Comparison of proportions and prognostic impact of pathological complete response between evaluations of representative specimen and total specimen in primary breast cancer after neoadjuvant chemoradiotherapy: an ancillary study of JCOG0306.

BACKGROUND: In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. METHODS: We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. RESULTS: ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175-0.946], P = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073-0.857], P = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. CONCLUSIONS: RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

Significance of MUC1 and ß-Catenin Localization in Mucinous Carcinoma of the Breast.

BACKGROUND/AIM: There are two main subtypes of mucinous carcinoma (MC) based on the quantification of the mucinous component: the pure variant (pMC) and the mixed variant (mMC). pMC has been subdivided into pure A with a hypocellular variant, and pure B with a hypercellular variant. PATIENTS AND METHODS: We retrospectively analyzed the clinicopathological features of 99 patients with MC who were treated at our institution from January 2002 to December 2014. We evaluated the expression profiles of markers, including mucin (MUC) family members, in the patients groups representing different MC subtypes by performing immunohistochemistry to identify factors involved in the differentiation and progression of MCs. RESULTS: Among the 99 patients, 76 (76.8%) had pure mucinous carcinomas (pMC) and the other 23 (23.2%) had mixed mucinous carcinomas (mMC). Of the pMCs, 54 were pure A and 22 were pure B. The prognosis was worse for pure B than pure A and worse for mMC than pMC. Although there was no significant difference in clinicopathological factors between the pure A and pure B groups, immunohistochemical staining revealed differences in the localization of mucin MUC1 and ß-catenin. A comparison of the pMC and mMC cases revealed more lymphovascular invasion in mMC and differences in the localization of ß-catenin between the two groups. CONCLUSION: The patients' prognoses were significantly poorer depending on the histologic subtype (in the order pure A, pure B, and mixed). MUC1 localization and ß-catenin were revealed as independent predictors contributing to the poorer prognosis.

Validation of a nuclear grading system for resected stage I-IIIA, high-risk, node-negative invasive breast carcinoma in the N·SAS-BC 01 trial.

BACKGROUND: This retrospective observational study validated nuclear grading criteria developed to identify a high-risk group with recurrence rate ≥20-30% and local pathology diagnosis used in a previous multi-institutional randomized N·SAS-BC 01 trial, where the efficacy of adjuvant chemotherapy regimens was evaluated in 733 high-risk node-negative invasive breast cancer patients. METHODS: Of 545 patients with long-term follow-up data (median 12.1 years), pathology slides, and local pathology diagnosis, 530 eligible patients were subjected to central pathology review (CPR) for histological type and nuclear grade (NG). Concordance in NGs was compared with local diagnosis. The 10/15-year recurrence-free survival (RFS) and overall survival (OS) rates stratified by NG and histological type were calculated. RESULTS: Local diagnoses were invasive ductal carcinoma (IDC)-NG2, IDC-NG3, invasive lobular carcinoma (ILC), and metaplastic carcinoma (MC) in 158/327/38/7 patients, respectively. The 10/15-year RFS rates were 87.2/82.6% for IDC-NG2 and 81.8/75.0% for IDC-NG3 (p = 0.061), and OS rates were 95.0/92.8% for IDC-NG2 and 90.8/85.7% for IDC-NG3 (p = 0.042). CPR graded 485 locally diagnosed IDCs as IDC-NG1/NG2/NG3/unknown in 98/116/267/4 patients, respectively. No significant difference was found among survival curves for the three NG groups. Although the agreement level between local and CPR diagnoses was low (κ = 0.311), both diagnoses identified a patient group with a 15-year recurrence rate ≥ 20%. The 10/15-year RFS rates were 79.4/63.5% for ILC and 68.6%/unknown for MC. CONCLUSIONS: The N·SAS grading system identified a patient group with high-risk node-negative invasive breast cancer, suggesting that local diagnosis was performed efficiently in the N·SAS-BC 01 trial. TRIAL REGISTRATION NUMBER: UMIN000022571. Date of registration: June 1, 2016.

Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer.

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16-7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35-8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

One DNA Methylation Regulates CHIP Gene Expression of Human Breast Cancer and Predicts Recurrence.

