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Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan–Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis ( P  = 0.020, HR = 2.515, CI 1.154–5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis ( P  = 0.008, HR = 3.22, CI 1.36–7.61; P  = 0.017, HR = 3.08, CI 1.22–7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial–mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.

PurposeDeleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. MethodsWe evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. ResultsAmong 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. ConclusionsThe prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.

Background The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (g BRCA1/2 ) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (s BRCA1/2 ) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1 , BRCA2 , and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. Methods A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1 , BRCA2 , and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. Results Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2 , BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1 -mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2 , p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2 , p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants ( BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant ( PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. Conclusion Our study depicted the mutational patterns of BRCA1 , BRCA2 , and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

Background Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. Methods The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher™ Oncomine™ Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). Results A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). Conclusion Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.

Background Women with breast cancer are known to suffer from disease and treatment, and the generic measurement tools may underestimate their frailty. A specific instrument comprehensively measuring frailty among women with breast cancer has not yet been developed. This study aims to develop and validate the tool of breast cancer comprehensive frailty scale (BCCFS). Methods A descriptive and explorative study design was used. We collected the data through systematic literature and modified Delphi method. After an initial search and screening process, a total of 33 articles were included for review and consideration in the item design. Ten experts were invited to generate and validate initial items. The validity was assessed using a sample of 205 women with breast cancer in Taiwan. Its validity was then tested using item analysis, exploratory factor analysis, confirmatory factor analysis, criterion-related validity and areas under the receiver-operating characteristic, while its reliability was evaluated through internal consistencies and test-retest analyses. Results A three-factor solution with 16 items was chosen and accounted for approximately 58.57% of the total variance by exploratory factor analysis (KMO = 0.85; Bartlett’s Test of Sphericity: χ2 = 2881.34, p  < 0.001). The factors were interpreted as (1) deterioration of body and mobility, (2) negative emotions, and (3) cognitive impairment. The goodness of fit indices of the confirmatory factor analysis were as follows: chi-square = 234.498 ( p  < 0.01), normed chi-square = 2.322, SRMR = 0.055, RMSEA = 0.08, CFI = 0.930, and LI = 0.917. The Cronbach’s alpha calculated for the BCCFS (16 items) was 0.91 (95% confidence interval: 0.89 to 0.93), and the test-retest reliability coefficient was 0.60. Using the G8 screening tool as a standard indicator of frailty, analysis of receiver operating characteristic curve showed that 31.5 was the best cut point (area under curve = 0. 816, 95% confidence interval: 0.757 to 0.874) with a sensitivity of 63.5% and specificity of 84.4%. Conclusion The instrument exhibited acceptable psychometric properties, proving it to be a valuable tool for evaluating frailty in women with breast cancer. Further assessments of its reliability, validity, and generality from health providers’ views in different contexts and cultures are recommended.

In this study, we evaluated the concordance of targeted sequencing between paired ctDNA and matched tumor samples from early breast cancers treated with curative intention. Molecular profiling was performed using the Oncomine Comprehensive Assay v3 and the Oncomine Breast cfDNA Assay v2. The liquid biopsy detection rate was 39% (all-stage breast cancers, n = 612). Among 246 early-stage patients assayed for both ctDNA and matched tumor, the cfDNA assay detected 73 (29.6%) and the comprehensive assay detected 201 (81.7%) breast cancers with at least one alteration (χ2 test, p = 0.001). In total, 67 (25.6%) cases tested positive on both platforms, while the cfDNA and comprehensive assays detected an additional 10 (4%) and 138 (56%) cases, respectively. The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while the PIK3CA (39.4%), AKT1 (45.9%), and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers, considering that the concordance rate between tumor and liquid biopsy was only one-quarter.

PurposeInvasive lobular cancer (ILC) is the second most common histology type of breast cancer followed by invasive ductal carcinoma (IDC). This study aimed to investigate the characteristic, treatment strategies, and clinical outcomes of ILC based on a national population-based cancer registry.MethodsThis study recruited 2671 ILC and 52,215 IDC patients diagnosed between 2011 and 2017 using the Taiwan Cancer Registry (TCR). Correlations between ILC and IDC subgroups were assessed using 1:4 propensity score matching and compared using the χ2 test. Disease free survival(DFS) and overall survival(OS) were estimated using the Kaplan–Meier method with the log-rank test. The risk of disease relapse and mortality were assessed using Cox proportional hazards model.ResultsILC patients had larger tumor sizes, more positive axillary lymph node involvement, lower tumor grade, and higher cancer stage than IDC patients. After matching, ILC patients had a significantly higher rate of receiving mastectomy (58.93% and 53.85%) and positive surgical margin regardless of surgery type. ILC exhibited a significantly higher rate of distant metastasis than IDC(3.67% and 2.93%), but no difference in local recurrence rate, DFS or OS between the two groups. Higher cancer stage, higher grade, and mastectomy were risk factors for disease relapse and cancer-specific mortality. The hormone receptor-positive and HER2 over-expression subtypes were found to be associated with a reduced risk of disease relapse, while only PR positivity was associated with a decreased risk of mortality. (all P-values < 0.05).ConclusionILC patients had a higher mastectomy rate, higher surgical margin rate and distant metastasis rate than IDC patients. There is no significant difference in DFS or OS between ILC and IDC patients. Mastectomy was associated with poor outcomes regardless of ILC or IDC.

