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Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To examine the cost-effectiveness of using granulocyte colony-stimulating factor (G-CSF) for primary or secondary prophylaxis in patients with breast cancer from the perspective of Taiwan's National Health Insurance Administration., Methods: A Markov model was constructed to simulate the events that may occur during and after a high-risk chemotherapy treatment. Various G-CSF prophylaxis strategies and medications were compared in the model. Effectiveness data were derived from the literature and an analysis of the National Health Insurance Research Database (NHIRD). Cost data were obtained from a published NHIRD study, and health utility values were also obtained from the literature. Sensitivity analyses were performed to assess the uncertainty of the cost-effectiveness results., Results: In the base-case analysis, primary prophylaxis with pegfilgrastim had an incremental cost-effectiveness ratio (ICER) of NT$269,683 per quality-adjusted life year (QALY) gained compared to primary prophylaxis with lenograstim. The ICER for primary prophylaxis with lenograstim versus no G-CSF prophylaxis was NT$61,995 per QALY gained. The results were most sensitive to variations in relative risk of febrile neutropenia (FN) for pegfilgrastim versus no G-CSF prophylaxis. Furthermore, in the probabilistic sensitivity analysis, at a willingness-to-pay threshold of one times Taiwan's gross domestic product per capita, the probability of being cost-effective was 88.1% for primary prophylaxis with pegfilgrastim., Conclusions: Our study suggests that primary prophylaxis with either short- or long-acting G-CSF could be considered cost-effective for FN prevention in breast cancer patients receiving high-risk regimens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tseng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer., Methods: DNA methylation profiling was performed for 524 Asian Chinese individuals, comprising 256 breast cancer patients and 268 age-matched healthy controls, using the Infinium MethylationEPIC array. Feature selection was applied to 649,688 CpG sites in the training set. Predictive models were built by training three machine learning models, with performance evaluated on an independent test set. Enrichment analysis to identify transcription factors binding to regions associated with the selected CpG sites and pathway analysis for genes located nearby were conducted., Results: A methylation profile comprising 51 CpGs was identified that effectively distinguishes breast cancer patients from healthy controls achieving an AUC of 0.823 on an independent test set. Notably, it outperformed all four previously reported breast cancer-associated methylation profiles. Enrichment analysis revealed enrichment of genomic loci associated with the binding of immune modulating AP-1 transcription factors, while pathway analysis of nearby genes showed an overrepresentation of immune-related pathways., Conclusion: This study has identified a breast cancer-associated methylation profile that is immune-related to potential for early cancer detection., (© 2024. The Author(s).)

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution., Competing Interests: Declaration of interests A.R.V. is a member of Cell’s advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases., Methods: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory)., Results: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%., Conclusions: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014., (© 2023. The Author(s).)

Objectives: The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore., Methods: A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties., Results: The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained., Conclusions: This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.

Background: Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge., Methods: From 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS)., Results: After post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02)., Conclusion: In patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor's hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings., (© 2023. The Author(s).)

Purpose: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib., Methods: Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived., Results: Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months)., Conclusion: This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

