Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Reproductive factors and mammographic density within the International Consortium of Mammographic Density: A cross-sectional study.

BACKGROUND: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). METHODS: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. RESULTS: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (ß: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (ß: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (ß:0.06, 95% CI:0.03, 0.10) and √DA (ß:0.06, 95% CI:0.02, 0.10), and lower √NDA (ß: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. CONCLUSIONS: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Adipogenesis biomarkers as the independent predictive factors for breast cancer recurrence: a systematic review and meta-analysis.

BACKGROUND: Comprehensive analysis of clinical evidence for breast cancer adipogenesis with prognosis is lacking. This study aims to consolidate the latest evidence on the relationship between adipogenesis and breast cancer outcomes. DATA SOURCES: Medline, Web of Science, Embase, Scopus, Clinicaltrials.gov, Cochrane library. METHODS: A systematic review was conducted according to the PRISMA guidelines. Studies that reported the correlation between tumor adipogenesis and cancer recurrence or empirical pathological markers were included for meta-analysis. The standard reference for pathological markers determination was set as histopathological examination. The PROSPERO ID was CRD489135. RESULTS: Eleven studies were included in this systematic review and meta-analysis. Several adipogenesis biomarkers involved in the synthesis, elongation, and catabolism of fatty acids, such as FASN, Spot 14, pS6K1, lipin-1, PLIN2, Elovl6, and PPARγ, were identified as the potential biomarkers for predicting outcomes. Through meta-analysis, the predictive value of adipogenesis biomarkers for 5-year recurrence rate was calculated, with a pooled predictive risk ratio of 2.19 (95% CI: 1.11-4.34). In terms of empirical pathological markers, a negative correlation between adipogenesis biomarkers and ki-67 was observed (RR: 0.69, 95% CI: 0.61-0.79). However, no significant correlation was found between the adipogenesis and ER, PR, HER2, or p53 positivity. CONCLUSIONS: Biomarker of adipogenesis in breast cancer is a significant predictor of long-term recurrence, and this prediction is independent of HR, HER2, and ki-67. The diverse roles of adipogenesis in different breast cancer subtypes highlight the need for further research to uncover specific biomarkers that can used for diagnosis and prediction. PROTOCOL REGISTRATION: PROSPERO ID: CRD489135.

Implementing a nurse-led screening clinic for symptom distress with community-based referral for cancer survivors: A feasibility study.

INTRODUCTION: This prospective, single-arm, pragmatic implementation study evaluated the feasibility of a nurse-led symptom-screening program embedded in routine oncology post-treatment outpatient clinics by assessing (1) the acceptance rate for symptom distress screening (SDS), (2) the prevalence of SDS cases, (3) the acceptance rate for community-based psychosocial support services, and (4) the effect of referred psychosocial support services on reducing symptom distress. METHODS: Using the modified Edmonton Symptom Assessment System (ESAS-r), we screened patients who recently completed cancer treatment. Patients screening positive for moderate-to-severe symptom distress were referred to a nurse-led community-based symptom-management program involving stepped-care symptom/psychosocial management interventions using a pre-defined triage system. Reassessments were conducted at 3-months and 9-months thereafter. The primary outcomes included SDS acceptance rate, SDS case prevalence, intervention acceptance rate, and ESAS-r score change over time. RESULTS: Overall, 2988/3742(80%) eligible patients consented to SDS, with 970(32%) reporting ≥1 ESAS-r symptom as moderate-to-severe (caseness). All cases received psychoeducational material, 673/970(69%) accepted psychosocial support service referrals. Among 328 patients completing both reassessments, ESAS-r scores improved significantly over time (p < 0.0001); 101(30.8%) of patients remained ESAS cases throughout the study, 112(34.1%) recovered at 3-month post-baseline, an additional 72(22%) recovered at 9-month post-baseline, while 43(12.2%) had resumed ESAS caseness at 9-month post-baseline. CONCLUSION: Nurse-led SDS programs with well-structured referral pathways to community-based services and continued monitoring are feasible and acceptable in cancer patients and may help in reducing symptom distress. We intend next to develop optimal strategies for SDS implementation and referral within routine cancer care services.

