A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer.

PURPOSE: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups. METHODS: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated. RESULTS: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33-0.78) and 29% (HR: 0.71, 95% CI 0.49-1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29-0.74). CONCLUSIONS: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study.

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.

Case-based survey: The impact of breast-cancer treatment on fertility in Japan.

AIM: To assess the impact of breast-cancer treatment on fertility. METHODS: We conducted a retrospective, case-based survey of treatments administered for infertility and pregnancy outcomes after patients underwent treatment for breast cancer. Surveys were distributed to breast oncology facilities and reproductive endocrinology and infertility (REI) facilities. RESULTS: As high as 60% of the pregnancies in women under the age of 35 years occurred spontaneously. Additionally, the fertility rates decreased as age increased (under 35 years of age: 40%, 35-39 years of age: 21%, 40-44 years of age: 10%, respectively). In women who became pregnant after treatment for breast cancer, conception was achieved within 1 to 3 years after beginning to try for pregnancy. CONCLUSIONS: After treatment for breast cancer, women can expect spontaneous pregnancy, especially if they are under 35 years of age. It is important for patients 35 years of age and older to commence assisted reproductive technology in a timely manner when pursuing fertility after treatment for breast cancer.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Downregulated ATP6V1B1 expression acidifies the intracellular environment of cancer cells leading to resistance to antibody-dependent cellular cytotoxicity.

Among several mechanisms for the resistance of human epidermal growth factor receptor 2-overexpressing (HER2 +) cancer cells to trastuzumab, little is known regarding the mechanism underlying the resistance to trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Cell death due to ADCC is caused by apoptosis of target cells induced by granzymes released from natural killer cells. Because optimal granzyme physiological activity occurs at neutral pH, we assumed that the pH of the intracellular environment influences the cytotoxic effects of granzymes. We established ADCC-resistant cells and compared them with wild-type cells in terms of the expression of intracellular pH-regulating genes. The expression of ATP6V1B1, which encodes a component of vacuolar ATPases, was downregulated in the ADCC-resistant cells. Thus, to functionally characterize ATP6V1B1, we used a CRISPR/Cas9 system to generate ATP6V1B1-knockout SKBR3 and JIMT-1 cells (both HER2 + human breast cancer cell line). The resulting cells exhibited significantly less ADCC than the control SKBR3 and JIMT-1 cells. The intracellular pH of the ATP6V1B1-knockout SKBR3 and JIMT-1 cells was significantly lower than control SKBR3 and JIMT-1cells. An analysis of granzyme dynamics during the ADCC reaction in cancer cells revealed that granzymes degraded intracellularly in the control SKBR3 and JIMT-1 cells and accumulated in ATP6V1B1-knockout cells, but were not cytotoxic. These findings suggest that decreased vacuolar ATPase activity alters the cytoplasmic pH of cancer cells to create an environment that is less suitable for granzyme bioactivity, which adversely affects the induction of apoptosis of cancer cells by NK cells.

Prognostic significance of PD-L1-positive cancer-associated fibroblasts in patients with triple-negative breast cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are some of the most abundant components of the tumour microenvironment. A recent study suggested that in some cancers, CAFs express programmed death ligand 1 (PD-L1), which can act as a prognostic marker. The aim of this study was to investigate the clinicopathological significance of CAF PD-L1 expression in patients with triple-negative breast cancer (TNBC) and to identify the most suitable primary antibody for immunostaining for CAF PD-L1. METHODS: Immunohistochemical staining (primary antibodies of 73-10, SP142, and E1L3N) and tissue microarrays were used to analyse the expression profiles of PD-L1 in CAF in 61 patients with TNBC who underwent surgery. Overall survival (OS) was compared based on CAF PD-L1 expression, and the risk factors for OS were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Thirty-four (55.7%) patients were positive for CAF PD-L1 (73-10) expression. Compared with CAF PD-L1 negativity, there was a significant correlation between CAF PD-L1 positivity and better OS (p = 0.029). CAF PD-L1 expression, evaluated using SP-142 or E1L3N, did not correlate with OS. CAF PD-L1-positivity (73-10) correlated significantly with better prognosis in multivariate analyses (hazard ratio: 0.198; 95% confidence interval: 0.044-0.891; p = 0.035). CONCLUSIONS: CAF PD-L1 expression is a novel marker for a better prognosis of patients with TNBC, and the 73-10 assay may be suitable for immunostaining CAF PD-L1.