Background and Objectives: Myelosuppressive chemotherapy is effective for breast cancer but carries a potential risk of febrile neutropenia (FN). Clinical practice guidelines have recommended prophylaxis with granulocyte colony-stimulating factor (G-CSF) to reduce the incidence of FN in patients receiving chemotherapy. We aimed to examine the use of G-CSFs for primary prophylaxis for FN and to see whether it follows the guidelines. In addition, we examined the changes in the use of long-acting and short-acting G-CSFs in patients with breast cancer over the past ten years., Methods: This was a retrospective observational real-world study. The data were obtained from the clinical research database of three hospitals affiliated with Taipei Medical University. Patients with breast cancer who initiated their first chemotherapy regimen between January 1, 2011, and December 31, 2020, were identified by the ICD codes and their use of filgrastim or pegfilgrastim was identified by the Anatomical Therapeutic Chemical codes. Whether and how G-CSF was prescribed during the study patients' first chemotherapy regimen was examined, and the annual change in the total number of short- and long-acting G-CSFs prescribed to the study patients from 2011 to 2020 was analyzed., Results: Among the 2,444 patients who were prescribed at least one of the examined 15 breast cancer chemotherapy drugs, 1,414 did not use any G-CSFs during their first chemotherapy regimen while 145 used G-CSFs for primary prophylaxis and 185 for treatment. Among the patients receiving high FN risk regimens, only 8.6% used G-CSF for primary prophylaxis. The average (± SD) number of days for short-acting G-CSF use was 2.3 (± 1.5) days with a median of 2 days. In addition, it was found that there was a significant reduction in long-acting G-CSF use (p = 0.03) whereas the changes in short-acting G-CSF use over time were not significant (p = 0.50)., Conclusions: Our study results show that G-CSFs are used for primary prophylaxis in a small percentage of patients with breast cancer and the duration of short-acting G-CSF use is relatively short. Considering the significant clinical and economic impact of FN, it is hoped that the prescription patterns of G-CSFs observed can provide an important reference for future clinical practice and reimbursement policy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung., Methods: Exome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K&#95;Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case-control association analyses were performed., Results: Altogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations., Conclusions: We have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers., (© 2023. The Author(s).)

Objectives: This review explores the cost-effectiveness of the strategies used in the breast cancer early detection programs of low- to middle-income countries., Methods: A systematic review was performed to identify related studies, published up to August 2021, on PubMed, Cochrane, ProQuest, and the Cumulative Index to Nursing and Allied Health Literature. The Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol were referenced during the reporting process. The Consolidated Health Economic Evaluation Reporting Standards 2022 criteria were used to assess the requirements of the selected studies. Articles with original data and full texts were included in the review. Non-low- to middle-income countries and non-English articles were excluded., Results: This review identified 12 suitable studies, wherein 6 investigated the cost-effectiveness of clinical breast examinations (CBEs), whereas 10 looked into mammogram (MMG) with or without CBE. In 2 studies, the cost-effectiveness of raising awareness through mass media and the use of ultrasounds combined with CBE were investigated. Although cost-effective, MMG incurs greater costs and requires more skill to be performed. MMG screenings before the age of 40 years were not cost-effective. The limitations of this review include variability in the methodological approaches of its selected studies. Most of the chosen studies met the Consolidated Health Economic Evaluation Reporting Standards 2022 criteria., Conclusions: This review shows that adopting an age- and risk-based MMG screening approach could be viable in countries with limited resources. Future cost-effectiveness analysis research should include a section on patient and stakeholder engagement with the study's results., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population., Methods: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020., Results: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic., Conclusions: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date., (© 2023. The Author(s).)

The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2 + breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2 + BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2 + , but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2 + BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2 + BC to confer resistance to trastuzumab treatment.

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer., Patients and Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion., Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index., Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies., (©2022 American Association for Cancer Research.)

Background: Breast cancers are heterogeneous with variable clinical courses and treatment responses., Objective: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents., Patients and Methods: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco ® ). Observed genomic changes were correlated with the Miller-Payne histological response to treatment., Results: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029)., Conclusions: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy., Clinical Trial Registration: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2022. The Author(s).)

The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy ( n  = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.

Background: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers., Objective: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab., Methods: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed., Results: Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m 2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel., Conclusions: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108)., Clinical Trial Registration: NCT02396108, date of registration: 25 March, 2015., (© 2022. The Author(s).)

Purpose: Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can "normalize" the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients., Methods: This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2., Results: In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004)., Conclusion: Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery., Trial Registry: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2021. The Author(s).)

Background: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent., Methods: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease., Results: PTV 9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV 25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV 25genes carriership, but not PTV 9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28])., Conclusions: PTV 9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions., (© 2021. The Author(s).)

