Risk-reducing decisions regarding germline BRCA pathogenic variant: focusing on the timing of genetic testing and RRSO.

BACKGROUND: In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan. METHODS: This retrospective analysis included 350 women with germline BRCA (gBRCA) pathogenic variants (PVs) who had visited gynaecologists; they received gBRCA genetic testing at 45.1±10.6 (20-74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher's exact tests. RESULTS: The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with gBRCA-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO. CONCLUSION: Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.

Impact of the coverage of risk-reducing salpingo-oophorectomy by the national insurance system for women with BRCA pathogenic variants in Japan.

To determine the impact of the coverage of risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) as well as genetic testing for BRCA pathogenic variants by the national insurance system in Japan. We compared the clinical background of women who underwent RRSO at our institution before and after its coverage by the national insurance system. Those who underwent RRSO between January 2017 and December 2019 and between April 2020 and March 2022 were classified as Period. A and B, respectively. Overall, 134 women underwent RRSO during the study period. In Period A and B, 45 and 89 women underwent RRSO for the study period was 36 and 24 months, respectively. Compared with Period A, the number of women who underwent RRSO per month increased by threefold in Period B (p < 0.01). In addition, the number of women who underwent surgery for breast cancer along with RRSO increased in Period B (p < 0.01). Although the number of women who underwent concurrent RRM with RRSO in Period B increased, the difference was not statistically significant. Compared with Period A, the number of women diagnosed with BRCA pathogenic variant increased by 3.9-fold, and the proportion of women who underwent concurrent hysterectomy at the time of RRSO decreased from 66 to 7.9% in Period B (p < 0.01). Owing to the introduction of the national insurance system, the number of women who underwent RRSO and concurrent surgery for breast cancer at the time of RRSO increased in Japan.

Clinicopathological features of breast cancer patients with internal mammary and/or supraclavicular lymph node recurrence without distant metastasis.

BACKGROUND: Internal mammary and/or supraclavicular (IM-SC) lymph node (LN) recurrence without distant metastasis (DM) in patients with breast cancer is rare, and there have been few reports on its clinical outcomes. METHODS: We enrolled 4237 patients with clinical stage I-IIIC breast cancer treated between January 2007 and December 2012. Clinicopathological features of patients with IM-SC LN recurrence and patients with DM were retrospectively reviewed. RESULTS: With a median follow-up time 78 (range, 13-125) months after the primary operation, 14 (0.3%) had IM-SC LN recurrence without DM and 274 (6.5%) had DM at the first recurrence among 4237 patients. No statistical differences were found in the baseline characteristics of the primary tumor between the two groups. The 5-year overall survival (OS) rate after recurrence in patients with IM-SC LN recurrence was 51% compared with 27% in patients with DM (P = 0.040). In patients with IM-SC LN recurrence, clinically positive axillary LN at diagnosis and pathologically positive axillary LN at primary surgery were poor prognostic factors for distant disease-free survival (DDFS) (P = 0.004 and 0.007, respectively). Clinical and pathological axillary nodal status at primary surgery was associated with OS (P = 0.011 and 0.001, respectively). CONCLUSIONS: Patients with IM-SC LN recurrence without DM who had no clinical and pathological axillary LNs involved at primary surgery had a favorable prognosis. A larger validation study is required.

Survival in Cytologically Proven Node-Positive Breast Cancer Patients with Nodal Pathological Complete Response after Neoadjuvant Chemotherapy.