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ovarian hyperstimulation closely associated with resumption of follicular growth after chemotherapy during tamoxifen treatment in premenopausal women with breast cancer: a multicenter retrospective cohort study.

BACKGROUND: We previously reported that tamoxifen (TAM)-induced ovarian hyperstimulation (OHS) is associated with high serum concentrations of estradiol in premenopausal women with breast cancer. To investigate risk factors for TAM-induced OHS, we performed a retrospective multicenter study. METHODS: Premenopausal patients who received surgical therapy for endocrine-dependent breast cancer (n = 235) were recruited in this study and classified into 4 groups: group A, treated with TAM alone; group B, TAM treatment after 2-year-combined therapy with a gonadotropin-releasing hormone (Gn-RH) agonist; group C, TAM treatment after chemotherapy; group D, 5-year-combined therapy with TAM and a Gn-RH agonist. A serum estradiol value of more than 300 pg/mL or mean follicular diameter of more than 30 mm was defined as OHS. RESULTS: The incidence of OHS in group A (n = 13/26, 50.0%) was significantly higher than those in group B (n = 17/63, 27.0%), group C (n = 20/110, 18.2%), and group D (n = 0/36, 0%). The incidence of OHS was significantly correlated with aging, and the median serum concentration of estradiol in the presence of OHS was 823.0 pg/mL. The incidence of OHS (less than 47 years old) was 62.5% in group A, 48.6% in group B, and 28.2% in group C, respectively. Notably, the incidence rate of OHS following amenorrhea in group C (n = 13/20, 65.0%) was significantly higher than that in group B (n = 1/17, 5.9%). CONCLUSIONS: These findings indicate that the onset of OHS following amenorrhea was common in the post-chemotherapeutic group, while its ratio was low in the group after Gn-RH analog treatment, suggesting that combined treatment-based management involving TAM therapy is necessary for premenopausal patients with breast cancer.

Direct comparison of magnetic resonance imaging and pathological shrinkage patterns of triple-negative breast cancer after neoadjuvant chemotherapy.

BACKGROUND: We aimed to investigate the usefulness of magnetic resonance imaging (MRI) and histopathological shrinkage patterns to formulate a predictive equation for estimating residual tumor size after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. METHODS: We enrolled 34 TNBC patients who underwent MRI before and after NAC. The MRI and histopathological shrinkage patterns were analyzed and classified into five categories-types I and II (concentric shrinkage without or with surrounding lesions, respectively), type III (shrinkage with residual multinodular lesions), type IV (diffuse contrast enhancement in the entire quadrant), and non-visualization. The residual tumor sizes following MRI and histopathological examination were also compared. RESULTS: The most common MRI and histopathological shrinkage pattern was type I (41.2% and 38.2%, respectively), followed by non-visualization (26.5% and 32.4%, respectively); the concordance rate between MRI and histopathological shrinkage patterns was 41.2%. There was a strong correlation between MRI tumor size and pathological tumor size (r = 0.89). Based on these findings, a predictive equation for pathological tumor size was formulated as follows: pathological tumor size (mm) = 1.1502 × (MRI tumor size [mm]) + 8.4277. CONCLUSIONS: Our equation may aid accurate preoperative assessment. Further studies are needed to determine its predictive value and applicability.

Nationwide survey of Japanese breast oncology and reproductive endocrinology departments about the impact of breast cancer treatment on fertility.

The purpose of this study is to assess the impact of breast cancer treatment on the reproductive potential. We conducted a nationwide survey of breast oncology and reproductive endocrinology and infertility (REI) departments using a questionnaire designed to assess the impact of breast cancer treatment on fertility. We received responses from 312 breast oncology departments (response rate, 31.9%) and 541 REI departments (response rate, 50.9%). The most common method of achieving pregnancy reported by breast oncology departments was natural insemination (69.6%), followed by assisted reproductive technology ( 15.6%) and intrauterine insemination (IUI; 14.8%). The most common method of achieving pregnancy reported by REI departments was conventional in vitro fertilization and/or intracytoplasmic sperm injection (51.0%), followed by natural insemination with or without ovulation induction (40.0%) and IUI (8.0%). The overall pregnancy rate for patients who underwent treatment for infertility at REI departments after breast cancer treatment was 39.0%. Vast patients who experienced breast cancer treatments conceived mainly by natural insemination based on the data from breast oncology departments. On the other hand, 61.0% of the patients who visited REI departments presumably due to infertility by natural insemination did not conceive even by infertility treatments with exclusive knowledge in REI departments.