Abstract: To determine the economic burden of metastatic breast cancer (MBC) in Taiwan, we conducted a national retrospective claim database analysis to evaluate the incremental healthcare costs and utilization of MBC patients as compared to their breast cancer (BC) and breast cancer free (BCF) counterparts.Data were obtained from the National Health Insurance Claim Database and the Taiwan Cancer Registry database between 2012 and 2015. All healthcare utilization and costs were calculated on a per-patient-per-month (PPPM) basis and were compared among groups using the generalized linear model adjusting for age group, residential area, and Charlson comorbidity index group.A total of 1,606 MBC patients were matched to 6,424 BC patients and 6,424 BCF patients. The majority of overall MBC healthcare costs were attributed to outpatient costs (75.1%), followed by inpatient (23.2%) and emergency room costs (1.7%). The PPPM total healthcare costs of the MBC, BC, and BCF groups were TWD 7,422, 14,425, and 2,114, respectively. The adjusted PPPM total healthcare cost ratio of MBC to BCF was 4.1. Compared to BCF patients, the patients receiving both human epidermal growth factor receptor 2-targeted therapy and endocrine therapy incurred 28.1 times PPPM total costs. The adjusted PPPM total healthcare cost ratio of recurrent MBC to BCF was 2.3, while the ratio was 12.2 in the de novo MBC group.Patients with MBC are associated with substantial economic burden, particularly in outpatient costs. The study findings could be useful for MBC-related economic evaluations and health resource allocation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer., Methods: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET., Results: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (β = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (β = - 0.381, 95% CI: - 0.511 to - 0.251, p < 0.001). There was no effect of Necessity (β = 0.006, 95% CI: - 0.145 to 0.158, p = 0.933) or Concerns (β = 0.041, 95% CI: - 0.117 to 0.199, p = 0.614) on adherence. Necessity-concerns beliefs were also not significant mediators in the relationship between socio-clinico factors and medication adherence., Conclusions: Older age and lower barriers to adherence were associated with higher adherence scores. Necessity-concerns beliefs did not have a significant effect on adherence as majority of the patients identified forgetfulness as a reason for non-adherence., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers., Competing Interests: The authors have declared that no competing interests exist.

Background: CDK4/6 inhibitors have shown promising results for treating advanced breast cancer (ABC) and are routinely used in Singapore. In view of their high costs, it is important to assess their relative value compared to existing standards of care in the local setting., Aims: This study evaluates the cost-effectiveness of adding ribociclib to goserelin and a nonsteroidal aromatase inhibitor or tamoxifen as initial therapy for premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC in Singapore., Methods: A partitioned survival model with four health states (progression-free on first-line treatment, progression-free on second-line treatment, progressed disease, and death) was developed from a healthcare system perspective over a 10-year time horizon. Key clinical inputs were derived from the MONALEESA-7 trial, and survival curves were extrapolated beyond the trial period. Health state utilities were derived from the literature and direct medical costs were obtained from local public healthcare institutions. A discount rate of 3% was applied to both costs and outcomes. One-way deterministic and probabilistic sensitivity analyses were conducted to explore uncertainties., Results: The base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of SGD197, 667 per quality-adjusted life-year. Sensitivity analyses showed that the ICER was sensitive to the survival parametric distribution, ribociclib price, time horizon, and utility weights used. Even when these were varied, ICERs remained high and not cost-effective in the local context., Conclusion: At its current price, adding ribociclib to endocrine therapy is unlikely to be cost-effective in Singapore for HR+, HER2- ABC. Results from this study are useful to inform future funding decisions for CDK4/6 inhibitors alongside other factors including clinical effectiveness, safety, and budget impact considerations., (© 2020 The Authors. Cancer Reports published by Wiley Periodicals LLC..)

Purpose: Resistance to treatment with endocrine therapy in patients with HR + , HER2 - advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib., Patients and Methods: In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR + , HER2 - ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant., Results: The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8-46.7)., Conclusions: Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR + , HER2 - ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation. See related commentary by Clark et al., p. 371 ., (©2020 American Association for Cancer Research.)

