence of all grades of oral mucositis. Target accrual was 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction. This trial has been registered at ClinicalTrials.gov, number NCT 02069093. Result: Between May 26, 2014 and Dec 28, 2017, we enrolled 174 women from 31 institutions; 168 were evaluable for efficacy but 5 were excluded (had not received the protocol treatment [n=4]; no efficacy data [n=1]). In 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 81 patients) and control group (89.7%, 78 of 87 patients) (p=0.035). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 81 patients) and control group (54%, 47 of 87 patients) (p= 0.015). As a result of oral mucositis, 18 (22.2%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction. Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This could be a new standard in oral care for patients undergoing this treatment. Primary Analysis: Incidence Probability of Oral Mucositis POC Group (n=81) Controll (n=87)P-valuneOral Mucositis over Grade1n% n% Yes6276.5 7889.70.035No1923.5 910.3 Risk Difference, % (95% CI)-11.83 (-22.80, -0.85) POC: Professional oral Care Citation Format: Niikura N, Nakatukasa K, Amamiya T, Watanabe K-i, Hata H, Kikawa Y, Taniike N, Yamanaka T, Mitsunaga S, Nakagami K, Adachi M, Kondo N, Horii K, Hayashi N, Naito M, Kashiwabara K, Yamashita T, Umeda M, Mukai H, Ota Y. Oral care evaluation to prevent oral mucositis in estrogen receptor positive metastatic breast cancer patients treated with everolimus (Oral Care-BC): A randomized controlled phase III trial [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 P1-11-01.

Background The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. Methods Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. Results There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI 2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. Conclusions POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI 2, and who did not receive BMA while receiving EVE and EXE may have better prognoses. Trial registration The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. Results: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI < 25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses.Trial registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

The Japanese Breast Cancer Society (JBCS) registry began data collection in 1975, and it was integrated into National Clinical Database in 2012. As of 2016, the JBCS registry contains records of 656,896 breast cancer patients from more than 1400 hospitals throughout Japan. In the 2016 registration, the number of institutes involved was 1422, and the total number of patients was 95,870. We herein present the summary of the annual data of the JBCS registry collected in 2016. We analyzed the demographic and clinicopathologic characteristics of registered breast cancer patients from various angles. Especially, we examined the registrations on family history, menstruation, onset age, body mass index according to age, nodal status based on tumor size and subtype, and proportion based on ER, PgR, and HER2 status. This report based on the JBCS registry would support clinical management for breast cancer patients and clinical study in the near future.

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients that received POC to those that had not and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated by an oncologist over 8 weeks between groups. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. Results: There were no significant differences in PFS between the POC and Control Groups ( P = 0.801). A BMI < 25 mg/m 2 and non-visceral metastasis were associated with longer PFS ( P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS ( P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m 2 , and who did not receive BMA while receiving EVE and EXE may have better prognoses. Trial registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

