Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis.

PURPOSE: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. METHODS: This retrospective study consecutively included previously untreated patients with stage I-III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. RESULTS: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). CONCLUSION: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM).

Therapeutic options for breast cancer patients with brain metastases (BM)/leptomeningeal carcinomatosis (LMC) are limited. Here, we report on the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2-positive breast cancer patients with BM. Data were analyzed for 104 patients administered T-DXd. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR, and IC-PFS were evaluated. ORR by investigator assessment was 55.7% (total population). Median PFS was 16.1 months; 12-month OS rate was 74.9% (total population). Median time-to-treatment failure was 9.7 months. In 51 patients with BM imaging, IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months, respectively. In 19 LMC patients, 12-month PFS and OS rates were 60.7% and 87.1%, respectively. T-DXd showed effectiveness regarding IC-ORR, IC-PFS, PFS, and OS in breast cancer patients with BM/active BM, and sustained systemic and central nervous system disease control in LMC patients.Trial Registration: UMIN000044995.

Diagnostic Utility of an Adjusted DWI Lexicon Using Multiple b-values to Evaluate Breast Lesions in Combination with BI-RADS.

PURPOSE: We aimed to investigate the diagnostic feasibility of an adjusted diffusion-weighted imaging (DWI) lexicon using multiple b values to assess breast lesions according to DWI-based breast imaging reporting and data system (BI-RADS). METHODS: This Institutional Review Board (IRB)-approved prospective study included 127 patients with suspected breast cancer. Breast MRI was performed using a 3T scanner. Breast DW images were acquired using five b-values of 0, 200, 800, 1000, and 1500 s/mm2 (5b-value DWI) on 3T MRI. Two readers independently assessed lesion characteristics and normal breast tissue using DWI alone (5b-value DWI and 2b-value DWI with b = 0 and 800 s/mm2) according to DWI-based BI-RADS and in combination with the standard dynamic contrast-enhanced images (combined MRI). Interobserver and intermethod agreements were assessed using kappa statistics. The specificity and sensitivity of lesion classification were evaluated. RESULTS: Ninety-five breast lesions (39 malignant and 56 benign) were evaluated. Interobserver agreement for lesion assessment on 5b-value DWI was very good (k ≥ 0.82) for DWI-based BI-RADS categories, lesion type, and mass characteristics; good (k = 0.75) in breast composition; and moderate (k ≥ 0.44) in background parenchymal signal (BPS) and non-mass distribution. Intermethod agreement between assessments performed using either 5b-value DWI or combined MRI was good-to-moderate (k = 0.52-0.67) for lesion type; moderate (k = 0.49-0.59) for DWI-based BI-RADS category and mass characteristics; and fair (k = 0.25-0.40) for mass shape, BPS, and breast composition. The sensitivity and positive predictive values (PPVs) for 5b-value DWI were 79.5%, 84.6% and 60.8%, 61.1% for each reader, respectively; 74.4%, 74.4% and 63.0%, 61.7% for 2b-value DWI; and 97.4%, 97.4% and 73.1%, 76.0% for combined MRI. The specificity and negative predictive values (NPVs) were 64.3%, 62.5% and 81.8%, 85.4% for 5b-value DWI; 69.6%, 67.9% and 79.6%, 79.2% for 2b-value DWI; and 75.0%, 78.6% and 97.7%, 97.8% for combined MRI. CONCLUSION: Good observer agreement was observed in the 5b-value DWI. The 5b-value DWI based on multiple b-values might have the potential to complement the 2b-value DWI; however, their diagnostic performance tended to be inferior to that of combined MRI for the characterization of breast tumors.

Non-bacterial Cystitis With Increased Expression of Programmed Cell Death Ligand 1 in the Urothelium: An Unusual Immune-Related Adverse Event After Atezolizumab Administration for Metastatic Breast Cancer.

We report a case of non-bacterial cystitis that occurred after administration of atezolizumab, an antibody against programmed cell death ligand 1 (PD-L1). This cystitis was considered an immune-related adverse event (irAE). A 67-year-old woman with advanced breast cancer (cT4bN1M1, cStage IV) was treated with atezolizumab and nanoparticle albumin-bound (nab) paclitaxel. She consulted a physician for urethral pain and frequent urination during the fourth cycle of treatment. Cystitis symptoms were not relieved by antibiotic treatment and worsened. The results of her urine culture and cytology were negative for malignancy. Cystoscopy showed diffuse redness of the bladder mucosa. A bladder biopsy revealed no evidence of malignancy. Since the patient's symptoms resolved with steroid therapy, urethral pain and frequent urination associated with atezolizumab were considered to be irAE by the diagnosis of exclusion. After immunostaining of the bladder biopsy sections, high PD-L1 expression was detected in the urothelium, which could explain the cause of irAE.