BACKGROUND/AIM: Carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase that induces ubiquitination and degradation of its target proteins including oncoproteins. We reported that its down-regulation is associated with tumor progression and metastasis of breast cancer. However, the mechanism through which CHIP gene affects cancer cells is unclear. MATERIALS AND METHODS: We extracted RNA from 45 primary breast cancer samples and compared CHIP mRNA expression profiles, promoter DNA methylation status, and clinicopathological information. RESULTS: CHIP mRNA expression was significantly correlated with the tumor progression status. In several samples, a pinpoint CpG methylation in the CHIP gene promoter region was significantly correlated with CHIP mRNA expression. When this specific CpG was methylated in estrogen receptor (ER)-positive cases, a significant difference in 5-year recurrence was not found compared with ER-negative cases. CONCLUSION: CpG methylation contributes to the long-term prognosis of ER-positive breast cancer.

Nuclear grade and comedo necrosis of ductal carcinoma in situ as histopathological eligible criteria for the Japan Clinical Oncology Group 1505 trial: an interobserver agreement study.

OBJECTIVE: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. METHODS: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. RESULTS: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). CONCLUSION: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.

Optimal Treatment Duration of Neoadjuvant Endocrine Therapy for Women Aged 60 Years or Older with Estrogen Receptor-Positive, HER2-Negative Invasive Breast Cancer.

BACKGROUND: Neoadjuvant endocrine therapy is not the standard of care for breast cancer, primarily because the optimal treatment duration remains unclear. This phase 2 prospective multicenter study analyzed time to progression, time to maximal response, and time to treatment failure for neoadjuvant exemestane. METHODS: Inclusion criteria were women aged ≥60 years with Stage II or III breast cancer classified as estrogen receptor-positive/human epidermal growth factor receptor 2-negative. Response was defined as a ≥10% and minimum of 3 mm decrease in tumor size, as compared with the most recent or smallest value, and no new lesion. Progression was defined as a >10% and minimum of over 3 mm increase in tumor size, as compared with the most recent or smallest value, or a new lesion. Maximal response was defined as the final recorded response. RESULTS: This study included 24 women, most of whom had T2 N0 tumors with high estrogen receptor expression. We initially observed a response in 23 patients (96%); however, 6 patients (25%) later experienced progression. Time to progression, time to maximal response, and time to treatment failure ranged from 7 to 22 months (estimated median, 35), 1 to 22 months (estimated median, 10), and 2 to 22 months (estimated median, 22), respectively. Treatment duration varied widely, but the estimated optimal duration of neoadjuvant exemestane therapy was 22 to 35 months in patients seeking to avoid surgery and 10 months in patients wishing to receive breast-conserving surgery. CONCLUSIONS: Neoadjuvant exemestane therapy is long effective for older women with hormone-sensitive breast cancer.

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

PURPOSE: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes. METHODS: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status. RESULTS: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02). CONCLUSIONS: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

Correction to: Histological classification of breast tumors in the General Rules for Clinical and Pathological Recording of Breast Cancer (18th edition).

In the original publication of the article, the author group and acknowledgements were published incorrectly.

Clinicopathological values of PD-L1 expression in HER2-positive breast cancer.

Several ongoing clinical trials are investigating the use of immuno-targeting therapy with programmed cell death protein-1 and programmed death-ligand 1 (PD-L1) inhibitors for triple-negative breast cancer. However, the role of PD-L1 expression in HER2-positive breast cancer remains unclear. We investigated the clinicopathological utility of PD-L1 expression in HER2-positive breast cancer. Cohort A included 248 patients with invasive breast cancer (all subtypes). Cohort B included 126 HER2-positive patients who received neoadjuvant chemotherapy (NAC) concomitant with trastuzumab. The relationship of PD-L1 expression on the cancer cells with clinicopathological factors including pathological complete response (pCR) and prognosis was investigated. In cohort A, 8.1% patients were PD-L1-positive; PD-L1 positivity showed a correlation with high degree of tumor-infiltrating lymphocytes (TILs), estrogen receptor negativity, progesterone receptor negativity, and high histological grade. In cohort B, 17.5% patients were PD-L1-positive; PD-L1 positivity showed a significant correlation with high degree of TILs and high abundance of CD8-positive TILs. The pCR rates were related to TILs and PD-L1 expression. Among PD-L1-negative patients, high CD8-positive TILs were associated with significantly better prognosis. In conclusion, 17.5% of HER2-positive type patients were PD-L1-positive. PD-L1 expression was associated with response to NAC with trastuzumab in patients with HER2-positive breast cancer.

