Randomized phase II clinical trial and biomarker analysis of paclitaxel plus epirubicin versus vinorelbine plus epirubicin as neoadjuvant chemotherapy in locally advanced HER2-negative breast cancer with TEKT4 variations.

PURPOSE: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. METHODS: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. RESULTS: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). CONCLUSIONS: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.

Metronomic capecitabine combined with aromatase inhibitors for new chemoendocrine treatment of advanced breast cancer: a phase II clinical trial.

PURPOSE: This study was designed to determine the safety and clinical efficacy of metronomic chemotherapy combined with aromatase inhibitors (AIs) for hormone receptor (HR)-positive advanced breast cancer (ABC) patients who cannot tolerate conventional-dose chemotherapy. METHODS: Postmenopausal patients with HR-positive ABC, who exhibited disease progression after first-line AIs treatment and who could not tolerate or rejected conventional chemotherapy, were enrolled in this study. Patients received capecitabine 500 mg PO TID (could be reduced to 500 mg QD in case of adverse effects) and exemestane 25 mg QD (after PD with letrozole) or letrozole 2.5 mg QD (after PD with exemestane). The primary endpoints were safety and tolerance, the secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and time to treatment failure (TTF). RESULTS: In our analysis of 44 patients, the median age was 64 years (range 38-90) and 68.2% patients had at least two recurrences or metastatic lesions. Grade 3 toxicities (hand-foot syndrome) were observed only in 4 of the patients. Most patients exhibited no or mild toxicities. After a median follow-up of 14.8 months, ORR was 70.5%, CBR-77.3%, PFS-16.2 months, and TTF-14.4 months. CONCLUSIONS: Metronomic oral capecitabine combined with AIs showed good efficacy, minimal toxicities, and good tolerance in HR-positive patients with ABC. It is a potential treatment option especially for postmenopausal HR-positive ABC patients in poor general condition who cannot tolerate conventional chemotherapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT01924078.

Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC. METHODS: Using human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs. RESULTS: All of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses. CONCLUSIONS: We developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.

GATA3 mutations define a unique subtype of luminal-like breast cancer with improved survival.

BACKGROUND: The GATA3 gene (GATA-binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations. METHODS: The authors examined the somatic mutation status of GATA3 and performed survival analysis in The Cancer Genome Atlas (TCGA) cohort (n=934) and the Fudan University Shanghai Cancer Center (FUSCC) cohort (n=308). Patient characteristics, including age; menopausal status; tumor laterality; tumor size; lymph node status; tumor grade; molecular subtypes; adjuvant radiotherapy, chemotherapy, and endocrine therapy; and prognosis, together with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and TP53 (tumor protein p53) mutation status, were collected. RESULTS: GATA3 mutations were detected in 8.8% of patients (82 of 934 patients) in the TCGA cohort and 14.9% of patients (46 of 308 patients) in the FUSCC cohort. GATA3 mutations were found to be significantly associated with luminal-like breast cancer (P=.002 in the TCGA cohort and P<.001 in the FUSCC cohort), and were highly mutually exclusive to PIK3CA mutations (P=.001 in the TCGA cohort and P=.003 in the FUSCC cohort) and TP53 mutations (P<.001 in both cohorts). Furthermore, GATA3 mutations were correlated with improved overall survival in the entire population (P=.025 in the TCGA cohort and P = .043 in the FUSCC cohort) as well as in patients with luminal-like disease who received adjuvant endocrine therapy. CONCLUSIONS: GATA3 mutations mainly occur in patients with luminal-like breast cancer and have identifiable clinicopathologic and genetic characteristics, highlighting a subgroup of patients with breast cancer in whom limited therapy may be appropriate.

Rational and trial design of FASCINATE-N: a prospective, randomized, precision-based umbrella trial.

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study - neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HER2+, and HR-/HER2-. The HR+/HER2- patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR-/HER2+ subtypes; and HR-/HER2- patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 (https://classic.clinicaltrials.gov/ct2/show/NCT05582499).

Rational and trial design of FASCINATE-N (Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study- neoadjuvant therapy): a prospective, randomized, precision-based umbrella trial Our FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. We will first divide patients into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. Then, we will further classify patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients.

Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: The FUTURE phase II umbrella clinical trial.