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer. In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer. Since then, BRK has been found both in vitro and in vivo to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development. The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK. This review highlights recent advances in BRK biology in contributing to the "hallmarks of cancer", as well as BRK's therapeutic significance. Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects. Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase. Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors., Methods: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ 2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ 2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat., Results: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups., Conclusion: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest that is related to this submission., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies., Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy., Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB ( n = 9) included multiple cycles of NK cells (1 × 10 7 /kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 10 7 /kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment., Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials., (©2020 American Association for Cancer Research.)

Background: New developments in medications for metastatic breast cancer (MBC) can be of great benefit to patients, but unfortunately these medicines also increase expenditures. Cost-utility analyses (CUAs) are needed to allocate health resources properly, and health utility values are required to calculate quality-adjusted life years in those CUAs., Objective: The aims of this study were to measure health utility values for several MBC-related health states and certain breast cancer treatment-related grade 3/4 adverse drug reactions (ADRs). In addition, we examined whether different methods and respondents' characteristics would influence the utility values elicited., Methods: A cross-sectional survey was conducted. The visual analogue scale (VAS) and time trade-off (TTO) methods were used to measure health utilities. Four MBC and nine ADR health states were selected for evaluation based on literature review and expert opinion. Information about respondents' demographic and clinical characteristics were collected to examine the relationship between utilities and participant characteristics., Results: A total of 102 patients participated in this study. The TTO-elicited values were higher than the VAS-derived scores except for two MBC-related health states. Among the MBC health states assessed, the TTO preference score ranged from 0.04 (palliative MBC) to 0.62 (responding MBC). For grade 3/4 ADRs, the mean TTO-derived utility values ranged from 0.35 (nausea/vomiting) to 0.79 (fatigue). The ranking of the preference scores derived from the VAS was similar to that of the TTO-elicited scores., Conclusion: This study obtained health state utility values for MBC and grade 3/4 ADRs using both the TTO and the VAS, which provides useful data for future CUAs., Competing Interests: Declaration of competing interest All author declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer survival has improved with significant progress in treatment and disease management. However, compliance with treatment varies. Treatment guidelines for older patients are unclear. We aim to identify predictors of noncompliance with recommended therapy in a large breast cancer population and assess the impact of noncompliance on survival. Our study included 19,241 non-metastatic female breast cancer patients, of whom 3,158 (16%) died within 10 years post-diagnosis (median survival = 5.8 years). We studied the association between treatment noncompliance and factors with logistic regression, and the impact of treatment noncompliance on survival with a flexible parametric survival model framework. The highest proportion of noncompliance was observed for chemotherapy (18%). Predictors of noncompliance with chemotherapy, radiotherapy and endocrine therapy included age, tumor size, nodal involvement and subtype (except radiotherapy). Factors associated with not receiving surgery included age and subtype. Treatment noncompliance was associated with worse overall survival for surgery (HR: 2.26 [1.80-2.83]), chemotherapy (1.25 [1.11-1.41]), radiotherapy (2.28 [1.94-2.69]) and endocrine therapy (1.70 [1.41-2.04]). Worse survival was similarly observed in older patients for whom guidelines generally do not apply. Our results highlight the importance of following appropriate treatment as recommended by current guidelines. Older patients may benefit from similar recommendations.

