Risk factors for recurrence in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in Japan: a systematic literature review and meta-analysis.

BACKGROUND: The clinicopathological factors indicating risk of recurrence are used to guide the choice of perioperative therapy in patients with breast cancer. Although several risk factors for recurrence have been reported in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer in Japan, there has been no systematic review quantifying potential risk factors. METHODS: We performed a systematic literature review and meta-analysis using the MEDLINE, Embase, Cochrane CENTRAL, and Japan Medical Abstract Society databases to identify risk factors for recurrence in HR+/HER2- early breast cancer in Japan. The primary outcome was relapse-free or disease-free survival (RFS/DFS), and the secondary outcomes were overall survival and breast cancer-specific survival (BCSS). RESULTS: Searches identified 42 eligible publications. Meta-analyses identified lymph node metastasis (hazard ratio: 2.76 [95% confidence interval: 1.97-3.88]), large tumor size (1.67 [1.24-2.23]), high histological grade (1.50 [1.04-2.16]), and high nuclear grade (2.02 [1.61-2.54]) as risk factors for RFS/DFS. Lymph node metastasis (2.43 [1.28-4.63]), large tumor size (1.80 [1.24-2.62]), and high histological grade (2.02 [1.44-2.84]) were also risk factors for overall survival, and high progesterone status was a possible favorable prognostic factor for BCSS (0.20 [0.10-0.42]). CONCLUSIONS: Identified risk factors were consistent with the previous reports, and this study provides quantitative summary of risk factors for HR+/HER2- early breast cancer recurrence in Japan. (PROSPERO Registration ID, CRD42022338391.).

[A Case of Triple Negative Breast Cancer with Successful Control of Recurrent Disease Activity for More than Ten Years].

A woman in her 70s underwent mastectomy plus axillary lymph node excision(Bt plus Ax)in December 2011 for left breast cancer classified as pT2N1M0, pStage ⅡB. The tumor was identified as an invasive ductal carcinoma(IDC), neural/ glial antigen 2(NG2), pT2(35 mm), INF γ, ly2, v0, g+, f+, s+, extensive intraductal component(EIC)-negative, ICT- positive, NCAT-positive, n(4/18), estrogen receptor(ER)-negative, progesterone receptor(PgR)-negative, human epidermal growth factor receptor 2(HER2)-negative, Ki-67 30-40%. Postoperative adjuvant fluorouracil plus epirubicin HCl plus cyclophosphamide(FEC)plus paclitaxel(PTX)therapy was administered. The patient refused to undergo postoperative radiation therapy. Two years after the surgery, she was diagnosed as having a lung metastasis and local disease recurrence. Biopsy of the local recurrent lesion revealed the same histopathological diagnosis as before. Capecitabine was selected for treatment of the recurrent lesion. After 2 years of capecitabine treatment, the response was rated as progressive disease (PD). At this time, eribulin mesylate was selected, along with intensity-modulated radiation therapy(IMRT). This resulted in disappearance of the tumor on imaging. However, considering that the histological findings did not suggest complete response(CR)and that the tumor was triple-negative(TN), we adopted a strategy of continuing the drug therapy at reduced dose level. With this strategy, the disease activity could be successfully controlled for 6.5 years. Subsequently, liver metastasis was detected, and the drug was switched to vinorelbine ditartrate(a drug with less non-hematological toxicity). Meanwhile, a breast cancer susceptibility gene(BRCA)analysis was performed in January 2021, which was negative. Subsequently, in September 2021, we obtained a positive result for PDL1-SP142 and negative result for 22C3. About half a year later, ie, in October 2021(11 years after the surgery), we detected an increase in the size of the liver metastasis and selected atezolizumab and nab-PTX for treatment. Applicable regimens of drug therapy are still available at present and drug therapy has been continued based on a discussion and mutual understanding of the adverse reactions, etc. with the patient. Few reports have been published concerning long-term survivors among TN breast cancer cases.

A Case of Brachial Lymph Node Recurrences after the Resection of Locally Advanced Breast Cancer.

