[Treatment Strategy for HER2 Positive and HER2 Low Breast Cancer].

Human epidermal growth factor receptor 2(HER2)positive breast cancer has been regarded as a poor prognosis breast cancer, but since the development of trastuzumab and various anti-HER2 drugs, the prognosis has significantly improved. Also, combining anti-HER2 drugs with chemotherapy as preoperative treatment, shows high ratings of pathological complete response(pCR). In terms of breast cancer, pCR is a prognosis predictive factor. As a result, in perioperative treatment for HER2 positive breast cancer, residual disease-guided approach which means to select postoperative treatment according to the response to preoperative chemotherapy has become the main stream. Furthermore, trastuzumab deruxtecan, which had been covered by insurance only for HER2 positive metastatic or recurrent breast cancer, was newly reimbursed for breast cancer with low HER2 expression at the end of March 2023, and the future movement is attracting attention.

Factors associated with financial toxicity in patients with breast cancer in Japan: a comparison of patient and physician perspectives.

BACKGROUND: Financial toxicity (FT) is a notable concern for patients with breast cancer worldwide. The situation regarding FT in Japan, however, has not been well explored. This study examined FT in patients with breast cancer in Japan and presented an overview of the group study's overall findings. METHODS: The survey used the Questant application and primarily targeted patients with breast cancer attending research facilities and physicians who are members of the Japanese Breast Cancer Society. The Japanese version of the Comprehensive Score for FT (COST) was used to quantify patients' FT. Multiple regression analysis was used to identify factors related to FT in patients with breast cancer in Japan and evaluate the sufficiency of information support level (ISL) for medical expenses. RESULTS: We collected 1558 responses from patients and 825 from physicians. In terms of factors affecting FT, recent payments had the highest impact, followed by stage, and related departments positively affecting FT. Conversely, factors such as income, age, and family support were found to negatively affect FT. A significant discrepancy was identified between patients and physicians in perceived information support, with patients frequently feeling unsupported and physicians believing that they have provided adequate support. Furthermore, differences in the frequency of explanations and opportunities to ask questions about medical costs across FT grades were found. The analysis also showed that physicians with a better understanding of information support needs and greater knowledge of medical costs tended to provide more support that is comprehensive. CONCLUSION: This study emphasizes the importance of addressing FT in patients with breast cancer in Japan and highlights the need for enhanced information support, deeper understanding by physicians, and collaborative efforts among professionals to mitigate financial burden and provide personalized, tailored support for individual needs.

Phosphodiesterase 4 mRNA Level Suppression is Important for Extract of Black Carrot to Protect Against Hepatic Injury Induced by Ethanol.

Excessive alcohol use often results in alcoholic liver disease (ALD). An early change in the liver due to excessive drinking is hepatic steatosis, which may ultimately progress to hepatitis, liver fibrosis, cirrhosis, and liver cancer. Among these debilitating processes, hepatic steatosis is reversible with the appropriate treatment. Therefore, it is important to find treatments and foods that reverse hepatic steatosis. Black carrot has antioxidant and anti-inflammatory effects. In this study, we examined the effectiveness of black carrot extract (BCE) on hepatic steatosis in in vivo and in vitro ethanol-induced liver injury models. For the in vivo experiments, serum aminotransferase activities enhanced by ethanol- and carbon tetrachloride were significantly suppressed by the BCE diet. Furthermore, morphological changes in the liver hepatic steatosis and fibrosis were observed in the in vivo ethanol-induced liver injury model, however, BCE feeding resulted in the recovery to an almost normal liver morphology. In the in vitro experiments, ethanol treatment induced reactive oxygen species (ROS) levels in hepatocytes at 9 h. Conversely, ROS production was suppressed to control levels and hepatic steatosis was suppressed when hepatocyte culture with ethanol were treated with BCE. Furthermore, we investigated enzyme activities, enzyme protein levels, and messenger RNA levels of alcohol dehydrogenase (ADH), cytochrome p450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) using enzyme assays, western blot, and quantitative reverse transcription-polymerase chain reaction analyses. We found that the activities of ADH, CYP2E1, and ALDH were regulated through the cAMP-PKA pathway at different levels, namely, translational, posttranslational, and transcriptional levels, respectively. The most interesting finding of this study is that BCE increases cAMP levels by suppressing the Pde4b mRNA and PDE4b protein levels in ethanol-treated hepatocytes, suggesting that BCE may prevent ALD.

Black carrot extract protects against hepatic injury through epigenetic modifications.