Objective: Clinical genetic testing to diagnose germline mutations often requires blood sample or saliva smear from a cancer-affected individual. This rules out testing in families when cancer-affected individuals are deceased. We explored the use of a next-generation sequencing (NGS) platform to diagnose germline pathogenic mutations from tumors., Methods: Archival tumors (ovarian = 26, breast = 25, others = 9) were retrieved from 60 cancer patients who have undergone multi-gene panel blood testing. Genomic DNA was extracted and sequenced for BRCA1/2 using a NGS platform. 41/60 specimens were sequenced for 5 other genes (APC, ATM, PALB2, PTEN, TP53). Tumor testing and results interpretation were performed blinded to the blood test result., Results: All 38 patients with no BRCA1/2 mutations on blood testing were correctly tested negative on tumor. Tumor testing correctly diagnosed BRCA1/2 pathogenic mutations in 15/22 (68%) patients while in 7/22 (32%) patients, the mutation was either detected but incorrectly classified as VUS (n = 3) or not detected at all (n = 4). Overall concordance rate for tumor and blood testing for BRCA1/2 mutations was 88%, with 0% false positive and 32% false negative rate for pathogenic mutations. Tumor testing correctly diagnosed 1/2 pathogenic germline ATM mutation, 1/1 pathogenic germline PALB2 mutation and 2/2 pathogenic germline TP53 mutations. False positive germline mutations were diagnosed in 4 genes at a rate of 2.4%-10.3% (APC = 2.4%, PALB2 = 2.4%, PTEN = 4.9%, TP53 = 10.3%)., Conclusion: Tumor testing for BRCA1/2 germline mutations using an NGS platform is fairly reliable with no false positive findings, and correctly diagnosed more than two-thirds of pathogenic germline BRCA1/2 mutations. However, it is not reliable to diagnose pathogenic germline mutations in genes frequently mutated in sporadic cancers, such as PTEN and TP53., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Trastuzumab-based chemotherapy has shown remarkable clinical benefits for patients with HER2-positive breast cancer. However, treatment regimens involving trastuzumab had little or no effect for a subset of patients. Preliminary studies revealed WW-binding protein 2 (WBP2), an oncogenic transcription coactivator, to be coamplified with HER2 in 36% of HER2-positive breast cancers. We hypothesize that WBP2 regulates and correlates with the response of HER2-positive breast cancer to trastuzumab., Experimental Design: The coexpression of WBP2 and HER2 in breast tumors was validated using IHC. The role and mechanism of WBP2 in regulating breast cancer response to trastuzumab was elucidated using in vitro , patient-derived xenograft and murine xenograft models. A multicenter retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine whether WBP2 expression correlates with pathologic complete response (pCR)., Results: Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced HER2 downregulation and cell-cycle arrest via inhibition of cyclin D expression. High level of WBP2 correlated with better pCR (67.19%) compared with low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors also aged below 50 years (77.78%) or were premenopausal in status (73.33%). Retrospectively, WBP2 demonstrated sensitivity of 80% to 81% and specificity of 76.5% to 80% in discriminating between patients showing pCR and non-pCR., Conclusions: WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy., (©2018 American Association for Cancer Research.)