Molecular characteristics of Asian male BRCA-related cancers.

PURPOSE: Germline mutations of BRCA1 or BRCA2 predispose men to develop various cancers, including breast cancers and prostate cancers. Male breast cancer (MBC) is a rare disease while prostate cancer (PRC) is uncommon in young men at the age of less than 40. The prevalence of BRCA genes in Asian male patients has to be elevated. METHODS: Germline mutations screening was performed in 98 high-risk Chinese MBC and PRC patients. RESULT: We have identified 16 pathogenic BRCA2 mutation carriers, 12 were MBC patients, 2 were PRC patients and 2 were patients with both MBC and PRC. The mutation percentages were 18.8%, 6.7% and 50% for MBC, PRC and both MBC and PRC patients, respectively. BRCA2 gene mutations confer a significantly higher risk of breast/prostate cancers in men than those with BRCA1 mutations. BRCA mutated MBC patients had a younger age of diagnosis and strong family histories of breast cancers while BRCA mutated PRC patients had strong family histories of ovarian cancers. CONCLUSION: Male BRCA carriers with breast cancers or prostate cancers showed distinct clinical and molecular characteristics, a male-specific genetic screening model would be useful to identify male cancer patients who have a high risk of BRCA mutation.

Use of Superparamagnetic Iron Oxide (SPIO) Versus Conventional Technique in Sentinel Lymph Node Detection for Breast Cancer: A Randomised Controlled Trial.

BACKGROUND: The objective of this study is to compare the efficacy of the superparamagnetic iron oxide (SPIO)-guided and standard techniques for sentinel lymph node (SLN) detection in early breast cancer. Multiple inferiority trials have concluded the non-inferiority of SPIO to the conventional radioisotope technique, with or without blue dye, in detecting SLNs. PATIENTS AND METHODS: From July 2018 to August 2022, patients clinically diagnosed with node-negative invasive breast cancer were randomised into the study group (SPIO) and control group (radioisotope and blue dye). Patient data and disease characteristics were prospectively collected. SLN detection rates were compared between the two groups. RESULTS: A total of 282 patients undergoing 288 sentinel lymph node biopsy (SLNB) procedures were recruited, and 144 SLNB procedures were randomised into each group. The baseline patient and disease characteristics were comparable. SLN localisation failed in one patient in each group; the success rate of SLNB was 99.3%. The SPIO group demonstrated a higher mean number of SLNs harvested (3.3 versus 2.8, p = 0.039) and longer mean procedure duration (33.1 min versus 22.3 min, p = 0.01) than the control group did. In the study group, the concordance rates per patient and node were 99.3% and 94.6%, respectively. Sixty-seven positive SLNs were detected in 37 patients. The concordance rates per malignant SLNB procedure and positive SLN were 97.3% and 96.8%, respectively. CONCLUSION: Single-tracer SPIO-guided SLNB was non-inferior to the dual technique (radioisotope and blue dye) and could safely replace the gold standard for SLN mapping in early breast cancer.

Delayed Sentinel Lymph Node Dissection in Patients with a Preoperative Diagnosis of Ductal Cancer In Situ by Preoperative Injection with Superparamagnetic Iron Oxide (SPIO) Nanoparticles: The SentiNot Study.