Abstract Importance This study highlights the potential negative impact of the co-administration of proton pump inhibitors (PPI) on treatment outcomes in patients with hormone receptor-positive (HR+) metastatic and recurrent breast cancer who were receiving CDK4/6 inhibitor (CDK4/6i) treatment, providing real-world evidence to guide treatment strategies. Objective To determine whether the co-administration of proton pump inhibitors (PPI) affects treatment outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with HR+ metastatic and recurrent breast cancer receiving CDK4/6i treatment. Design This was a retrospective analysis. Setting The study was conducted at a single medical institution in Taipei, Taiwan. Participants The study included 359 patients with HR+ metastasis and relapse breast cancer treated between 2018 and 2023. Intervention(s) or Exposure(s) Patients were grouped into those receiving CDK4/6i plus endocrine therapy without any antacid medications, and those with a combination of either a PPI or H2 receptor blocker. Main Outcome(s) and Measure(s) The main outcomes measured were PFS and OS. Results There were 55.7% patients in the no-antacid group, 33.1% in the PPI group, and 11.1% in the H2-blocker only group. Patients receiving PPI in combination with CDK4/6i and endocrine therapy had significantly shorter PFS (hazard ratio [HR] = 2.298, P < 0.001) and OS (HR = 3.03, P < 0.001). The H2 blocker group also showed a trend toward poorer PFS (HR = 1.987, P < 0.001) and OS compared with those without antacid use (HR = 3.380, P = 0.226). These trends were shown in both the overall cohort and first-line treatment, regardless of the specific CDK4/6i used. No significant differences were observed between types of PPIs. Additionally, increased PPI usage time proportion during CDK4/6i treatment was associated with a higher risk of disease progression and mortality. Conclusion and Relevance The use of PPIs and H2 blockers, in combination with CDK4/6i, was associated with adverse effects on PFS and OS in patients with HR+ metastatic or recurrent breast cancer in a real-world setting. Clinicians should exercise caution when prescribing PPIs to patients undergoing CDK4/6i therapy. Key Points In this retrospective analysis of 359 patients, the co-administration of PPIs with CDK4/6i was associated with significantly shorter PFS and OS. Clinicians should be cautious when prescribing PPIs to patients receiving CDK4/6i therapy due to the potential for adverse effects on treatment outcomes.

The pregnancy rate after cancer treatment for female survivors is lower than that of the general population. Future infertility is a significant concern for patients with breast cancer and is associated with a poor quality of life. Reproductive-age patients with breast cancer have safe options when choosing a type of fertility preservation method to be applied. Better information and support resources aimed at women to support their decision making are needed. The objective of this study was to develop a web-based shared decision-making tool for helping patients with breast cancer make decisions on fertility preservation. We used the action research cycle of observing, reflecting, planning, and acting to develop a web-based shared decision-making tool. The following four phrases were applied: (1) observe and reflect-collect and analyze the decision-making experiences of patients and health care providers; (2) reflect and plan-apply the initial results to create a paper design and modify the content; (3) plan and act-brainstorm about the web pages and modify the content; (4) act and observe-evaluate the effectiveness and refine the website's shared decision-making tool. Interviews, group meetings, and constant dialogue were conducted between the various participants at each step. Effectiveness was evaluated using the Preparation for Decision-Making scale. Five major parts were developed with the use of the action research approach. The Introduction (part 1) describes the severity of cancer treatment and infertility. Options (part 2) provides the knowledge of fertility preservation. The shared decision-making tool was designed as a step-by-step process (part 3) that involves the comparison of options, patient values, and preferences; their knowledge regarding infertility and options; and reaching a collective decision. Resources (part 4) provides information on the hospitals that provide such services, and References (part 5) lists all the literature cited in the website. The results show the web-based shared decision-making meets both patients' and health providers' needs and helps reproductive-age patients with breast cancer make decisions about fertility preservation. We have created the first web-based shared decision-making tool for making fertility preservation decisions in Taiwan. We believe female patients of reproductive age will find the tool useful and its use will become widespread, which should increase patient autonomy and improve communication about fertility preservation with clinicians. Clinicaltrials.gov NCT04602910; https://clinicaltrials.gov/ct2/show/NCT04602910.