BACKGROUND: It is unknown whether patients with cytologically proven axillary node-positive breast cancer who achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have comparable prognosis to patients with axillary pathological node-negative disease (pN-) without NAC. METHODS: We retrospectively reviewed the data of patients with cytologically proven axillary node-positive disease who received NAC and those with axillary pN- without NAC for control between January 2007 and December 2012. We compared outcomes according to response in the axilla to NAC and between patients with axillary pCR and matched pairs with axillary pN- without NAC using propensity scores. RESULTS: We included 596 patients with node-positive breast cancer who received NAC. The median follow-up period was 64 months. Patients with axillary pCR showed significantly better distant disease-free survival (DDFS) and overall survival (OS) than patients with residual axillary disease (both p < 0.01). There was no significant difference in DDFS and OS between patients with axillary pCR and matched pairs with axillary pN- without NAC. CONCLUSION: Axillary pCR was associated with improved prognosis. Patients with axillary pCR and matched pairs with axillary pN- without NAC had comparable outcomes. This information will be useful when considering the intensity of follow-up and adjuvant therapy.

Correction to: A comparison of clinicopathological characteristics and long-term survival outcomes between symptomatic and screen-detected breast cancer in Japanese women.

In the original publication of this article, Table 1 was published incorrectly with rows out of order under "Distant metastasis (n, %)".

Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression of distant metastatic lesions in patients with metastatic breast cancer.

BACKGROUND: Surgical biopsy of metastatic lesions followed by pathological confirmation for the investigation of biomarkers is occasionally proposed as an effective strategy in the treatment of metastatic breast cancer. However, few reports have examined Ki-67 immunohistochemical expression in distant metastatic lesions of breast cancer patients. This study aimed to investigate the clinicopathological significance of subtypes and Ki-67 immunohistochemical expression in metastatic breast cancer lesions. METHODS: We retrospectively studied surgical specimens of primary breast cancer tumors and their corresponding metastatic lesions from patients (n = 68) who underwent surgery for primary breast cancer tumors between December 1977 and March 2013. Tissue microarrays were constructed using primary and metastatic lesions, and were stained with antibodies against estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. We also examined the clinicopathological characteristics and outcome measures of patients with metastatic breast cancer using primary and paired metastatic lesions. RESULTS: Compared with the primary lesions, there was no significant difference in subtypes in the metastatic lesions according to metastatic sites. Metastatic lesions of the brain, viscera, and bone exhibited slightly higher levels of Ki-67 immunohistochemical expression compared with primary lesions. A Cox proportional hazards model using multivariate analysis demonstrated that high Ki-67 immunohistochemical expression in distant metastatic lesions was associated with poorer overall survival outcomes after biopsy of recurrence lesion (hazard ratio 2.307; 95% confidence interval 1.207-4.407, P = 0.011). CONCLUSIONS: High Ki-67 immunohistochemical expression levels in distant metastatic lesions were independently associated with poorer overall survival outcomes after biopsy of recurrence lesion in breast cancer patients.

Expression of enhancer of zeste homolog 2 correlates with survival outcome in patients with metastatic breast cancer: exploratory study using primary and paired metastatic lesions.

BACKGROUND: In metastatic breast cancer, the status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as the Ki-67 index sometimes change between primary and metastatic lesions. However, the change in expression levels of enhancer of zeste homolog 2 (EZH2) between primary and metastatic lesions has not been determined in metastatic breast cancer. METHODS: Ninety-six metastatic breast cancer patients had biopsies or resections of metastatic lesions between September 1990 and February 2014 at the Kanagawa Cancer Center. We evaluated ER, PR, HER2, Ki-67, and EZH2 in primary lesions and their corresponding metastatic lesions using immunohistochemistry. We examined the change in expression of EZH2 between primary and metastatic lesions, the correlation between the expression of EZH2 and the expression of other biomarkers, and the relationship between EZH2 expression and patient outcome in metastatic breast cancer. RESULTS: EZH2 expression was significantly higher in metastatic lesions compared with primary lesions. EZH2 expression was highly correlated with Ki-67 expression in primary and metastatic lesions. High-level expression of EZH2 was associated with poorer disease-free survival (DFS) outcomes in patients with primary lesions (P < 0.001); however, high-level expression of EZH2 was not associated with poorer DFS outcomes in patients with metastatic lesions (P = 0.063). High-level expression of EZH2 was associated with poorer overall survival (OS) postoperatively in patients with primary (P = 0.001) or metastatic lesions (P = 0.005). High-level expression of EZH2 was associated with poorer OS outcomes after recurrence in patients with metastatic lesions (P = 0.014); however, high-level expression of EZH2 was not associated with poorer OS outcomes after recurrence in patients with primary lesions (P = 0.096). High-level expression of EZH2 in metastatic lesions was independently associated with poorer OS outcomes after recurrence. CONCLUSIONS: EZH2 expression was significantly increased in metastatic lesions compared with primary lesions. High-level expression of EZH2 in metastatic lesions was associated with poorer OS outcomes after primary surgery and recurrence.