Effectiveness of eribulin as first-line or second-line chemotherapy for HER2-negative hormone-resistant advanced or metastatic breast cancer: findings from the multi-institutional, prospective, observational KBCRN A001: E-SPEC study.

BACKGROUND: The optimal positioning of eribulin treatment remains unclear. This study aimed to investigate the effectiveness of eribulin administration as first- and second-line chemotherapy in patients with endocrine-resistant advanced or metastatic breast cancer (AMBC) in the real-world clinical setting. METHODS: This multi-institutional prospective cohort study enrolled patients with triple-negative AMBC or estrogen receptor-positive AMBC refractory to at least one previous endocrine therapy. The overall survival (OS) from the start of first-line (OS1) and second-line chemotherapy (OS2) was assessed. Data analysis included real-world chemotherapy sequences of first- to third-line chemotherapy regimens. The adjusted hazard ratio (HR) with 95% confidence interval (CI) for treatment regimen comparison was calculated using a stratified proportional hazards model. RESULTS: Among 201 patients enrolled, 180 were included in the final analysis. Eribulin was administered as first- and second-line chemotherapy to 46 (26.6%) and 70 (47.9%) patients, respectively. Median OS1 and OS2 were 2.25 (95% CI 1.07-2.68) and 1.75 (95% CI, 1.28-2.45) years for first- and second-line eribulin, respectively. Oral 5-FU followed by eribulin had a numerically longer OS1 (2.84 years) than the other sequences. Among patients who proceeded to second-line or later chemotherapy, the median OS1 for those treated with anthracycline or taxane as first- or second-line (n = 98) was 2.56 years (95% CI 2.27-2.74), while it was 2.87 years (95% CI 2.20-4.32) for those who avoided anthracycline and taxane as first- and second-line (n = 48) (adjusted HR, 1.20; 95% CI 0.70-2.06). In the exploratory analysis, OS1 was 2.55 (95% CI 2.14-2.75) and 2.91 years (95% CI 2.61-4.32) for those aged < 65 and ≥ 65 years, respectively (adjusted HR of ≥ 65, 0.91; 95% CI 0.56-1.46). CONCLUSIONS: Eribulin or oral 5-FU administration in first- and second-line chemotherapy without anthracycline/taxane was acceptable in the real-world setting. TRIAL REGISTRATION: This study is registered with Clinical Trials.gov (NCT 02,551,263).

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Effectiveness and safety of surgical glove compression therapy as a prophylactic method against nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy.

BACKGROUND: We have developed a surgical glove (SG)-compression therapy and reported that this method significantly reduced the overall occurrence of grade 2 or higher nanoparticle albumin-bound-paclitaxel (nab-PTX)-induced peripheral neuropathy (PN) from 76.1% to 21.4%. In this multicenter single-arm confirmatory study, we investigated the efficacy and safety of SG-compression therapy for the prevention of nab-PTX-induced PN, compared with the incidence of grade 2 or higher PN in published literature as controls. PATIENTS AND METHODS: Primary breast cancer patients who received 260 mg/m2 of nab-PTX were eligible for this study. Patients wore two SGs (one size smaller than the tight-fitting size) in each hand for 90 min. PN was evaluated at each treatment cycle using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The temperature of each fingertip was measured using thermography. RESULTS: Between October 2016 and June 2017, 58 patients were evaluated. The incidence of CTCAE grade 2 or higher PN was as low as 13.8% following SG-compression therapy. A goodness-of-fit test proved that the overall incidence of 13.8% grade 2 or higher PN in this study was comparable to the hypothesis-predicted value (13%). No adverse events, including compression intolerance or skin disorders caused by use of SG, were observed. SG-compression therapy significantly reduced the temperature of each fingertip by 1.3°C-2.3 °C compared to pre-chemotherapy level. CONCLUSIONS: This study suggested the safety and efficacy of SG-compression therapy for the amelioration of CIPN. CLINICAL TRIAL NUMBER: UMIN 000024836.

Assisted reproductive technology is effective for but does not affect the prognosis of young patients with breast cancer: Experience in a single institution.

Assisted reproductive technology (ART) helps women preserve fertility after chemotherapy for cancer treatment. We examined the long-term survival of patients with early breast cancer who did or did not receive ART, as well as post-treatment pregnancy and childbirth rates. Our study consisted of 44 young patients (≤35 years of age). Eight patients were pregnant post-treatment; however, none of these patients received ART intervention. ART intervention prevented patient omits of necessary treatment to avoid adverse events. It did not affect the prognosis of patients with breast cancer. Technical improvements are needed to increase the likelihood of pregnancy after breast cancer treatment.

The relationship between serum E2 levels and recurrence in premenopausal, ER-positive breast cancer patients: A retrospective study.