Background: Neoadjuvant chemotherapy (NAC) for breast cancer has been improved and pathological complete response (pCR) achieved in about 50% of Her2 positive tumor and over 30% of triple negative tumor. It is possible that not to perform surgery if pCR is diagnosed accurately. This study was performed to examine diagnostic ability of core needle biopsy (CNB) to detect pCR by NAC. (Study registry number: UMIN000012035) Methods: In this multicenter study, we registered histologically proved breast cancer patients who were diagnosed as clinical complete response (cCR) after NAC. The cCR was diagnosed by contrast-enhanced magnetic resonance imaging (MRI) after NAC by radiologists in each facility. Regimens of NAC were not specified by study protocol. A clip marker was not placed in the tumor before NAC. At the operating table, ultrasound-guided CNB is performed before starting the surgery. The CNB was performed with 14 gauge needle without vacuum assistance and requiring three biopsy specimens. The concordance of pathological results between a core needle biopsy and a surgical specimen is examined by pathologists at each facility. The pathological diagnosis was categorized as i) no carcinoma (pCR), ii) carcinoma in situ (CIS) and iii) invasive carcinoma. Results: The study included 86 women from 10 facilities, accrued from December 2013 to March 2017. Median age was 53.5 (31-75) years and median tumor size before NAC was 2.3 (0.9-7.3) cm. Estrogen receptor was positive in 32 (37%). HER2 was positive in 40 (47%). The clinical stage before NAC was stage I 19 (22%), II 48 (56%), III 16 (19%) and IV 3 (3%). All cases were administered cytotoxic agents. Both anthracycline and taxane were given in 70 cases (81%), and trastuzumab was administered in 35 (41%) cases. As for breast surgery, partial resection was performed in 53 cases (62%), whereas 33 cases (38%) underwent mastectomy. Pathological examination on surgical specimen revealed pCR (i) in 41 cases (48%), CIS (ii) in 17 cases (20%) and invasive carcinoma (iii) in 28 cases (32%). Results of pathology of CNB and surgical specimens are shown in table 1. Table 1. Pathological diagnosis of CNB and surgical specimens Surgical specimen No carcinoma (pCR)Residual carcinomaTotalCNBNo carcinoma (pCR)41 (NPV=63%, spec.=100%)24 (FNR=53%, 14 were CIS)65 (76%) Residual carcinoma021 (PPV=100%, sens.=47%)21 (24%)Total41 (48%)45 (52%)86 (100%)CNB: core needle biopsy, FNR: false-negative rate, CIS: carcinoma in situ, NPV: negative predictive value, PPV: positive predictive value, sens.: sensitivity, spec.: specificity. The kappa value was 0.455 which was not enough for accurate diagnosis. In 24 discordant cases, residual tumor was found in surgical specimen but not in CNB, residual disease was CIS in 14 cases. Conclusions: Up to 10% false negative rate of pCR may allow us to proceed to an observational study without performing surgery.This study revealed that the ultrasound-guided CNB for cCR cases by MRI was not accurate enough to omit surgery. Thus, imaging diagnosis and biopsy methods need to be improved. However, it is still possible to consider because the post-operative radiotherapy may compensate for surgery in cases with CIS after NAC. Citation Format: Narui K, Ishikawa T, Hasegawa Y, Kaise H, Kawate T, Yamada K, Suzuki Y, Niikura N, Kohno N, Kimoto T, Sugae S, Yamada A, Kosaka Y, Miyashita M, Okamura T, Shimizu D, Tanino H, Sakamaki K, Tokuda Y. Feasibility study to diagnose pathological complete response by neoadjuvant chemotherapy in breast cancer adding core needle biopsy (KBOG1301 supported by JONIE) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-09.

Background: Postmastectomy radiotherapy (PMRT) has been shown to be beneficial in node-positive breast cancer patients. However, the role of PMRT for patients receiving modern neoadjuvant chemotherapy (NAC) are controversial. We aimed to evaluate the efficacy of radiotherapy for breast cancer patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry. Methods: Patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer were included in this analysis. We assessed locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) using the Kaplan-Meier method and compared them between the groups with and without PMRT by nodal status after NAC; ypN0, ypN1, and ypN2-3. We also performed multivariable cox regression analysis to evaluate the association of radiotherapy and these outcomes adjusting for baseline patient and cancer characteristics. Results: Of the 145,530 patients registered from 2004 to 2009, we identified 3,226 patients who met our inclusion criteria with the 5-year follow-up information including 1,299 ypN0, 1,036 ypN1, and 879 ypN2-3 cases. PMRT was performed in 185 patients (14.2%) with ypN0, 265 patients (25.6%) with ypN1, and 543 patients (61.8%) with ypN2-3. There was no difference in LRR, DDFS, and OS between the groups with and without radiotherapy for ypN1 patients who received NAC (P=0.72, P=0.29, and P=0.36, respectively). For patients with ypN2-3 breast cancer, radiotherapy significantly improved LRR (P Effect of PMRT on locoregional recurrence by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN00.8550.4581.5960.623ypN10.8320.5491.2620.387ypN2-30.6080.4520.8180.001 Effect of PMRT on overall survival by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN01.3250.8412.0870.224ypN10.8800.5991.2930.514ypN2-30.6850.5310.8850.004 Radiotherapy was not associated with OS among patients with ypN0 [HR: 1.325, 95% CI: 0.841–2.087, P=0.224] and ypN1 [HR: 0.880, 95% CI: 0.599–1.293, P=0.514]. There was no significant difference in DDFS with the addition of radiotherapy for all ypN subgroups. Conclusions: The results from this nationwide database study of breast cancer patients following modern NAC showed that PMRT did not improve survival for patients with ypN1 and ypN0. Radiotherapy might be only beneficial for ypN2-3 breast cancer patients who received NAC and mastectomy in the modern era. Randomized clinical trials are needed to optimize the use of PMRT for breast cancer patients treated with neoadjuvant chemotherapy. Citation Format: Miyashita M, Niikura N, Kumamaru H, Miyata H, Ishida T, Kinoshita T, Tsuda H, Nakamura S, Tokuda Y. Role of postmastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A study from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-11.