A comparison of clinicopathological characteristics and long-term survival outcomes between symptomatic and screen-detected breast cancer in Japanese women.

BACKGROUND: Several studies from other countries have reported that patients with screen-detected breast cancer have better survival than those with symptomatic breast cancer. However, no such comparison has been performed in Japan. Therefore, we aimed to compare the clinicopathological characteristics and survival rates between symptomatic and screen-detected breast cancer in Japanese women. METHODS: From January 2000 to December 2004, 977 and 182 women with symptomatic or screen-detected breast cancer, respectively, underwent surgery at a single Japanese hospital. We retrospectively reviewed these patients' clinicopathological data. Likelihood of death was estimated using the Kaplan-Meier method and the log-rank test. Multivariate analysis including mode of detection, tumor size, lymph node status, hormone receptor status, and adjuvant therapy administration was performed using the Cox proportional hazards model. RESULTS: Screen-detected breast cancer was associated with increased rate of breast-conserving surgery, non-invasive carcinoma, smaller tumor size, decreased lymph node involvement, increased hormone receptor positivity, and decreased adjuvant chemotherapy administration. Compared to women with symptomatic tumors, those with screen-detected tumors had improved overall and breast cancer-specific survival rates. Factors associated with survival in univariate analysis were screen detection, tumor size, lymph node status, progesterone receptor status, and adjuvant chemotherapy administration. CONCLUSIONS: Breast cancer screening in Japanese women has led to increases in the rates of breast-conserving surgery, hormone receptor positivity, and survival rates along with reductions in axillary lymph node dissection and adjuvant chemotherapy administration.

A propensity score-matching analysis comparing the oncological outcomes of laparoscopic and open surgery in patients with Stage I/II colon and upper rectal cancers.

PURPOSE: Previous studies from Western countries have shown similar survival outcomes after both open and laparoscopic resections. In Japan, radical D3 dissections performed by open resection have been routinely performed for ≥T2- or ≥N1-stage cancers, and relatively favorable survival outcomes were obtained. This study compared the survival in patients with Stage I/II colon and upper rectal cancers undergoing laparoscopic and open resection. METHODS: A total of 145 patients were initially enrolled. Propensity score matching was applied to assemble a study cohort. D2 lymph node dissection for T1 cancer and D3 for ≥T2- and ≥N1-stage cancers were applied. The primary outcome measure was the disease-free survival; the cancer-specific and overall survival rates were secondary outcomes. RESULTS: A total of 64 patients were matched for the analysis. The length of hospitalization, postoperative complication rates, number of lymph nodes removed and surgical margins were similar between the groups. The disease-free survival following laparoscopic surgery was better than that following open surgery, but the difference was not statistically significant. Neither the cancer-specific nor overall survival rates following laparoscopic surgery were inferior to those associated with open surgery. CONCLUSIONS: The outcomes of the laparoscopic approach were comparable to those for open surgeries accompanied by radical lymph node dissection.

[A case of postmenopausal breast cancer becoming HER2 positive after neoadjuvant hormone therapy].