BACKGROUND: Among estrogens, estradiol (E2) has the strongest physiological activity as a stimulator in estrogen receptor (ER)-positive breast cancer. The aim of this study is to investigate E2 dynamics during endocrine therapy and to explore the optimal environment in which tamoxifen (TAM) exhibits better efficacy for ER-positive premenopausal early breast cancer patients. METHODS: This is a retrospective study enrolled 194 patients with premenopausal ER-positive early-stage breast cancer who aging ≤45 years at onset and receiving luteinizing hormone-releasing hormone-agonist (LHRH-a) and TAM-therapy. Approximately half of the patients also received pre- or post-operative chemotherapy as adjuvant systemic therapy. We studied the relationship between recurrence and serum hormonal dynamics during adjuvant therapy. We monitored the concentrations of E2 and, follicle-stimulating hormone (FSH) in the blood before, during, and after treatment. The median follow-up period was 80 (14-555) months. RESULTS: Forty-six (23.7%) patients developed recurrent breast cancer after surgery. The prognoses were favorable in the group receiving longer LHRH-a exposure if those patients did not receive chemotherapy as their adjuvant therapy. Paradoxically, patients with high serum E2 levels after LHRH-a showed a low recurrence ratio. This phenomenon might be explained by the similar mechanisms of estrogen therapy after estrogen depletion by aromatase inhibitor (AI) therapy for metastatic breast cancer. CONCLUSION: Among patients who received endocrine therapy without adjuvant chemotherapy, those with longer LHRH-a exposure had favorable prognoses. A potential association was observed between recurrence and E2 concentrations in women with premenopausal ER-positive early-stage breast cancer.

Experience with Bilateral Risk-Reducing Mastectomy for an Unaffected BRCA Mutation Carrier.

Women with BRCA1/2 mutations have a high risk of breast cancer and may opt for risk-reducing mastectomy (RRM). We report a 38-year-old Japanese woman who was diagnosed as a BRCA2 mutation carrier. She underwent prophylactic bilateral skin-sparing mastectomy (SSM) with excision of the nipple and preservation of the areola skin. It is unclear whether a bilateral RRM leads to better survival compared with intensive surveillance. The oncological risk associated with the presence of remnant breast glandular tissue after SSM or nipple-sparing mastectomy has been obscure. We report the first case of RRM for a Japanese BRCA mutation carrier and provide a literature review on risk management for BRCA mutation carriers with a focus on the concepts and procedures of RRM.

Relationship between intrinsic subtypes and tumor responses to neoadjuvant chemotherapy in patients with locally advanced breast cancer.

BACKGROUND: For locally advanced breast cancer, neoadjuvant chemotherapy (NAC) is the standard of care for downstaging the tumor prior to surgery, and improved prognoses that are associated with pathological complete responses (pCR) have been noted, particularly in patients with human epidermal growth factor receptor 2 (HER2)-positive and triple negative (TN) tumors. OBJECTIVE: The aim of this study was to assess the differences in pathological responses among intrinsic subtypes of local lesions and status of axillary lymph nodes (Ax LN). METHODS: A consecutive series of 134 patients with locally advanced breast cancer who were treated with NAC was analyzed. Tumors were classified into the following 5 subtypes according to immunohistochemical staining results: Luminal A type, Luminal B type (HER2-negative and HER2-positive), HER2 type, and TN type. RESULTS: In Luminal A, Luminal B (HER2-negative), Luminal B (HER2-positive), HER2, and TN tumors, the pCR rates were 10% (4 of 40), 19% (8 of 42), 42% (8 of 19), 59% (10 of 17), and 38% (6 of 16), respectively. HER2-positive tumors showed good therapeutic effects, while Luminal A tumors showed less therapeutic effects. CONCLUSIONS: Strategies that are determined according to intrinsic subtypes are becoming very important in the treatment of locally advanced breast cancer.

Preoperative diagnosis of ductal carcinoma in situ arising within a mammary fibroadenoma: a case report.

Fibroadenoma is the most common form of benign breast tumor and the most common breast tumor in women under 30 years of age. However, carcinoma arising within a fibroadenoma is unusual, with over 100 cases reported in the literature. Histological diagnosis is typically unexpected. A 46-year-old female with no family history of breast malignancies was admitted for an elastic hard lump in the upper-outer quadrant of her right breast. At a clinic that she visited previously, her condition was diagnosed by core needle biopsy with four specimens showing fibroadenoma with borderline atypical ductal hyperplasia at pathology. Excisional biopsy was recommended for pathological diagnosis. The patient requested a definitive diagnosis and alternative treatment to tumorectomy. More biopsy specimens were needed for pathological diagnosis; therefore, ultrasonography-guided vacuum-assisted core needle biopsies were obtained, confirming ductal carcinoma in situ with questionable microinvasion of intracanalicular- and pericanalicular-type fibroadenoma. Right breast-conserving surgery and sentinel lymph node biopsy were immediately performed for radical therapy. We present this case to increase awareness of this entity and stress the need for histological evaluation of some breast masses.