We studied the epigenetic regulation of how black carrot extract (BCE) protects against ethanol-induced hepatic damage. We have shown that the butanol-extracted fraction of BCE (BCE-BuOH) increased intracellular cyclic adenosine monophosphate (cAMP) levels by suppressing the expression of phosphodiesterase 4b (PDE4b); however, the detailed mechanism remains to be elucidated. We focused on changes in histone modifications involved in the suppression of pde4 expression. The methylation level of histone H3 lysine 9 (H3K9), which regulates gene expression of PDE4b, decreased after treatment with 100 mM ethanol but was significantly increased by treatment with 400 µg/ml BCE-BuOH. In contrast, ethanol induced an increase in H3K9 acetylation. However, treatment with BCE-BuOH inhibited the increase in acetylation through an increase in Sirtuin 1 (Sirt1), a histone deacetylase. Furthermore, BCE-BuOH treatment increased the level of methionine adenosyltransferase (MAT) 2a mRNA and increased intracellular S-adenosylmethionine. The present results indicate that BCE-BuOH is useful for protection against alcohol-induced hepatic injury. PRACTICAL APPLICATIONS: We have reported that black carrot extract (BCE) suppressed liver steatosis and liver fibrosis on a rat alcoholic liver disease model. The results from this study have shown that BCE regulated the alcoholic-induced hepatic injury at the level of epigenetic modifications. These results suggested that BCE is useful for protection against alcoholic-induced hepatic injury.

Characteristics, treatment trends, and long-term outcomes of Japanese patients with pregnancy-associated breast cancer (PABC).

PURPOSE: To clarify the characteristics, treatment trends, and long-term outcomes of patients with pregnancy-associated breast cancer (PABC). METHODS: PABC includes breast cancer diagnosed during pregnancy (PBC) and breast cancer diagnosed within 1 year after childbirth or during lactation (LBC). We compared clinical characteristics of 126 patients with LBC and 49 patients with PBC who underwent surgery at our hospital from 1946 to 2018. Survival was compared between patients with LBC and those with PBC in terms of breast cancer-specific disease-free survival (BC-DFS) and overall survival (OS). RESULTS: Patients with LBC were more likely to have family history, lymph node metastasis, lymphatic invasion, and to receive chemotherapy than patients with PBC. Patients with LBC showed poorer BS-DFS and OS than patients with PBC. Among patients with LBC, those treated after 2005 were older at surgery, had a smaller tumor size, received more systemic therapy, and had a more favorable prognosis than patients treated before 2004. Family history, breast cancer within 1 year after childbirth, and surgery before 2004 as well as cStage, lymph node metastasis, and lymphatic invasion were significantly associated with poor prognosis in patients with LBC. In the multivariate analysis for BC-DFS and OS among patients with PABC, LBC vs PBC did not remain as an independent prognostic factor while cStage remained. CONCLUSION: Patients with LBC had a poorer prognosis than those with PBC, most likely due to disease progression rather than biological characteristics. Early detection and optimization of systemic treatments are critical for improving the outcomes of patients with LBC.

Does breast-conserving surgery with radiotherapy in BRCA-mutation carriers significantly increase ipsilateral breast tumor recurrence? A systematic review and meta-analysis.

BACKGROUND: Breast-conserving surgery (BCS) is often preferred for localized, small breast cancers, but its safety and efficacy in BRCA-mutation carriers is still controversial. This meta-analysis aimed to determine whether there was any significant difference in the incidence of ipsilateral breast tumor recurrence (IBTR) between BRCA-mutation carriers who underwent BCS and controls with sporadic breast cancer. METHODS: A PubMed search was conducted through March 2020 to identify studies examining the risk of IBTR after BCS in BRCA-mutation carriers versus controls. The Cochrane risk-of-bias tool was used to assess the risk of bias. The pooled risk ratio (RR) was calculated using the random-effects model. RESULTS: Thirteen studies involving 701 BRCA-mutation carriers and 4788 controls in total were eventually analyzed. In the meta-analysis, IBTR after BCS was significantly higher in BRCA-mutation carriers (RR: 1.589; 95% confidence interval (CI) 1.247-2.024; P < 0.001). Subgroup analysis of the follow-up time found that the RR for IBTR increased as the observation period lengthened (median follow-up: ≧ 7 years [RR: 1.505; 95% CI 1.184-1.913] and ≧ 10 years [RR: 1.601; 95% CI 1.201-2.132], respectively). However, a qualitative meta-analysis of overall survival in three cohort studies found no evidence to suggest a deterioration in overall survival in patients with BCS. CONCLUSIONS: The present study demonstrated that BRCA-mutation carriers with BCS have a higher risk of IBTR, which tended to persist for a long period and become more apparent with longer observation.