BACKGROUND: Difficulty in preoperatively assessing the risk for occult invasion or surgery that precludes future accurate axillary mapping in patients with ductal cancer in situ (DCIS) account for overutilization of SLND. METHODS: Prospective, multicenter, cohort study, including women with any DCIS planned for mastectomy or DCIS grade 2 and > 20 mm, any DCIS grade 3, any mass-forming DCIS and any planned surgery. Patients received an interstitial SPIO injection during breast surgery, but no upfront SLND was performed. If invasion was identified on final pathology, delayed SLND (d-SLND) was performed separately with the coadministration of isotope ± blue dye (BD). Study outcomes were proportion of upfront SLNDs that were avoided, detection rates during d-SLND, and impact on healthcare costs. RESULTS: In total, 78.7% of study participants (N = 254, mean age 60 years, mean DCIS size 37.8 mm) avoided upfront SLND. On d-SLND (median 28 days, range 9-46), SPIO outperformed Tc99 with (98.2% vs. 63.6%, p < 0.001) or without BD (92.7% vs. 50.9%, p < 0.001) and had higher nodal detection rate (86.9% vs. 32.3%, p < 0.001) and with BD (93.9% vs. 41.4%, p < 0.001). Only 27.9% of all SLNs retrieved were concordant for Tc99 and SPIO. Type of breast procedure (WLE vs. oncoplastic BCT vs. mastectomy) affected these outcomes and accounted for the low performance of Tc99 (p < 0.001). d-SLND resulted in a 28.1% total cost containment for women with pure DCIS on final pathology (4190 vs. 5828 USD, p < 0.001). CONCLUSIONS: Marking the SLN with SPIO may avoid overtreatment and allow for accurate d-SLND in patients with DCIS.

The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

BACKGROUND: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. METHODS: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. RESULTS: In pooled analyses, later age at menarche was associated with higher per cent density (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. CONCLUSIONS: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

The role of pre-operative axillary ultrasound in assessment of axillary tumor burden in breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Recent studies have suggested that a significant proportion of patients with axillary nodal metastases diagnosed by pre-operative axillary ultrasound (AUS)-guided needle biopsy were over-treated with axillary lymph node dissection (ALND). The role of routine AUS and needle biopsy in early breast cancer was questioned. This review aims to determine if pre-operative AUS could predict the extent of axillary tumor burden and need of ALND. METHODS: PubMed and Embase literature databases were searched systematically for abnormal AUS characteristics and axillary nodal burden. Studies were eligible if they correlated the sonographic abnormalities in AUS with the resultant axillary nodal burden in ALND according to the ACOSOG Z0011 criteria. RESULTS: Eleven retrospective studies and one prospective study with 1658 patients were included. Sixty-five percent of patients with one abnormal lymph node in AUS and 56% of those with two had low axillary nodal burden. Using one abnormal lymph node as the cut-off, the pooled sensitivity and specificity in prediction of axillary nodal burden were 66% (95%CI 63-69%) and 73% (95% CI 70-76%), respectively. Across the six studies that evaluated suspicious nodal characteristics, increased nodal cortical thickness may be associated with high axillary nodal burden. CONCLUSION: More than half of the patients with pre-operative positive AUS and biopsy proven axillary nodal metastases were over-treated by ALND. Quantification of suspicious nodes and extent of cortical morphological changes in AUS may help identify suitable patients for sentinel lymph node biopsy.

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Prospective clinical trial on the learning curve of high-intensity-focused ultrasound for the treatment of breast fibroadenoma.

INTRODUCTION: High-intensity-focused ultrasound (HIFU) is a safe and feasible treatment option for breast fibroadenoma. However, its learning curve has not been described in the medical literature. METHODS: All patients with biopsy-proven fibroadenoma considered indicated for HIFU were screened for eligibility for HIFU treatment. A total of 60 patients were recruited according to the pre-defined sample size calculation. RESULTS: Sixty consecutive patients were divided into three cohorts in chronological order. The mean tumor volume shrinkage rates in cohorts 1, 2, and 3 at 6 months post-HIFU ablation were 38%, 34%, and 59%, respectively. Significant tumor shrinkage was observed from case 41 onward (p < 0.0001). Similarly, the mean tumor volume shrinkage rates in cohorts 1, 2, and 3 at 12 months post-HIFU ablation were 45%, 51%, and 71%, respectively. Significant tumor shrinkage was observed from case 41 onwards (p < 0.0473). The mean procedure time for the first 20 patients was 48.5 (range 45-75) minutes, while that in the second 20 patients was 39.7 (range 20-60) minutes, and that in the last 20 patients was 28.9 (range 15-45) minutes. The treatment time was significantly shorter from case 41 onwards (p = 0.0481). CONCLUSION: Treatment outcomes and treatment time improved significantly after performing approximately 40 HIFU procedures.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Different strategies in marking axillary lymph nodes in breast cancer patients undergoing neoadjuvant medical treatment: a systematic review.