Background: Due to historically low uptake of genetic testing, the mutational spectrum of Asians with Hereditary Breast Cancer (HBC) is not well understood. This study sought to understand the incidence and spectrum of germline mutations in Asian patients with suspected HBC in a clinic setting., Methods: 1056 patients with suspected HBC were seen in our Cancer (CA) Genetics Clinic from 2000-2017, of which 460 underwent genetic testing., Results: Of 460 probands tested, 93% were female, 61% Chinese, 90% had prior CA, with 19% (77/414) having ≥2 primary CA. Median age at CA-diagnosis was 43y (17-83); 70% had Breast CA (BC) and 25% Ovarian CA (OC). 34% had young-onset BC, 8% bilateral BC, and 4% BC/OC. Majority had family history of BC (53%) or OC (20%). 57% underwent multigene testing (14-49 genes), 34% targeted testing, and 8% predictive testing. 30% were found to have a pathogenic mutation: 80% in BRCA1/2 (8 novel mutations noted). Of 33 non-BRCA1/2 pathogenic mutations detected, 61% were in 11 BC genes while 39% were in non-BC genes suggestive of alternative CA syndromes. Testing beyond BRCA1/2 impacted management for 15.9% (22/138) of carriers, but extensive testing identified variants of uncertain significance (VUS) in up to 44.5% of probands. Restricting multigene panel testing to a guideline-based 20-gene panel including Lynch Syndrome genes was found to be most optimal, detecting 94.6% of mutation carriers while reducing VUS rate to 21.5%., Conclusions: Evolution of CA Genetics testing strategy to a multigene approach facilitated detection of pathogenic mutations in non-BRCA1/2 genes and aided management. Guideline-based panel testing is feasible and can be offered in Asians with suspected HBC., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Aberrant cellular proliferation due to dysregulation of the cyclin-dependent kinase (CDK) retinoblastoma (Rb)-pathway occurs in several cancers. Selective inhibition of CDK4/6 is an attractive target particularly in hormone-receptor positive (HR+) metastatic breast cancer (MBC), where it has transformed the treatment of these cancers in recent years. Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of HR+, HER2 negative (HER2-) MBC. Areas covered: We reviewed and compared the pharmacology, clinical efficacy, and toxicity profiles of the three CDK4/6 inhibitors and discussed several challenges in the use of these drugs, particularly in identifying biomarkers, optimizing dosing strategies, and finding best combinations with other therapies. Expert opinion: All three CDK4/6 inhibitors have shown remarkable efficacy when added to endocrine therapy in the treatment of HR+/HER2- MBC with consistent improvements in progression-free survival across all phase III trials. As efficacy appears similar between the drugs, differences in toxicities, dosing schedule, and monitoring requirements may influence the choice of CDK4/6 inhibitor. There is a paucity of predictive biomarkers that have been identified thus far, but a few promising biomarkers have been studied in the preclinical setting and results of ongoing clinical studies are awaited to validate their utility.

Purpose: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen., Experimental Design: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study., Results: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs., Conclusion: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Workability is of increasing importance especially in Asia given the increasing incidence rates and young age of onset of breast cancer. This study explores the determinants of employment and suboptimal workability. And evaluate the association between workability and patient-reported physical, psychological, and social outcomes., Methods: In a hospital-based cross-sectional study, 327 breast cancer survivors, < 65 years of age and > 1 year post-diagnosis were recruited. Employed survivors filled out the workability index, which measures a person's capacity to meet work demands in relation to current health status. The EORTC-QLQ-C30, EORTC-QLQ-BR23, hospital anxiety and depression scale, multidimensional fatigue inventory, and brief pain index were administered. Fisher's exact test and Kruskal-Wallis test were used to test for associations of workability and employment status with demographic, clinical characteristics, and patient-reported outcomes. Linear models with standardised scores for patient-reported outcomes were fitted to study the associations of workability with patient-reported outcomes., Results: Of the 327 survivors, < 65 years of age (working age), 140 (43%) were in full-time and 34 (10%) in part-time employment. Employed survivors were younger at time of diagnosis and at time of survey. Employment status was not associated with time since diagnosis, ethnicity, or clinical characteristics. Suboptimal workability was present in 37% of employed survivors of the working age, and more common in jobs that include physical work activities. Higher level of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status were independently associated with poorer workability., Conclusions: Lower employment and reduced workability in breast cancer survivors is common, and reduced workability is associated with higher levels of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status. Longitudinal research on psychosocial support with workability in Asia may find tailored approach to improve or maintain workability in employed breast cancer patients.

Background: Medication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk-benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy., Methods/design: In this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the χ 2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (< 18.4 pmol/L versus ≥18.4 pmol/L) will be compared using the χ 2 test, and the logistic regression. Further, the assessment of knowledge, attitude, behaviour, and barriers and facilitating factors of medication adherence will be made via logistic regression., Discussion: This will be the first study to evaluate short-term clinical outcomes from SMS reminder for breast cancer patients on aromatase inhibitor therapy. Random allocation to SMS reminder or control arm ensures that patients in both arms will be comparable with respect to demographic and clinical characteristics, and any difference in outcomes can be attributed to the intervention. Participants are not blinded to the assignment of intervention, thus there may be potential for bias in outcome assessments., Trial Registration: NCT02524548 . Retrospectively registered on 17 August 2015.

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.