Multicenter Observational Study of Fulvestrant 500 mg in Postmenopausal Japanese Women with Estrogen Receptor-Positive Advanced or Recurrent Breast Cancer after Prior Endocrine Treatment (SBCCSG29 Study).

BACKGROUND: Fulvestrant 500 mg has been an option for endocrine therapy for advanced or recurrent breast cancer after prior endocrine treatment since November 2011 in Japan. This study aimed to clarify the effectiveness and safety of fulvestrant 500 mg in clinical settings. METHODS: This was a multicenter, both prospective and retrospective, observational study of 132 postmenopausal women (median age 66) with locally advanced or metastatic breast cancer, who had been treated with fulvestrant. Information from medical records was retrospectively obtained from 9 hospitals (Saitama Breast Cancer Clinical Study Group: SBCCSG) in Saitama prefecture, Japan, from October 2012 to April 2014. The primary end point was time to treatment failure (TTF). The secondary end points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AE) (CTCAE ver. 4). The choice of subsequent therapy after fulvestrant was also evaluated. RESULTS: The median TTF was 6.1 months. Median OS was 28.5 months (the starting date was the first day of fulvestrant). ORR was 12.9% and CBR was 45.5%. The most common AEs were injection site reactions (9.1%). The rate of grade 3 AE was only 2.3% (3/132). The number of patients who underwent subsequent therapy after fulvestrant were 54 (55.7%) receiving chemotherapy, 42 (43.3%) receiving non-fulvestrant endocrine therapy, and 1 (1%) receiving mammalian target of rapamycin inhibitor (mTORi) + endocrine therapy (ET). CONCLUSION: Fulvestrant 500 mg is an effective and safe treatment for patients with advanced or recurrent breast cancer after prior endocrine treatment.

ß2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer.

PURPOSE: Antitumor immunity plays an important role in the progression of breast cancer. ß2-adrenergic receptor (ß2AR) was found to regulate the antitumor immune response and breast cancer progression in preclinical studies. To understand the clinical role of ß2AR in cancer progression, we investigated the clinicopathological and prognostic significance of ß2AR expression in invasive breast cancer. METHODS: ß2AR levels in breast tumors were evaluated by immunohistochemistry in a well-characterized patient cohort with long-term follow-up (n = 278). We evaluated the relationship of ß2AR expression to patient survival and clinicopathological factors, including immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. Breast cancer-specific survival was compared between high- and low-ß2AR expression groups. RESULTS: Although ß2AR was not related to clinicopathological factors across the whole cohort, high ß2AR was significantly related to PD-L1 negativity in estrogen receptor (ER)-negative patients. Tumors with high ß2AR tended to have low TIL grade, and high ß2AR was an independent prognostic factor for reduced survival in ER-negative patients. CONCLUSIONS: ß2AR is an independent poor prognostic factor in ER-negative breast cancer. The findings suggest that tumor ß2AR regulates immune checkpoint activity, which may have therapeutic implications for patients with ER-negative breast cancer.

Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy.

In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments.

Prognostic significance of tumour-infiltrating lymphocytes for oestrogen receptor-negative breast cancer without lymph node metastasis.

Tumour-infiltrating lymphocytes (TILs) are regarded as significant prognostic markers in patients with breast cancer. However, the prognostic utility of TIL expression based on the intrinsic subtypes has just been identified. The present study investigated the relationship between TIL grades and prognosis in 294 Japanese paitents with breast cancer stratified based on the intrinsic subtypes and clinicopathological characteristics. Stromal TIL status was evaluated using haematoxylin and eosin staining, and TIL grades were categorised into low (<10%), intermediate (≥10 and ≤40%) and high (>40%) groups. The relationship between TIL expression and the intrinsic subtypes, clinicopathological characteristics and patient prognosis was analyzed. It was revealed that high TIL expression was correlated with negative oestrogen receptor (ER) expression and high histological grade (P<0.001). Among the ER-negative patients, the relapse-free survival (RFS) rate of the high-grade TIL group was significantly higher than that of the low-grade TIL group (P=0.04). Among the ER-negative patients without lymph node metastasis, RFS and cancer-specific survival (CSS) rates of patients with high-grade TILs were significantly higher than the RFS and CSS rates of patients with low-grade TILs (P=0.01). However, among ER-positive patients, RFS was significantly higher in the low-grade TIL group than in the high-grade TIL group (P=0.02). In conclusion, TIL expression correlated with ER status and tumour proliferation. High TIL expression was a poor prognostic marker in ER-positive patients but was a good prognostic marker in ER-negative patients. Therefore, the biological association between TILs and primary breast tumours may differ between ER-positive and ER-negative breast cancer.