We present a case of two recurrences in the brachial lymph nodes after initial resection, which was performed for radical cure. A 66-year-old woman was diagnosed with left breast cancer T4bN3cM0 Stage IIIC and an immunohistochemistry assay showed estrogen receptor (ER) positivity (5%), progesterone-receptor (PgR) positivity (1%), human epidermal growth factor receptor-2 (HER2) positivity (3+), and low Ki-67 (15%). After four courses of adriamycin and cyclophosphamide, followed by four courses of trastuzumab plus docetaxel, the patient underwent left mastectomy and axillary dissection. Postoperatively, she was diagnosed with breast cancer ypT1cN0M0, and trastuzumab and anastrozole were started. Postoperative irradiation was performed. Three years and 5 months after the initial breast cancer surgery, she had left brachial lymph node recurrence. It was resected, and tamoxifen was administered postoperatively. One year and 9 months after, she had another left brachial lymph node recurrence, and it was resected. She received radiation therapy to her upper limb and started taking exemestane. After 1 year and 3 months since the second recurrence surgery, there has been no recurrence. Our case suggests that the replacement of regional lymph nodes with tumor cells may result in the reconstruction of lymph flow to the upper arm and the development of brachial lymph node metastasis. There are no reports of resection of the recurrent tumor in the brachial lymph node for curative treatment. Therefore, careful follow-up is important in the future.

Establishment of a deep-learning system to diagnose BI-RADS4a or higher using breast ultrasound for clinical application.

Although the categorization of ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) has become widespread worldwide, the problem of inter-observer variability remains. To maintain uniformity in diagnostic accuracy, we have developed a system in which artificial intelligence (AI) can distinguish whether a static image obtained using a breast ultrasound represents BI-RADS3 or lower or BI-RADS4a or higher to determine the medical management that should be performed on a patient whose breast ultrasound shows abnormalities. To establish and validate the AI system, a training dataset consisting of 4028 images containing 5014 lesions and a test dataset consisting of 3166 images containing 3656 lesions were collected and annotated. We selected a setting that maximized the area under the curve (AUC) and minimized the difference in sensitivity and specificity by adjusting the internal parameters of the AI system, achieving an AUC, sensitivity, and specificity of 0.95, 91.2%, and 90.7%, respectively. Furthermore, based on 30 images extracted from the test data, the diagnostic accuracy of 20 clinicians and the AI system was compared, and the AI system was found to be significantly superior to the clinicians (McNemar test, p < 0.001). Although deep-learning methods to categorize benign and malignant tumors using breast ultrasound have been extensively reported, our work represents the first attempt to establish an AI system to classify BI-RADS3 or lower and BI-RADS4a or higher successfully, providing important implications for clinical actions. These results suggest that the AI diagnostic system is sufficient to proceed to the next stage of clinical application.

Pathologic method for extracting good prognosis group in triple-negative breast cancer after neoadjuvant chemotherapy.

The area of residual tumor (ART) is a prognostic factor in patients treated with neoadjuvant chemotherapy (NAC) for lung, pancreatic, and rectal cancers. This study aimed to evaluate the usefulness of ART as a method for predicting the prognosis of triple-negative breast cancer (TNBC) patients after NAC. We included 143 patients with TNBC treated with NAC. The ART at the maximum cut surface of the residual tumor was measured. We divided the patients into three groups: ART-0 (ART = 0 mm2 ), ART-low (0 mm2  < ART ≤ 136mm2 ), and ART-high (ART > 136 mm2 ), and compared their clinicopathologic factors and prognosis. There were no significant differences in either recurrence-free survival (RFS) or overall survival (OS) between ART-0 and ART-low; however, the ART-high group had significantly shorter RFS and OS than the ART-0 and ART-low groups. Multivariate analysis showed that ART-0 and -low and ypN(-) were independent favorable prognostic factors for RFS. Groups with both ART-low and ypN(-) as well as those with ART-0 and ypN(-) showed significantly longer OS and RFS than the other groups (P < .05). Moreover, there was no significant difference in the RFS and OS between the ART-0 and ypN(-) groups and the ART-low and ypN(-) groups (P = .249 and P = .554, respectively). We concluded that ART is a candidate histopathological evaluation method for predicting the prognosis of TNBC patients treated with NAC. Furthermore, postoperative chemotherapy could be omitted in patients with ART-0 and ypN(-) (pathological complete response) and those with ART-low and ypN(-).