Gemcitabine-carboplatin (GC) chemotherapy was efficacious in metastatic breast cancer (MBC) patients probably resistant to anthracyclines and taxanes, but showed significant interindividual variation in treatment responses. Early prediction of response to treatment is clinically relevant to identify patients who will achieve clinical benefit. In this study, nuclear magnetic resonance (NMR) based pharmacometabonomics was used to noninvasively predict the response to GC chemotherapy of 29 MBC patients with prior exposure to both anthracyclines and taxanes from a phase II study. Formate and acetate levels in the baseline serum collected prior to GC chemotherapy were identified as potential predictive markers to select patients who will achieve clinical benefit and to identify those who should not be treated with the therapy to avoid futile treatment. The significantly lower baseline levels of serum formate and acetate in patients with resistant disease may reflect the higher demand of them as alternate/additional nutritional sources to fuel the accelerated proliferation of breast cancer cells that are biologically more aggressive or resistant to therapy. The results suggest that pharmacometabonomics can be a potential useful tool for predicting chemotherapy response in the context of precision medicine. Prospective studies with larger patient cohorts are required for validation of the findings.

Little research has been done into cosmetic outcomes in non-Western breast cancer populations. We aimed to study the prevalence and determinants of dissatisfaction with cosmetic outcome after breast cancer surgery of Asian breast cancer survivors, and its association with patient-reported anxiety, depression, and quality of life. In a hospital-based cross-sectional study, 384 breast cancer survivors of at least 12 months after diagnosis completed questionnaires on satisfaction with cosmetic appearance, quality of life (EORTC-QLQ-C30) and anxiety and depression (HADS). Cumulative logit models were used to examine the adjusted association between dissatisfaction with cosmetic appearance and demographic and clinical characteristics. Kruskal-Wallis test was used to test for associations between dissatisfaction with cosmetic appearance and patient-reported outcomes. Overall, 20% of women reported to be (very) dissatisfied with cosmetic appearance. Survivors of Chinese ethnicity were more likely dissatisfied with cosmetic appearance compared to Malay survivors (22% and 14% respectively, adjusted OR = 2.4, 95%CI: 1.4-3.9). Women with DCIS (adjusted OR = 2.2, 95%CI: 1.3-3.7) or advanced stage disease (adjusted OR = 2.2, 95%CI: 1.2-3.9) had a higher risk of being dissatisfied with their cosmetic appearance. Women treated with mastectomy were at a higher risk of dissatisfaction with cosmetic appearance (adjusted OR = 1.7, 95%CI: 1.1-2.5). Dissatisfaction with cosmetic appearance was associated with increased depression scores. In this South-East Asian population, one in five breast cancer patients were (very) dissatisfied with the cosmetic outcome of treatment. Chinese women, women with larger tumors and women treated with mastectomy were most likely to report dissatisfaction with cosmetic appearance.

Background: To determine if mammography combined with digital breast tomosynthesis (DBT), leads to superior performance in screening for breast cancer compared to digital mammography (DM) alone., Methods: We retrospectively collected data from A) the results of population-based mammography-screening provided by the National Cancer Registry in Taiwan, and B) the results from all screening mammography performed with DBT from 2012 through 2015 at Kaohsiung Veterans General Hospital (VGHKS) since the institution of DBT at the end of 2011. This was compared data from 3 years with DM performed prior to DBT implementation. We calculated the results of medical audit of VGHKS and compared this with national data. Fisher's exact test is applied., Results: VGHKS data demonstrated a higher cancer detection rate (CDR) and positive predictive value 1 (PPV 1) than the national average. Most prominently in the year 2014, our CDR was 120% better than that of the national average. CDR ranged from 6.3 to 8.1‰ prior to the introduction of DBT, and following DBT implementation this improved to 8.5-11.4‰, reflecting a mean increase of 32.2%. Early cancer detection was 50% higher and node negative rate was 25% higher than the national average of latest year. A 17.8% reduction in recall rate (RR) was achieved due to a decrease in unnecessary recall., Conclusion: There was a 32.2% increase in CDR and a 17.8% decrease in RR when DBT was used as an adjunct to DM, as compared to DM alone. CDRs were approximately twofold better than national average data. DBT was more effective at detecting cancer in ductal carcinoma in situ and stage 1., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.