BACKGROUND: Marking of cytology-proven metastatic axillary lymph node in breast cancer patients before neoadjuvant treatment and its subsequent surgical retrieval have been shown to reduce the false-negative rate of sentinel lymph node biopsy. A systematic review was performed to evaluate different strategies in nodal marking and localization. METHODS: PubMed, Embase, EBSCOhost, and the Cochrane library literature databases were searched systematically to address the identification rate and retrieval rate of marked axillary lymph nodes. Studies were eligible if they performed nodal marking before neoadjuvant treatment, followed by selective extirpation of these marked axillary lymph nodes in definitive surgery RESULTS: Fifteen studies with a total of 703 patients were included. Index axillary lymph nodes were marked by clips or tattooed prior to the commencement of neoadjuvant treatment. In our pooled analysis, eighty-eight percent of the clipped nodes and ninety-seven percent of the tattooed nodes were successfully retrieved. Among these patients, seventy-seven percent of these marked axillary lymph nodes were also sentinel lymph nodes. CONCLUSION: Marking and selectively removing cytology-proven metastatic axillary lymph nodes after neoadjuvant treatment is feasible. An acceptably high nodal retrieval rate could be achieved using various methods of nodal marking and localization techniques.

Trastuzumab emtansine (T-DM1) versus trastuzumab in Chinese patients with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy for HER2-positive breast cancer in the phase 3 KATHERINE study.

PURPOSE: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE. METHODS: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event. RESULTS: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm). CONCLUSIONS: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

PURPOSE: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. METHODS: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. RESULTS: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]). CONCLUSION: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

Circulating high-sensitivity troponin T and microRNAs as markers of myocardial damage during childhood leukaemia treatment.

BACKGROUND: We investigated whether plasma high-sensitivity cardiac troponin T (hs-cTnT) and circulating heart-associated microRNA (miRs) are increased in children with leukaemias during anthracycline-based chemotherapeutic treatment. METHODS: In vitro human pluripotent stem cell (hPSC)-derived cardiomyocyte model showed that miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from cells into culture medium in a time- and dose-dependent manner on doxorubicin exposure. Left ventricular (LV) myocardial deformation and circulating heart-associated miRs and plasma hs-cTnT during and after completion of chemotherapy were determined in 40 children with newly diagnosed acute leukaemia. RESULTS: Significant reduction of LV global longitudinal strain and strain rates were found within 1 week after completion of anthracycline therapy in the induction phase of treatment (all p < 0.05). Hs-cTnT level peaked and miR-1 increased significantly at this time point. Log-transformed hs-cTnT correlated negatively with LV global systolic longitudinal strain (r = -0.38, p < 0.001). Receiver operating characteristic analysis revealed that area under the curve for changes in plasma hs-cTnT from baseline and plasma miR-1 levels in detecting a reduction in ≥20% of global longitudinal strain were respectively 0.62 (95% CI 0.38-0.87) and 0.62 (95% CI 0.40-0.84). CONCLUSION: Plasma hs-cTnT and circulating miR-1 may be useful markers of myocardial damage during chemotherapy in children with leukaemias. IMPACT: Heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b,and miR-499 were increased in the culture medium upon exposure of hPSC-derived cardiomyocytes to doxorubicin. Only miR-1 increased significantly during anthracycline-based therapy in paediatric leukaemic patients. In paediatric leukaemic patients, plasma hs-cTnT and circulating level of miR-1 showed the most significant increase within 1 week after completion of anthracycline therapy in the induction treatment phase. The study provides the first evidence of progressive increase in circulating miR-1 and plasma hs-cTnT levels during the course of anthracycline-based therapy in children with leukaemias, with hs-cTnT level also associated with changes in LV myocardial deformation.

Pertuzumab and trastuzumab as adjuvant treatment for HER2-positive early breast cancer: outcomes in Chinese patients in the APHINITY study.

BACKGROUND: The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites. METHODS: Patients were randomized to standard adjuvant chemotherapy plus 1 year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. RESULTS: Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39-1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm. CONCLUSIONS: Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.

A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient.

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.