Predictors of invasive disease in patients preoperatively diagnosed with ductal carcinoma without stromal invasion, with breast magnetic resonance imaging (MRI) and ultrasound (US).

BACKGROUND: A preoperative diagnosis of ductal carcinoma in situ (DCIS) is sometimes upstaged to invasive disease postoperatively. Our objective was to clarify the predictive factors of invasive disease using preoperative imaging and to investigate the positive ratio of sentinel lymph nodes (SLN) and the incidence of invasive disease. METHODS: The subjects were 402 patients with preoperatively diagnosed ductal carcinoma without stromal invasion who underwent breast surgery with concomitant SLN surgery in January 2007 to December 2016. Of the 306 included patients, all 306 patients underwent preoperative MRI and US assessment. Outcomes were analyzed for significance using univariate and multivariate analyses. RESULTS: Of the 306 patients, 115 (37.6%) had invasive disease and 191 (62.4%) had DCIS only. Of the 115 patients with invasive disease, 5 (4.4%) and 4 (3.5%) had macro- and micrometastases in SLN. On the other hand, of the 191 patients with DCIS, only 1 (0.5%) had a micrometastasis. Predictors of invasive disease in the univariate analysis included having a palpable mass, were varied by biopsy method, having a US hypoechoic mass, MRI enhancement, or MRI large enhanced lesion; the size of the mass enhancement ≥ 1.1 cm or a spread of non-mass enhancement ≥ 3.1 cm (P = 0.003). Predictors of invasive disease in the multivariate analysis included US hypoechoic mass and MRI large enhanced lesion. CONCLUSION: We need to perform SLN biopsy for preoperatively diagnosed DCIS when patients have predictors of invasive disease, but SLN biopsy will no longer be essential for patients when they have no predictors of invasive disease.

Survival outcomes in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer administered a therapy following trastuzumab emtansine treatment.

Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following T-DM1 and clarify the predictive factors of their prognosis.We retrospectively identified patients with HER2-positive MBC who received T-DM1 between April 1, 2014, and December 31, 2018, at the National Cancer Center Hospital, and focused on the population that received another line of therapy following T-DM1 discontinuation.Thirty patients were available for the outcome analysis. Median progression-free survival (PFS) of the first subsequent therapy was 6.0 months [95% confidence interval (95% CI) 4.1-6.4], whereas the median overall survival (OS) from the first subsequent therapy was 20.6 months (95% CI 13.5 months to not reached). We divided the patients into 2 groups according to their PFS with T-DM1 treatment and compared their PFS with the subsequent therapy. The results revealed a significant difference in the median PFS with the first subsequent treatment between patients with the PFS of less than and more than 3 months [5.1 (95% CI 1.7-6.2) vs 6.2 (95% CI 4.0-11.3) months, P = .03].This is the first study to evaluate the survival outcomes of post-T-DM1 therapy in Japanese patients with HER2-positive MBC. A short PFS with T-DM1 might affect the PFS with a treatment after T-DM1.

Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.

Invasive lobular carcinoma (ILC) has a different treatment response from invasive ductal carcinoma (IDC). We assessed whether perioperative chemotherapy was associated with improved prognosis in patients with ILC. Retrospective data of women who underwent surgery for ILC were extracted from the SEER database. Subjects were divided into non-chemotherapy and chemotherapy groups. Overall, 10 537 patients were included, and 2107 patients were stratified into each group after propensity score matching. Perioperative chemotherapy significantly improved 10-year survival rates for ILC, particularly in patients with large tumor size and lymph node metastases. Perioperative chemotherapy is effective for ILC patients with proper selection.

Identification of a Modified HOXB9 mRNA in Breast Cancer.