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

AIMS: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. METHODS AND RESULTS: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. CONCLUSIONS: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

[Locally Advanced Breast Cancer Treated with Mohs' Paste and Neoadjuvant Chemotherapy-A Case Report].

Cutaneous infiltration by breast cancer significantly reduces patient quality of life(QOL)due to bleeding, exudate, and pain. We report a case of combined treatment using Mohs' paste and neoadjuvant chemotherapy for locally advanced breast cancer. Mohs' paste decreased bleeding and exudate from the tumor and neoadjuvant chemotherapy combined with bevacizumab down-staged a large tumor to a volume that permitted mastectomy. Good local control using Mohs' paste and neoadjuvant chemotherapy can improve patient QOL and reduce the physical burden.

Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αß T cells resulted in some mice with circulating human αß T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

Impact of physiological hormonal fluctuations on 18F-fluorodeoxyglucose uptake in breast cancer.

PURPOSE: Premenopausal physiologic steroid levels change cyclically, in contrast to steady state low levels seen in postmenopausal patients. The purpose of this study was to evaluate whether 18F-fluorodeoxyglucose (18F-FDG) uptake in breast cancer is influenced by physiological hormonal fluctuations. METHODS: A total of 160 primary invasive breast cancers from 155 females (54 premenopausal, 101 postmenopausal) who underwent 18F-FDG positron emission tomography/computed tomography before therapy were retrospectively analyzed. The maximal standardized uptake values (SUVmax) of tumors were compared with menstrual phases and menopausal status according to the following subgroups: 'luminal A-like,' 'luminal B-like,' and 'non-luminal.' Additionally, the effect of estradiol (E2) on 18F-FDG uptake in breast cancer cells was evaluated in vitro. RESULTS: Among premenopausal patients, SUVmax during the periovulatory-luteal phase was significantly higher than that during the follicular phase in luminal A-like tumors (n = 25, p = 0.004), while it did not differ between the follicular phase and the periovulatory-luteal phase in luminal B-like (n = 24) and non-luminal tumors (n = 7). Multiple regression analysis showed menstrual phase, tumor size, and Ki-67 index are independent predictors for SUVmax in premenopausal luminal A-like tumors. There were no significant differences in SUVmax between pre- and postmenopausal patients in any of the subgroups. In in vitro studies, uptake in estrogen receptor-positive cells was significantly augmented when E2 concentration was increased from 0.01 to ≥ 1 nM. CONCLUSIONS: Our data suggest that 18F-FDG uptake may be impacted by physiological hormonal fluctuations during menstrual cycle in luminal A-like cancers, and that E2 could be partly responsible for these events.

[Current Status and Future Perspectives of the Navigation Surgery in Breast Cancer - The Clinical Utility of Sentinel Lymph Node Biopsy Using ICG].

Sentinel lymph node biopsy is the standard of care for breast cancer. The detection method using radioisotope(RI)is considered the standard method but has some drawbacks including radiation exposure and access of the nuclear medicine to RI. A novel method using indocyanine green(ICG)as a near infrared(NIR)fluorescence contrast agent was developed in Japan. This NIR fluorescence imaging system can visualize subcutaneous lymphatic channels in real-time and navigate the surgeon to harvest sentinel lymph node in the axillary basin. Accumulating results in previous studies demonstrated that the ICG fluorescence method has achieved a high detection rate of sentinel lymph node comparable with the RI method. Currently, the ICG fluorescence method is another standard method as an acceptable alternative to the RI method. Development of fluorescence tracer to visualize tumor cells may enable the novel navigation surgery using in vivo fluorescence imaging.

Sentinel lymph node biopsy using indocyanine green fluorescence in early-stage breast cancer: a meta-analysis.