Background Historically, humoral immunity was considered unimportant in anti-tumor immunity, and the differentiation and anti-tumor activity of B cells in breast cancer are poorly understood. However, it was recently discovered that B cells participate in tumor immunity through both antibody production and immunosuppressive mechanisms. We analyzed the expression of B-cell differentiation markers in detail using fluorescence-activated cell sorting to investigate the relationship between B-cell subsets and breast cancer etiology. Methods Blood samples were taken from breast cancer patients and healthy donors, and peripheral blood mononuclear cells were collected. B cells at various stages of differentiation were identified by the expression of combinations of the cell surface markers CD5, CD19, CD21, CD24, CD27, CD38, CD45, and IgD. Statistical analysis of the proportions of each B-cell subtype in the different patient groups was then performed. Results Twenty-seven breast cancer patients and 12 controls were considered. The proportion of total B cells was significantly higher in cancer patients than in controls (11.51 ± 2.059 vs 8.905 ± 0.379%, respectively; p = 0.001). Breast cancer patients were then classified as High-B or Low-B for further analysis. A significantly higher proportion of memory B cells was found in the High-B group than in the Low-B or control groups (p = 0.003 and p = 0.043, respectively). Conclusions Breast cancer patients generally have a higher proportion of B cells than healthy controls, but this is highly variable. Analysis of the major B-cell surface markers indicates that memory B cells in particular are significantly expanded, or more robust, in breast cancer patients. Electronic supplementary material The online version of this article (10.1007/s12282-017-0824-6) contains supplementary material, which is available to authorized users.

BACKGROUND Despite treatment advances, up to 50% of patients with advanced HER2+ BC develop BM (Zimmer. Cancer Rep. 2020). Patients with HER2+ BC with BM have a worse prognosis than patients without BM. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, median progression-free survival (PFS) of 19.4 and 18.1 mo, and median duration of response (DOR) of 20.8 and 16.9 mo (Modi. Cancer Res. 2021; Jerusalem. Ann Oncol. 2020). Here we describe a trial evaluating T-DXd in patients with previously treated advanced/metastatic HER2+ BC ±BM. DESIGN DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing T-DXd 5.4 mg/kg q3w efficacy and safety in patients with previously treated advanced/metastatic HER2+ BC ±BM that progressed with ≥1 prior anti-HER2–based regimen and received ≤2 lines of therapy in the metastatic setting (excluding patients with prior tucatinib). Patients (n=250/cohort) will be enrolled in cohort 1 (−BM at baseline) or 2 (+BM at baseline). BM must be untreated and not needing immediate local therapy or previously treated and stable or progressing. Primary endpoints are ORR (cohort 1) and PFS (cohort 2) (both by RECIST version 1.1 per ICR). Secondary endpoints are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL in both cohorts; incidence of new symptomatic CNS metastasis (CNSM) in cohort 1; and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM in cohort 2. This is an encore; the original presentation will be at The European Society for Medical Oncology 2021.