First identified as a developmental gene, HOXB9 is also known to be involved in tumor biological processes, and its aberrant expression correlates with poor prognosis of various cancers. In this study, we isolated a homeodomain-less, novel HOXB9 variant (HOXB9v) from human breast cancer cell line-derived mRNA. We confirmed that the novel variant was produced from variationless HOXB9 genomic DNA. RT-PCR of mRNA isolated from clinical samples and reanalysis of publicly available RNA-seq data proved that the new transcript is frequently expressed in human breast cancer. Exogenous HOXB9v expression significantly enhanced the proliferation of breast cancer cells, and gene ontology analysis indicated that apoptotic signaling was suppressed in these cells. Considering that HOXB9v lacks key domains of homeobox proteins, its behavior could be completely different from that of the previously described variationless HOXB9. Because none of the previous studies on HOXB9 have considered the presence of HOXB9v, further research analyzing the two transcripts individually is warranted to re-evaluate the true role of HOXB9 in cancer.

Optimal use of anthracycline-free perioperative chemotherapy in HER2-positive breast cancer patients.

PURPOSE: In adjuvant settings of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, anthracycline-based chemotherapy followed by taxane and trastuzumab is a standard regimen. Recent studies have reported the use of anthracycline-free adjuvant chemotherapy in selected HER2-positive breast cancer patients. We conducted a single-center retrospective study to identify the characteristics of HER2-positive breast cancer patients for whom anthracyclines can be safely omitted. METHODS: A total of 238 women were diagnosed with HER2-positive breast cancer and treated with neoadjuvant and/or adjuvant chemotherapy between January 1, 2008 and December 31, 2015 at Keio University Hospital. They were divided in two cohorts: an "anthracycline" cohort of 112 anthracycline-treated women and a "no anthracycline" cohort of 126 anthracycline-untreated women. Survival outcomes were estimated by Kaplan-Meier method. RESULTS: The 3-year disease-free survival rates in the no-anthracycline and anthracycline cohorts were 91.3% and 93.1%, respectively (P = 0.692). After using a statistical method with inverse probability of treatment weighting to minimize the selection bias, no significant differences were observed between the two cohorts (adjusted hazard ratio for disease-free survival: 1.042; P = 0.909). Stratified by tumor size, no significant differences were observed between the two cohorts in the cT1N0 and cT2N0 subsets (P = 0.516 and P = 0.579, respectively). The recurrence rate was low among patients who achieved pathological complete response after receiving neoadjuvant chemotherapy with or without anthracyclines. CONCLUSION: Our study suggests that anthracyclines can be safely omitted in selected patients with HER2-positive breast cancer, who have cT1N0 or cT2N0 and achieved pathological complete response after receiving neoadjuvant chemotherapy.

IgG4-related mastopathy: A case report and literature review.

IgG4-related sclerosing disease (IgG4-RD) occasionally involves breast entity, which is often difficult to distinguish from malignant tumor, as both radiologically resembles. We report a case of a breast mass diagnosed as IgG4-related mastopathy (IgG4-RM) through needle biopsy, which responded well to glucocorticoid therapy. Unnecessary excision should be avoided.

The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer.

BACKGROUND: We previously described a systematic assessment of the neoadjuvant therapies for human epidermal growth factor receptor-2 (HER2) positive breast cancer, using network meta-analysis. Accumulation of new clinical data has compelled us to update the analysis. METHODS: Randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting were included, and odds ratio for pathologic complete response (pCR) in seven treatment arms were assessed by pooling effect sizes. Direct and indirect comparisons using a Bayesian statistical model were performed. All statistical tests were two-sided. RESULTS: A database search identified 993 articles with 13 studies meeting the eligibility criteria, including three new studies with lapatinib (lpnb). In an indirect comparison, dual anti-HER2 agents with CT achieved a better pCR rate than other arms. The credibility intervals of CT + tzmb + lpnb arm were largely reduced compared to our former report, which we added sufficient clinical evidence by this update. Values of surface under the cumulative ranking (SUCRA) suggested that CT + tzmb + pzmb had the highest probability of being the best treatment arm for pCR, widening the difference between the top two dual-HER2 blockade arms compared to our former report. The overall consistency with our first report enhanced the credibility of the results. CONCLUSION: Network meta-analysis using new clinical data firmly establish that combining two anti-HER2 agents with CT is most effective against HER2-positive breast cancer in the neoadjuvant setting. New pzmb related trials are required to fully determine the best neoadjuvant dual-HER2 blockade regimen.