Physician's knowledge, attitudes and practice pattern for breast cancer diagnosed during pregnancy: a survey among breast care specialists in Japan.

BACKGROUND: Breast cancer diagnosed during pregnancy (BCP) is uncommon, and thus there is limited evidence on its treatment. However, the incidence of BCP is increasing probably due to women having children at an older age. We aimed to clarify the practice patterns and limitations in treatment for BCP in Japan. METHODS: A cross-sectional survey was developed for board-certified Japanese breast cancer specialists (n = 1583) to evaluate their knowledge, attitude, experience, and practice patterns regarding BCP. Survey items also included questions regarding potential barriers of practice toward patients diagnosed during pregnancy and respondents' background. RESULTS: In March 2018, 492 (31.1%) breast oncologists responded to the survey. Among them, 234 (48%) respondents had the experience of treating at least one case of BCP. The accuracy of knowledge about BCP was evaluated by three items regarding BCP treatment from the latest Japanese Breast Cancer Society treatment guideline, and 265 (54%) were categorized to have "appropriate knowledge". Majority of the physicians (89%) have responded that patients should be treated in a center where both a cancer-treating team and obstetrician exist, and 48% responded that treating patients by the collaboration of cancer-treating team and obstetric team in different institutes is an alternative reasonable option. CONCLUSIONS: Interest, knowledge, and awareness of the guidelines appear to influence physician attitude, and thus it is urgently important to lay out educational materials and learning opportunities regarding BCP for breast specialists. A regional network of oncologists, obstetricians, and pediatricians to support the BCP patients should be developed.

Factors associated with treatment delay in women with primary breast cancer who were referred to reproductive specialists.

PURPOSE: Cancer treatment delay due to fertility preservation procedures is a barrier for patients with breast cancer who wish to preserve their fertility. This study aimed to describe the associations between fertility preservation and treatment delay in patients with breast cancer with reproductive concerns and assess the factors related to treatment delay. METHODS: Patients with primary breast cancer who visited the reproductive unit at our institution before cancer treatment between 2007 and 2015 were enrolled. The treatment delay cut-off was defined as follows: time to chemotherapy (TTC) >8 weeks for patients intending to receive neoadjuvant chemotherapy, TTC >12 weeks for patients intending to receive adjuvant chemotherapy, time to endocrine therapy (TTE) >12 weeks for patients intending to receive endocrine therapy without radiation therapy and TTE >20 weeks for patients intending to receive endocrine therapy after radiation therapy. Multivariable models were constructed to examine the factors of treatment delay. RESULTS: Overall, 212 patients met the inclusion criteria. Using the defined cut-offs, treatment delay was noted in 18% of the patients. Endocrine therapy was related to treatment delay (OR 4.49, 95% CI 1.02 to 19.7; p=0.05), but fertility preservation by artificial reproductive treatment (ART) was not. Pregnancy and delivery following treatment for breast cancer were achieved in 18 (19%) and 15 (16%) patients who underwent fertility preservation with ART. CONCLUSION: Fertility preservation with ART was not associated with treatment delay in patients with breast cancer who were referred to reproductive specialists before cancer treatment.

Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site.

BACKGROUND: The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions. METHODS: Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed. RESULTS: A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis. CONCLUSIONS: Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

BACKGROUND: Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. METHODS: This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. FINDINGS: Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. INTERPRETATION: The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. FUNDING: Daiichi Sankyo Co, Ltd.

Prolonged Hypocalcemia Following a Single Dose of Denosumab for Diffuse Bone Metastasis of Gastric Cancer after Total Gastrectomy.

Hypocalcemia is a significant adverse effect of denosumab. We herein report a case of prolonged hypocalcemia in a patient with multiple risk factors for hypocalcemia, including gastrectomy, increased bone turnover, and a poor performance status. Hypocalcemia developed after denosumab treatment for diffuse bone metastasis of gastric cancer, despite oral supplementation with vitamin D and calcium. To avoid serious prolonged hypocalcemia, a thorough assessment of the bone calcium metabolism is required before initiating denosumab treatment.

Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer.

BACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is a favourable prognostic factor in patients with early breast cancer. Programmed cell death-1 (PD-1) and its ligand PD-L1 are associated with a variety of adverse features. The purpose of this study was to clarify the relationships between TILs, PD-1 and PD-L1 as well as their prognostic implications in early breast cancer. METHODS: We investigated 180 patients with breast cancer who received neoadjuvant chemotherapy and underwent subsequent surgery for stage II-III invasive breast carcinoma between 1999 and 2007. TIL expression was classified as low or high using a previously reported scoring model. PD-1 and PD-L1 expression levels were determined by immunohistochemistry. The correlation between PD-1 expression in TILs and PD-L1 expression in cancer cells was also investigated. RESULTS: Higher tumour grade was significantly correlated with PD-L1 expression in tumours (p<0.0001). PD-1 and PD-L1 expression levels were associated with tumour subtype and were highest in triple-negative tumours (p<0.0001). Furthermore, expression of each of PD-1 and PD-L1 was significantly correlated with higher TIL expression and pathological complete response (pCR) (p<0.0001). PD-L1 expression in cancer cells was significantly correlated with PD-1 expression in TILs (p=0.03). The correlations between pCR and expression of each of PD-L1 and PD-1 were not significant. CONCLUSION: Expression of PD-L1 and PD-1 in early breast cancer is associated with higher TIL scores and pCR; conversely, expression of these proteins correlates with poor prognostic clinicopathological factors such as tumour grade and subtype. TILs, PD-1 and PD-L1 can potentially predict the response to treatment.

Psychological impact of breast cancer screening in Japan.

OBJECTIVE: The purpose of this study was to evaluate the psychological impact of breast cancer screening by use of mammography and/or ultrasound, and to reveal factors related to psychological distress. METHODS: Three hundred and twenty women were recalled to our hospital because of suspicious malignant findings from breast cancer screening between March and November 2012. They were asked to complete three questionnaires: the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression, the Brief Coping Orientations to Problems Experienced scale (Brief COPE) for coping styles, and an original questionnaire for personal information. RESULTS: Complete data were available for 312 of 320 women (97.5 %). The median age was 45 years (range 23-73). The HADS revealed borderline or clinically significant anxiety for 70 % of the women. Family history of breast cancer, area of residence, number of times screened, number of recalls, and the period before the first visit were significantly related to psychological distress (p < 0.05). Brief COPE scores showed that self-blame, behavioral disengagement, self-distraction, use of emotional support, venting, denial, and less acceptance were related to increased anxiety. CONCLUSION: Seventy percent of women who were recalled after breast cancer screening experienced psychological distress. Thus, negative psychological impact should be regarded as an adverse effect of breast cancer screening.

A case of isolated adrenocorticotropic hormone deficiency: a rare but possible cause of hypercalcemia.

A 52-year-old woman presented with an 8-month history of epigastric pain, nausea, and weight loss. One year before, she was diagnosed with breast cancer. During the postoperative chemotherapy, she developed epigastric pain and nausea. As a result, she gradually lost 12 kg of her body weight. We performed upper gastrointestinal endoscopy, which revealed mild erosive gastritis. After the treatment with a proton pump inhibitor, her symptoms persisted. Before the admission, mild hypercalcemia was pointed out. Fluid replacement didn't improve hypercalcemia. We assessed adrenocortical function, which showed that her serum cortisol and adrenocorticotropic hormone were decreased. Through loading tests, we established diagnosis of isolated adrenocorticotropic hormone deficiency. She was treated with hydrocortisone. Soon after the treatment, her serum calcium level returned to normal and her symptoms improved. In a case of hypercalcemia unresponsive to fluid replacement, we recommend ruling out adrenal insufficiency after excluding more common diseases which induce hypercalcemia.

The present state and perception of young women with breast cancer towards breast reconstructive surgery.

PURPOSE: This study was conducted to identify factors influencing patients' decisions to undergo breast reconstruction, and to identify the influences of breast reconstruction on patient behavior and psychological well-being. METHODS: Data were collected from January to June 2011, using a questionnaire distributed to women ≤45 years old with breast cancer, at five medical institutes across Japan. RESULTS: Completed questionnaires were collected from 316 women (mean age: 39.46 ± 4.4 years, range: 27-45 years). Overall, 174 patients received breast-conserving surgery, 101 received mastectomy, 31 received subcutaneous mastectomy, 3 patients received none, and 49 were unreported). The data indicated a reconstruction rate of 36.7 % in women who underwent mastectomy. The most prevalent reason for not undergoing breast reconstruction was the fear of cancer relapse. Other factors mentioned were to avoid additional distress on the body from surgery, financial reasons, and a belief that breast reconstruction is unnecessary. The main factor that influenced the decision not to undergo delayed breast reconstruction, specifically, was the expense. Women who had completed breast reconstruction showed higher self-evaluations of physical attractiveness and were more active in comparison to those who did not. However, regardless of having undergone breast reconstruction or not, women who reported higher levels of self-consciousness over the treated areas showed more restrictions on activity and higher chances of a decline in psychological well-being. CONCLUSION: Regardless of deciding to undergo breast reconstruction or not, the results of this study suggested the need for cognitive interventions to avoid patients fixating on self-consciousness over treated areas.