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4-38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7-4.2) and 10.7 (95% CI: 9.1-12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody-drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

Tumor Size Still Impacts Prognosis in Breast Cancer With Extensive Nodal Involvement.

BACKGROUND AND PURPOSE: Although tumor size and nodal status are the most important prognostic factors, it is believed that nodal status outperforms tumor size as a prognostic factor. In particular, when patients have a nodal stage greater than N2 (more than nine positive lymph nodes), it is well accepted that tumor size does not retain its prognostic value. Even in the newest American Joint Committee on Cancer (AJCC) prognostic staging system, which includes molecular subtype as an important prognostic factor, T1-3N2 patients are categorized as the same population. The same is true for T1-4N3 patients. Moreover, some physicians have speculated that for tumors staged N2 or greater, the smaller the tumor is, the more aggressive the tumor. Thus, this study aims to investigate the prognostic value of tumor stage (T stage) in patients with extensive nodal involvement and to compare the survival of T4N × M0 and T × N3M0. PATIENTS AND METHODS: Female breast cancer patients with nine or more positive lymph nodes or with T4 tumors were identified in the SEER registry between 2010 and 2015. The effect of T stage on breast cancer-specific survival (BCSS) was assessed using the Kaplan-Meier survival curve method and risk-adjusted Cox proportional hazard regression modeling. Survival comparison of T4NxM0 and TxN3M0 patients was also achieved using the Kaplan-Meier survival curve method and risk-adjusted Cox proportional hazard regression model. RESULTS: Overall, 21,696 women with N2-3 tumors were included from 284,073 patients.T stage, nodal stage (N stage), ER, PR, HER2 and grade were all independent prognostic factors (p <0.001). HRs for ER, PR, HER2, grade, and N stage were 0.662 (0.595-0.738), 0.488 (0.438-0.543), 0.541 (0.489-0.598), 1.534 (1.293-1.418) and 1.551 (1.435-1.676), respectively. Notably, HER2 positivity was correlated with better BCSS possibly due to the wide adoption of anti-HER2 therapy. Using T1 as a reference, HRs of T2, T3, and T4 were 1.363 (1.200-1.548), 2.092 (1.824-2.399) and 3.497 (3.045-4.017), respectively. The same results held true when subgroup analysis based on N stage were conducted. In the two subgroups, namely, women staged as T1-3N2 and women staged as T1-4N3, T stage was also a significant negative prognostic factor independent of ER, PR, HER2 and grade. Moreover, 8,328 women staged as T4 with different nodal statuses were also identified from the whole database. When we compared T4Nx with TxN3, it was found that T4 tumors exhibited worse outcomes than N3 tumors independent of other prognostic factors. When molecular subtype was included in the subgroup analysis, survival could not be distinguished between T4 and N3 only in TNBC. CONCLUSIONS: In patients with extensive nodal status, tumor stage remains a prognostic factor independent of other factors, such as ER, PR, HER2, and grade. In patients with T4Nx or TxN3 tumors, T4 tumors exhibit worse outcomes than N3 tumors independent of other prognostic factors. The AJCC staging system should be modified based on these findings.

Serum HER2 levels predict treatment efficacy and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant treatment.

BACKGROUND: Controversy remains regarding the predictive and prognostic value of serum human epidermal growth factor receptor 2 (HER2) in breast cancer. The purpose of this retrospective study was to determine the clinical utility and efficacy of serum HER2 (sHER2) in predicting treatment response and prognosis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy and trastuzumab treatment. METHODS: A total of 309 HER2-positive breast cancer patients diagnosed at Fudan University Shanghai Cancer Center from July 2015 to January 2019 were analyzed. Baseline sHER2 levels were obtained for all patients and sHER2 levels were collected after 2 cycles of treatment in 208 patients. A sHER2 level ≥15 ng/mL was regarded as "high expression" and sHER2 <15 ng/mL was regarded as "low expression". Outcome measures of treatment efficacy and prognosis were pathological complete response (pCR) and invasive disease-free survival (iDFS), respectively. RESULTS: In patients with high baseline sHER2, more were ER-negative (P=0.029), had larger tumor size (P=0.006), more advanced clinical stage (P=0.002), higher Miller-Payne grade (P=0.024) and higher likelihood of iDFS events (P=0.015). Patients with high sHER2 levels after 2 cycles of treatment had lower pCR rates (P=0.038), higher Miller-Payne grade (P=0.013) and higher likelihood of iDFS events (P=0.003). Kaplan-Meier analysis showed significant differences in iDFS between patients with high and low sHER2 levels at baseline (P=0.019) and after 2 cycles of treatment (P=0.000). Further analyses according to cancer subtypes found baseline sHER2 to be significantly correlated with the iDFS of Luminal B patients (p=0.002), while sHER2 levels after 2 cycles of treatment was significantly correlated with the iDFS of HER2-enriched patients (P=0.000). Univariate analysis showed significant association between iDFS and tumor size (P=0.026), lymph node status (P=0.008), clinical stage (P=0.031), baseline sHER2 (P=0.024), overall tumor response (P=0.011), pCR (P=0.043) and Miller-Payne grade (P=0.001). Multivariate analysis found Miller-Payne grade (P=0.037) to be significantly associated with iDFS. CONCLUSIONS: Our results demonstrate the clinical value of sHER2 in a population of Chinese breast cancer patients, suggesting that sHER2 levels after 2 cycles of neoadjuvant therapy may be more predictive of treatment outcomes and that the prognostic value of sHER2 may be time point and subtype dependent.

Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

Molecular subtypes and precision treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Despite the progress made in precision treatment of cancer patients, targeted treatment is still at its early stage in TNBC, and chemotherapy remains the standard treatment. With the advances in next generation sequencing technology, genomic and transcriptomic analyses have provided deeper insight into the inter-tumoral heterogeneity of TNBC. Much effort has been made to classify TNBCs into different molecular subtypes according to genetic aberrations and expression signatures and to uncover novel treatment targets. In this review, we summarized the current knowledge regarding the molecular classification of TNBC and explore the future paradigm for using molecular classification to guide the development of precision treatment and clinical practice.

Metastatic breast cancer patients with lung or liver metastases should be distinguished before being treated with fulvestrant.

BACKGROUND: Endocrine therapy is the preferred treatment for patients with hormone receptor -positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of patients with metastases at different visceral sites. PATIENTS AND METHODS: In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6-year period were analyzed. Logistic regression models were used to identify the prognostic factors associated with progression-free survival (PFS). Kaplan-Meier analysis was used to compare the PFS of patients with lung and liver metastases. RESULTS: Baseline visceral metastases were present in 233 patients, including 138 with lungw/o liver metastases (lung metastases without liver involvement), 51 with liverw/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = .028). PFS was longer in patients with lungw/o liver metastases than in those with liverw/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P < .001; liverw/o lung vs. lungw/o liver hazard ratio (HR) 1.70; lung and liver vs. lungw/o liver HR 2.85). Patients with liver metastases experienced significantly worse PFS than those without liver involvement (3.7 vs. 9.2 months, P < .001). PFS benefits were observed in patients with longer disease-free intervals, no liver metastases, and no previous chemotherapy. CONCLUSION: Fulvestrant treatment benefited patients with lungw/o liver or nonvisceral metastases. When treating hormone receptor-positive/HER2-negative MBC patients with endocrine therapy, it is important to differentiate patients with lung metastases from those with liver metastases.

The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation.

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies.

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.

Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients.

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.

PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression.

Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. ©2018 AACR.

Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer.

PURPOSE: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. EXPERIMENTAL DESIGN: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized. RESULTS: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase-specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions. CONCLUSIONS: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859-69. ©2016 AACR.

Clinicopathological Characteristics and Survival Outcomes of Invasive Cribriform Carcinoma of Breast: A SEER Population-Based Study.