Sentinel lymph node (SLN) biopsy using indocyanine green (ICG) fluorescence is safe and has a high detection rate for SLNs. However, the results of this novel technique are heterogeneous. The objective of this meta-analysis was to evaluate the diagnostic performance of the ICG fluorescence method compared with the standard radioisotope (RI) method. All eligible studies were identified from 2005 through 2015. A proportion meta-analysis was performed using a fixed effects and/or random effects model based on the study heterogeneity. A total of 12 studies met the inclusion criteria and included 1736 women. There was no significant difference between ICG fluorescence and RI for SLN detection using either the fixed effects model [odds ratio (OR) 1.29, 95% confidence interval (CI) 0.87-1.90] or the random effects model (OR 1.32, 95% CI 0.54-3.18). There were seven studies reporting the detection rate for tumor-positive SLN. The ICG fluorescence method was significantly better than the RI method in the fixed effects model (OR 1.87, 95% CI 1.00-3.49) for staging axilla. However, there was no difference in the random effects model (OR 1.90, 95% CI 0.74-4.86). There was study outcome heterogeneity for the detection of SLN but not for tumor-positive SLN. There was no publication bias observed in the studies included. The ICG fluorescence method has valid diagnostic performance for SLN detection and shows a trend toward better axilla staging compared with the RI method. ICG fluorescence is a useful alternative to RI for SLN biopsy.

Evaluation of the Clinical Utility of the ICG Fluorescence Method Compared with the Radioisotope Method for Sentinel Lymph Node Biopsy in Breast Cancer.

PURPOSE: This study compared the clinical utility of indocyanine green (ICG) fluorescence and radioisotope (RI) for sentinel lymph node (SLN) detection in breast cancer. METHODS: Women with node-negative breast cancer underwent SLN biopsy using ICG fluorescence and RI. The primary end point was the sensitivity of ICG fluorescence compared with RI in the patients with tumor-positive SLNs. Secondary end points included detection rates for SLN, the additive effect of ICG fluorescence to RI, signature of positive SLNs according to tier, and adverse events related to ICG administration. RESULTS: A total of 847 women with clinical node-negative breast cancer underwent SLN biopsy, and 821 patients were included in the per-protocol analysis. SLN mapping was performed using ICG fluorescence and RI. The overall detection of SLNs using ICG fluorescence was identical to RI (97.2 vs. 97.0 %, P = 0.88), and the combination of both methods achieved a significant improvement compared with RI alone (99.8 vs. 97.0 %, P < 0.001). The detection rate for tumor-positive SLN was 93.3 % for ICG fluorescence and 90.0 % for RI, and the sensitivity of the ICG fluorescence method was 95.7 % (95 % CI 91.3-98.3, P = 0.11). The additional use of ICG significantly improved positive SLN detection for RI (97.2 vs. 90.0 %, P < 0.001). There were no serious adverse events related to hypersensitivity to ICG. CONCLUSIONS: The ICG fluorescence method may be an acceptable alternative to SLN detection using RI in breast cancer.

[The Clinical Utility of Pegfilgrastim in Combination with Adjuvant FEC(100)and TC Chemotherapy for Breast Cancer].

BACKGROUND: More than 20%of breast cancer patients who undergo myelosuppressive chemotherapy involving FEC(100) or TC experience febrile neutropenia(FN), and pegfilgrastim is commonly recommended as the primary prophylaxis. Delays and/or dose-reductions in chemotherapy should be avoided as much as possible to maximize the clinical benefits of these adjuvant chemotherapies. PURPOSE: This study assessed the relative dose intensity(RDI), efficacy, and safety of pegfilgrastim in patients with breast cancer. The incidence of FN was also evaluated. METHODS: Twenty-six patients with breast cancer undergoing FEC(100)or TC were included in this retrospective study. RESULTS: Of the 26 patients, 19 patients who underwent FEC(100)and 7 patients who underwent TC received 3.6 mg of pegfilgrastim 24 hours after administration of the myelosuppressive chemotherapy. Four and 14 patients who underwent FEC(100)achieved 85-99% and 100% RDI, respectively. All 7 patients who underwent TC achieved 100% RDI. Grade 3 and 4 adverse events, as assessed using the CTCAE, were observed in 11 patients who underwent FEC(100): 2 patients experienced leukocytopenia, 7 experienced neutropenia, 1 experienced thrombocytopenia, and 1 experienced FN. Four patients who underwent TC experienced Grade 3 and 4 adverse events: 1 patient each experienced bone pain, neutropenia, anemia, and FN. CONCLUSIONS: Pegfilgrastim can reduce the incidence of FN and maintain RDI in patients with breast cancer undergoing myelosuppressive chemotherapy.

Personalization of loco-regional care for primary breast cancer patients (part 1).

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

Personalization of loco-regional care for primary breast cancer patients (part 2).

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.