[Safety evaluation of paclitaxel injection NK in adjuvant therapy for breast cancer].

A paclitaxel injection NK (NK) is a generic product containing the same amount of ingredients as a Taxol Injection. We examined the safety of NK in clinical practice compared to the original drug. Our results suggested that the safety of NK and the original drug are similar in adjuvant therapy for breast cancer.

[Marked efficacy of S-1 against hepatic metastasis of multiple drug-resistant breast cancer--a report of 2 cases].

S-1 was found to be highly effective against metastatic hepatic lesions from multiple drug-resistant breast cancers, in 2 patients. The details of these cases are presented below. Case 1, a 59-year-old woman, was HER2-positive. For chemotherapy following a recurrence, trastuzumab+weekly paclitaxel and trastuzumab+vinorelbine regimens were attempted, but the hepatic metastasis worsened. On the other hand, a trastuzumab+S-1 regimen resulted in a notable reduction in the metastatic foci of the liver approximately one month after the initiation of the therapy. This effect was sustained for 5 months thereafter. Case 2 involved a 67-year-old woman with HER2-negative breast cancer. Following a recurrence, chemotherapeutic agents, such as taxane and vinorelbine, were applied, which all resulted in PD. Treatment with S-1 alone reduced the size of the hepatic metastatic lesion, as seen in case 1. Currently (14 months after the initial treatment with S-1), therapeutic efficacy has been maintained. Adverse effects were minimal and QOL was not compromised in either case. We speculate that S-1 is not only effective as a therapeutic agent but is also useful in view of safety and QOL.

[A phase II study of weekly paclitaxel for advanced or recurrent breast cancer].

The present study investigated the efficacy and safety of weekly administration of paclitaxel (PTX) for 37 patients with advanced or recurrent breast cancer. PTX was administered at a dose of 60 mg/m(2), 6 times every 8 weeks. The mean number of treatment cycles was 2.1, and the mean number of administrations was 12.7. Response rate was 35.1%. Two patients achieved CR, 11 PR, 13 NC (3 patients of long NC), 9 PD, and 2 NE. The clinical benefit rate (CR+PR+NC) was 70.3%. Median survival time was 733 days, and median time to treatment failure was 151 days. Grade 3 or more leucopenia and neutropenia occurred in 3 of patients (8.1%), and no patients showed hypersensitivity reaction after administration of PTX. Weekly PTX (60 mg/m(2)) is one of the treatment options in advanced or recurrent breast cancer from the standpoint of palliation.

Programmed cell death is not a necessary prerequisite for fusion of the fetal mouse palate.

It has been widely accepted that programmed cell death (PCD) is an essential event in palatogenesis and that its failure can result in cleft palate, one of the most common birth defects in the human. However, some conflicting results have been reported concerning the timing of cell death occurring in the fusing palate and therefore the role of PCD in palatal fusion is controversial. In order to clarify whether cell death is indispensable for mammalian palatogenesis, we cultivated the palates of day-13 mouse fetuses in vitro and prevented cell death by treating them with the inhibitors of caspases-1 and -3 or with aurintricarboxylic acid which inhibits the activity of caspase-activated DNase. Even when cell death was almost completely inhibited, palatal fusion took place successfully. Histological examination revealed that in the absence of apoptotic cell death, the medial edge epithelia of opposing palatal shelves adhered to each other and subsequently, the midline epithelial seam was disrupted and disappeared to bring about mesenchymal confluence across the palate. It seems that cell death is not a necessary prerequisite for palatal fusion but it may help to efficiently eliminate unnecessary cells which failed to migrate or differentiate properly.

Palatal shelf movement during palatogenesis: a fate map of the fetal mouse palate cultured in vitro.

Day-13 fetal mouse palates (plug day=day 0) were labeled with carbon particles at various sites of palatal shelves and cultivated in a chemically defined medium for up to 48 h. During the culture period, the bilateral palatal shelves came in contact and fused with each other, which simulated in vivo palatogenesis. The carbon study revealed that at the midpalatal region, the medial edge of the palatal shelf elevated to the horizontal plane, elongated toward the midline, and made contact with the medial edge of the opposing shelf. On the other hand, near the anterior and posterior ends of the shelf, some new tissue was formed at the medial edge of the shelf by remodeling and this newly formed tissue took part in palatal fusion. The results of the present study indicate that during mouse palatogenesis, the anterior and posterior regions of the palatal shelf behave differently from the midpalatal region. It seems that in the fetal mouse palate, the midpalate closes mainly by means of rotation and medial elongation of the shelf, whereas the anterior and posterior parts of the palate close mainly by tissue remodeling of the medial edge and partly by medial elongation of the shelf.