Invasive cribriform carcinoma (ICC) is a rare histologic subtype of breast cancer. We aimed to investigate the clinicopathological characteristics and survival outcomes of ICC.Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 233,337 female patients diagnosed with ICC (n = 618) or infiltrating ductal carcinoma (IDC) (n = 232,719). Univariate and multivariate survival analyses were utilized to calculate and compare disease-specific survival (DSS) and overall survival (OS). A 1:1 paired match was carried out on age, tumor stage, tumor grade, estrogen receptor (ER) status, and progesterone receptor (PR) status. Baseline characteristics and survival outcomes were also analyzed in ER-positive tumors. Subgroup analyses summarized the hazard ratio (HR) of IDC versus ICC using a forest plot.ICCs presented smaller size, lower grade, higher ER and PR positive rate, less nodal metastasis, and were less likely to be treated with mastectomy compared to IDCs. Five-year DSS rates were significantly better for patients with ICC than for patients with IDC (98.8% vs. 93%, P < 0.001). Five-year OS rates were 95.3% versus 90.1% (P < 0.001). After adjustment for common clinicopathological factors in the multivariate analysis, patients with ICC showed limited DSS advantage over the IDC group (HR = 0.75, 95% CI: 0.38-1.51, P = 0.421). No significant difference in DSS nor OS was observed in matched groups between ICC and IDC. Analysis among ER-positive patients revealed similar prognostic factors as among all patients. Survival analysis in different tumor grade subgroups showed no significant difference between ICC and IDC.ICCs have unique clinicopathological characteristics, higher rates of breast-conserving surgery, and more favorable prognosis compared to the overall IDC population. Difference in tumor grade between the 2 groups may partially explain the different outcome. Improved clinical and biological understanding of ICC might lead to more individualized and tailored therapy for breast cancer patients.

PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: a systematic review and meta-analysis.

BACKGROUND: Mutations of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) are among the most common genetic aberrations in human breast cancer. At present, controversy exists concerning the prognostic value of the mutations. METHODS: We performed a systematic review and meta-analysis to clarify the association between PIK3CA mutations and survival outcomes. A comprehensive, computerized literature search of PubMed, Web of Science databases, the Chinese Biomedical Literature Database, and Wangfang Data until August 27, 2013 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated by using the fixed effects model or random effects model according to heterogeneity between studies. RESULTS: Eight eligible studies were included in the analysis, all of which were retrospective cohort studies. The overall meta-analysis demonstrated that the PIK3CA mutations were associated with better clinical outcomes (hazard ratio 0.72; 95% confidence interval: 0.57-0.91; P=0.006). None of the single studies materially altered the original results and no evidence of publication bias was found. Further subgroup analysis of mutations in exons 9 and 20 did not show statistical significance. CONCLUSION: PIK3CA mutations in operable primary breast cancer indicate a good prognosis. Further studies should be conducted to investigate the effect of PIK3CA mutations on clinical outcomes in different histologic types, different molecular subtypes of breast cancer, and different exons of PIK3CA.

An elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer following neoadjuvant chemotherapy.

PURPOSE: Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer. METHODS: A retrospective cohort of 542 locally advanced breast cancer patients (T3/T4 and/or N2/N3 disease) receiving NCT followed by radical surgery was recruited between May 2002 and August 2011 at the Fudan University Shanghai Cancer Center. Counts for pre-NCT peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR. RESULTS: Univariate and multivariate analysis revealed that higher LMR levels (≥4.25) were significantly associated with favorable DFS (P = 0.009 and P = 0.011, respectively). Additionally, univariate analysis revealed that a higher lymphocyte count (≥1.5×109/L) showed borderline significance for improved DFS (P = 0.054), while a lower monocyte count (<0.4×109/L) was associated with a significantly better DFS (P = 0.010). CONCLUSIONS: An elevated pre-NCT peripheral LMR level was a significantly favorable factor for locally advanced breast cancer patient prognosis. This easily obtained variable may serve as a valuable marker to predict the outcomes of locally advanced breast cancer.

Immediate postmastectomy breast reconstruction showed limited advantage in patient survival after stratifying by family income.

BACKGROUND: Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear. PATIENTS AND METHODS: We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models. RESULTS: In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [POOLED reconstruction (any types of reconstruction): hazard ratio (HR)  =  0.87, 95% confidence interval (CI) 0.80-0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65-0.75, P<0.001) compared to patients who underwent mastectomy alone. However, after stratifying by family income, patients receiving reconstruction showed limited advantage in BCSS and OS compared with those undergoing mastectomy alone. When comparing between the two reconstruction methods, no significant differences were observed in either BCSS (implant versus autologous reconstruction: HR = 1.11, 95%CI 0.90-1.35, P = 0.330) or OS (implant versus autologous reconstruction: HR = 1.07, 95% 0.90-1.28, P = 0.424). CONCLUSIONS: Compared to mastectomy alone, immediate postmastectomy reconstruction had limited advantage in survival after adjusting for confounding factor of family income. Our findings, if validated in other large databases, may help to illustrate the actual effect of immediate postmastectomy reconstruction on patient survival.