Prognostic utility of tumor-infiltrating lymphocytes in residual tumor after neoadjuvant chemotherapy with trastuzumab for HER2-positive breast cancer.

Predictive utility of tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancer patients receiving neoadjuvant chemotherapy (NAC) with concurrent trastuzumab remains unclear. We examined TILs grades of pretreatment cancer tissue specimens and residual tumors after NAC with trastuzumab and determined the predictive utility of the TILs grade in pathological complete response (pCR) and the prognostic power of TILs in HER2-positive breast cancer. This cohort study included 128 HER2-positive breast cancer who received NAC with trastuzumab. TILs grading of the tumor stroma in pretreatment biopsy specimens and residual tumors after NAC with trastuzumab was categorized as low, intermediate, and high based on the criteria of the International Working Group. In current study, the pCR rate was 64.8%, and the Relapse-free survival (RFS) was significantly worse in the non-pCR group than in the pCR group. The pCR rate correlated with the TILs grade in pretreatment tumors. In 45 non-pCR patients, TILs grade was higher in the residual tumors than in the pretreatment tumors. The RFS was significantly better in residual tumors with high TILs grade than those with low TILs grade (p = 0.033). In conclusion, assessment of the TILs grade in residual tumors after NAC with trastuzumab might be necessary to determine patients with good prognosis among those who do not achieve pCR.

Comparing protein and mRNA expressions of the human epidermal growth factor receptor family in estrogen receptor-positive breast cancer.

The human epidermal growth factor receptor (HER) family plays a vital role in the development of resistance to treatments in estrogen receptor (ER)-positive breast cancer. This study investigated the correlation between protein and mRNA expressions of the HER family in ER-positive breast cancer. We dissected regions of invasive cancer from the frozen tissues of 34 patients with ER-positive breast cancer using laser-capture microdissection, followed by evaluation of the mRNA levels of the ER and HER family (EGFR, HER2, HER3, and HER4) using the quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. In addition, we assessed the protein expressions of the ER and HER family using an immunohistochemical (IHC) assay. A significant correlation was observed between the ER protein and mRNA expressions. For HER2, HER3, and HER4, protein expressions significantly correlated with mRNA levels. We established significant correlations of the mRNA level between EGFR versus HER2, as well as EGFR versus HER3. Furthermore, a significant correlation of the mRNA level between HER2 and HER3 was illustrated. In conclusion, IHC evaluation may be reliable and representable for mRNA. Hence, this study established a marked correlation between the mRNA expressions of HER family members in patients with ER-positive breast cancer.

Impact of combining the progesterone receptor and preoperative endocrine prognostic index (PEPI) as a prognostic factor after neoadjuvant endocrine therapy using aromatase inhibitors in postmenopausal ER positive and HER2 negative breast cancer.

The preoperative endocrine prognostic index (PEPI) predicts survival after neoadjuvant endocrine therapy (NAE) using aromatase inhibitors (AIs) for women with postmenopausal estrogen receptor (ER)-positive breast cancer irrespective of the human epidermal growth factor receptor 2 (HER2) status. Although the progesterone receptor (PgR) is also a prognostic factor for ER-positive breast cancer, the PgR status was not considered a prognostic factor in the original PEPI scoring system. In this study, we investigated the utility of a modified PEPI including the PgR status (PEPI-P) as a prognostic factor after NAE for postmenopausal patients with ER-positive and HER2-negative breast cancer. We enrolled 107 patients with invasive ER-positive and HER2-negative breast cancer treated with exemestane for ≥4 months as NAE. We initially assessed PEPI and compared survival between the groups. Additionally, we obtained an effective cutoff for PgR through survival analysis. Then, we assessed the survival significance of PEPI-P. A PgR staining rate of 50% was the most significant cutoff for predicting recurrence-free survival (RFS) and cancer-specific survival (CSS). PEPI was a significant prognostic factor; moreover, PEPI-P was the most significant prognostic indicator for RFS and CSS. PEPI-P is a potent prognostic indicator of survival after NAE using AIs for postmenopausal patients with ER-positive and HER2-negative breast cancer. This modified PEPI may be useful for therapeutic decision-making regarding postmenopausal ER-positive and HER2-negative breast cancer after NAE.