A 75-year-old woman presented to a local doctor with a lump in the right breast. On physical examination, a tumor measuring 24mm was palpable in the BD area of her right breast. Mammography showed category 5 disease, and ultrasonography revealed a tumor measuring 24×16 mm. A mammotome biopsy provided a diagnosis of invasive ductal carcinoma of the breast(ER 7/PgR 4/HER2 1+), and the tumor was classified as stage IIA(T2N0M0)according to the UICC-TNM classification. She was recommended surgery but she rejected this option and underwent hormone therapy with anastrozole (1mg/day). One year and 8months after beginning the treatment, ultrasonography showed the tumor to measure 7.0×5.7 mm, and hormone therapy resulted in a partial response(PR). The patient hoped to undergo an operation, so she was referred to our hospital, and a right partial mastectomy and sentinel node biopsy was performed. A histopathological exami- nation indicated scirrhous carcinoma, 18mm, nuclear grade 1, f, ly1, v0, n0, ER 3/PgR 3/HER2 3+. The curative effect was grade 1a. The tumor had become HER2 positive, so the patient was then administered radiotherapy and trastuzumab and anastrozole as adjuvant therapy. Herein, we report our experience with a case of breast cancer that only became HER2 positive after hormone therapy, and also provide some bibliographic comments on this occurrence.

[Three patients with local recurrence of ER-positive breast cancer for whom anastrozole was clinically effective].

We treated three postmenopausal female patients with unresectable local recurrence from breast cancer. All pathological diagnoses of the local recurrence lesions were ER-positive breast cancer. For treatment, we administered anastrozole to these three patients. One has been stable disease for 25 months after taking anastrozole. Another has also showed stable disease for 18 months, and the last patient has been a partial response. We performed a biopsy from a recurring lesion on these three patients, and made a diagnosis of ER-positive breast cancer. This strategy of unresectable local recurrence revealed that these three patients could have had a stable condition for a long duration by taking anastrozole.

[Efficacy and toxicity of lapatinib plus capecitabine therapy in HER2-positive metastatic breast cancer].

We retrospectively investigated the efficacy and toxicity of lapatinib plus capecitabine in 45 HER2-positive breast cancer patients. The median number of treatment courses was 6(1-22). Brain metastasis developed in 18 cases(40%), and 19 cases(42.2%)had received previous capecitabine treatment for metastatic breast cancer. The objective response rate(ORR=CR+PR)was 22.2%(10/45), and clinical benefit rate(CR+PR+long SD=24w)was 46.7%(21/45).The median time to progression(TTP)was 24.9 weeks(95% CI: 15.2 -34.6 ), and the median overall survival(OS)was 78.1 weeks(95% CI: 55.7 -100.5)in all 45 cases. The median TTP was significantly longer in patients who had not received capecitabine previously(30 vs 16 weeks, 95% CI: 16.3 -43.7, p=0.0051 ). There was no statistical difference in median OS associated with previous capecitabine exposure(42.7 weeks, 95% CI: 21.4 -64, p=0.057 ). The median TTP was significantly longer in patients who received less than 2 treatment regimens with trastuzumab for MBC rather than 3 regimens more(27.3 vs 16 weeks, p=0.0257 ), but there was no statistical difference in median OS(81 vs 40.9 weeks, p=0.26 ). Lapatinib in combination with capecitabine is likely more useful in patients who are naive to capecitabine, who received less than two regimens for metastatic breast cancer.

[A case of metastatic breast cancer with liver metastasis effectively treated with capecitabine and vinorelbine].

A 31-year-old woman with cancer of the right breast underwent surgery in 1996. Histological examination demonstrated a solid tubular carcinoma that was positive lymph node metastasis and hormonal receptor, but negative for HER2 expression. The patient underwent adjuvant therapy with CAF and tamoxifen. At the age of 40 years old, Multiple liver metastasis appeared to the patient. We treated her with paclitaxel. But multiple liver metastasis became progressive disease. Next we treated with capecitabine and vinorelbine. The liver metastasis reduced, and, in the eighth month, the liver metastasis disappeared after 9 cycles. We changed treatment to goserelin, and anastrozole. The period of complete response was 1 year 3 months.