// Rin Ogiya 1 , Naoki Niikura 1 , Nobue Kumaki 2 , Hiroyuki Yasojima 3 , Tsutomu Iwasa 4 , Chizuko Kanbayashi 5 , Risa Oshitanai 1 , Michiko Tsuneizumi 6 , Ken-ichi Watanabe 7 , Akira Matsui 8 , Tomomi Fujisawa 9 , Shigehira Saji 10 , Norikazu Masuda 3 , Yutaka Tokuda 1 and Hiroji Iwata 11 1 Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan 2 Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan 3 Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan 4 Department of Medical Oncology, Kindai University School of Medicine, Osaka, Japan 5 Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan 6 Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Japan 7 Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan 8 Department of Surgery, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan 9 Department of Breast Oncology, Gunma Prefectural Cancer Center, Gunma, Japan 10 Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan 11 Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan Correspondence to: Naoki Niikura, email: niikura@is.icc.u-tokai.ac.jp Keywords: breast cancer, brain metastases, tumor infiltrating lymphocytes, PD-L1, immune microenvironment Received: July 11, 2017 Accepted: September 20, 2017 Published: October 27, 2017 ABSTRACT Background: Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. Results: The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1–70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t -test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t -test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04). Materials and Methods: We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed. Conclusions: There are significantly fewer TILs in brain metastases than in primary breast tumors.

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P

Introduction Axillary lymph node dissection is standard therapy for patients with positive-node breast cancer, and can be performed with an electrocautery scalpel and suture ligation in most cases. However, knot slipping can occur during suture ligation and this can spread thermal damage to peripheral tissues. The LigaSureTM Small Jaw vessel-sealing system was developed as an alternative to suture ligatures, staplers, and other energy-dependent devices for sealing blood and lymphatic vessels, but its use in axillary dissection for breast cancer is limited. We prospectively compared the duration until drain removal after surgery, total lymph fluid drainage volume, intraoperative blood loss, and incidence of complications after axillary dissections, between this device and conventional methods. Methods This prospective randomized study was conducted at the Department of Breast and Endocrine Surgery at Tokai University School of Medicine, Kanagawa, Japan, between October 2011 and March 2015. Major eligibility criteria included (1) pathologically confirmed breast cancer diagnosis, (2) age ≥20 and ≤80 years, and (3) a signed informed consent form. The primary endpoint was duration until drain removal after surgery. The secondary endpoints were total lymph fluid drainage volume, intraoperative blood loss, and incidence of postoperative surgical complications. We defined the criterion for drain removal as a lymph fluid drainage volume of Results Initially, 100 patients were assigned as eligible; however, two patients were later excluded because of the exclusion criteria. Of 98 patients, 49 were randomized to the study group, and 49 to the control group. The mean duration until drain removal after surgery was 5.2 days in the study group and 5.0 days in the control group (p=0.573). The mean total lymph fluid drainage volumes were 260.3 and 233.5 mL (p=0.502), and the mean intraoperative blood loss volumes were 17.8 and 18.0 mL (p=0.949), for the study and control groups, respectively. No significant differences were found between the two groups regarding drain removal duration, total drainage volume, and intraoperative blood loss volume. Both groups had low incidence rates of postoperative hematoma, wound infection, lymphedema, and pain, and had similar incidence rates of seroma formation after drain removal. Conclusion Our study results indicated that the use of the LigaSureTM Small Jaw in axillary dissection for breast cancer was as safe as conventional methods. However, using the LigaSureTM Small Jaw did not improve surgical outcomes such as duration until drain removal and total lymph fluid drainage volume compared with conventional methods. Citation Format: Okamura T, Niikura N, Yokoyama K, Ogiya R, Oshitanai R, Terao M, Morioka T, Tsuda B, Saito Y, Suzuki Y, Tokuda Y. Utility of LigaSureTM vessel-sealing device in axillary dissection for breast cancer surgery: A randomized single center study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-11.