Effectiveness of neo-adjuvant systemic therapy with trastuzumab for basal HER2 type breast cancer: results from retrospective cohort study of Japan Breast Cancer Research Group (JBCRG)-C03.

PURPOSE: While human epidermal growth factor receptor 2 (HER2) target therapies have significantly improved the prognosis of patients with HER2-enriched breast cancer, differing clinical benefits and gene expression analyses suggest a divergent HER2 subgroup. We aimed to investigate whether the basal HER2 subtype of breast cancer has distinguished characteristics. METHODS: We performed a substudy by using data from a retrospective multi-institutional cohort of JBCRG-C03. Between 2001 and 2011, we identified 184 eligible patients who received concurrent neo-adjuvant chemotherapy (NAC) with trastuzumab for hormone receptor-negative and HER2-positive breast cancer. We defined basal HER2 subtype breast cancer as HER2-positive, ER/PgR-negative, and basal markers (EGFR, CK14 or CK5/6) positive by immunohistochemistrical evaluation. The pathologic complete response (pCR) and disease-free survival (DFS) rates were compared between the two subtypes. RESULTS: A total of 127 (69.0%) patients achieved pCR after NAC and 29 (15.8%) patients experienced events of DFS within a 42 month median follow-up period (interquartile range 26-58 months). Although the basal HER2 subtype was related with poor DFS (3 year DFS: non-basal HER2, 95.0%; basal HER2, 86.9%; adjusted HR 3.4; 95% CI 1.2-14.5), neither the subtype (pCR: non-basal HER2, 75%; basal HER2, 66.7%; adjusted OR 0.60; 95% CI 0.27-1.28) nor the degree of expression of basal markers was significantly related with the pCR rate. CONCLUSION: Basal HER2 phenotype showed poor DFS, but equivalent pCR rate after concurrent neo-adjuvant chemotherapy with trastuzumab. A different treatment approach to basal-HER2 type is needed even for cases that achieved adequate clinical response after NAC.

Induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin in Japanese patients with HER2-negative metastatic breast cancer: a multicenter, collaborative, open-label, phase II clinical study for the SBCCSG 35 investigators.

BACKGROUND: To examine the efficacy and safety of induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin (ISMT) in Japanese patients with HER2-negative metastatic breast cancer (MBC). METHODS: Patients, who had previously undergone a maximum of 2 regimens of chemotherapy, received 3 cycles of induction therapy with paclitaxel (90 mg/m2 intravenously on days 1, 8, and 15 followed by 1-week drug holiday) and bevacizumab (10 mg/kg intravenously after the completion of paclitaxel administration on days 1 and 15). Patients who had complete response, partial response, or stable disease underwent switch maintenance therapy with eribulin (1.4 mg/m2 intravenously on days 1 and 8 followed by 1-week drug holiday). The primary endpoint was time to treatment failure (TTF) for ISMT. RESULTS: Fifty-one eligible patients (median age: 66 years; range: 35-74) were enrolled: 19 (37.3%) and 32 (62.7%) had stage IV and recurrence, respectively, 42 (82.4%) had visceral metastases, and 45 (88.2%) received eribulin-38 of whom showed disease progression, and 40 (78.4%) underwent post therapy. Median TTF was 9.2 months (95% confidence interval [CI]: 7.3-11.1), median progression-free survival was 10.7 months (95% CI: 9.6-11.8), and median overall survival was 20.0 months (95% CI: 16.0-24.0). Relative dose intensity was 97.7% (range: 33.3-100.0) for induction therapy and was 83.3% (range: 49.3-100.6%) for eribulin maintenance therapy. The most common adverse event was alopecia (51 [100%]) in induction therapy and was peripheral sensory neuropathy (37 [82.2%]) in eribulin maintenance therapy. Eribulin was effective with manageable tolerability. CONCLUSIONS: ISMT may be a promising therapeutic option for patients with MBC. TRIAL REGISTRATION: UMIN000015971 . Registration date: January 1, 2015.