Aim: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer., Methods: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15., Results: Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (P interaction  = 0.03)., Conclusions: Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors., Trial Registration Identifier: NCT01816594., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy. Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy ( P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response ( P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy ( P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR ., (©2016 American Association for Cancer Research.)

We aim to identify clinicopathologic predictors for response to neoadjuvant chemotherapy and to evaluate the prognostic value of pathologic complete response (pCR) on survival in Asia. This study included 915 breast cancer patients who underwent neoadjuvant chemotherapy at five public hospitals in Singapore and Malaysia. pCR following neoadjuvant chemotherapy was defined as 1) no residual invasive tumor cells in the breast (ypT0/is) and 2) no residual invasive tumor cells in the breast and axillary lymph nodes (ypT0/is ypN0). Association between pCR and clinicopathologic characteristics and treatment were evaluated using chi-square test and multivariable logistic regression. Kaplan-Meier analysis and log-rank test, stratified by other prognostic factors, were conducted to compare overall survival between patients who achieved pCR and patients who did not. Overall, 4.4% of nonmetastatic patients received neoadjuvant chemotherapy. The median age of preoperatively treated patients was 50 years. pCR rates were 18.1% (pCR ypT0/is) and 14.4% (pCR ypT0/is ypN0), respectively. pCR rate was the highest among women who had higher grade, smaller size, estrogen receptor negative, human epidermal growth factor receptor 2-positive disease or receiving taxane-based neoadjuvant chemotherapy. Patients who achieved pCR had better overall survival than those who did not. In subgroup analysis, the survival advantage was only significant among women with estrogen receptor-negative tumors. Patients with poor prognostic profile are more likely to achieve pCR and particularly when receiving taxane-containing chemotherapy. pCR is a significant prognostic factor for overall survival especially in estrogen receptor-negative breast cancers., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed., Objective: To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer., Design, Setting, and Participants: In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region., Interventions: Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory., Main Outcome and Measures: The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety., Results: The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed., Conclusions and Relevance: In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm., Trial Registration: clinicaltrials.gov Identifier: NCT00915018.

Background: CancerMath is a set of web-based prognostic tools which predict nodal status and survival up to 15 years after diagnosis of breast cancer. This study validated its performance in a Southeast Asian setting., Methods: Using Singapore Malaysia Hospital-Based Breast Cancer Registry, clinical information was retrieved from 7064 stage I to III breast cancer patients who were diagnosed between 1990 and 2011 and underwent surgery. Predicted and observed probabilities of positive nodes and survival were compared for each subgroup. Calibration was assessed by plotting observed value against predicted value for each decile of the predicted value. Discrimination was evaluated by area under a receiver operating characteristic curve (AUC) with 95 % confidence interval (CI)., Results: The median predicted probability of positive lymph nodes is 40.6 % which was lower than the observed 43.6 % (95 % CI, 42.5 %-44.8 %). The calibration plot showed underestimation for most of the groups. The AUC was 0.71 (95 % CI, 0.70-0.72). Cancermath predicted and observed overall survival probabilities were 87.3 % vs 83.4 % at 5 years after diagnosis and 75.3 % vs 70.4 % at 10 years after diagnosis. The difference was smaller for patients from Singapore, patients diagnosed more recently and patients with favorable tumor characteristics. Calibration plot also illustrated overprediction of survival for patients with poor prognosis. The AUC for 5-year and 10-year overall survival was 0.77 (95 % CI: 0.75-0.79) and 0.74 (95 % CI: 0.71-0.76)., Conclusions: The discrimination and calibration of CancerMath were modest. The results suggest that clinical application of CancerMath should be limited to patients with better prognostic profile.