Impact of environmental temperature on the survival outcomes of breast cancer: A SEER-based study.

BACKGROUND: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates. METHODS: A retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information. RESULTS: A total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7-62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90-0.95 and HR 0.93, 95% CI 0.91-0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7-62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90-0.96 and HR 0.93, 95% CI 0.90-0.96). CONCLUSIONS: Higher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.

The intricate pathways of the sympathetic nervous system hold an inherently protective role in the setting of acute stress. This is achieved through dynamic immunomodulatory and neurobiological networks. However, excessive and chronic exposure to these stress-induced stimuli appears to cause physiologic dysfunction through several mechanisms that may impair psychosocial, neurologic, and immunologic health. Numerous preclinical observations have identified the beta-2 adrenergic receptor (ß2-AR) subtype to possess the strongest impact on immune dysfunction in the setting of chronic stressful stimuli. This prolonged expression of ß2-ARs appears to suppress immune surveillance and promote tumorigenesis within multiple cancer types. This occurs through several pathways, including (1) decreasing the frequency and function of CD8 + T-cells infiltrating the tumor microenvironment (TME) via inhibition of metabolic reprogramming during T cell activation, and (2) establishing an immunosuppressive profile within the TME including promotion of an exhausted T cell phenotype while simultaneously enhancing local and paracrine metastatic potential. The use of nonselective ß-AR antagonists appears to reverse many chronic stress-induced tumorigenic pathways and may also provide an additive therapeutic benefit for various immune checkpoint modulating agents including commonly utilized immune checkpoint inhibitors. Here we review the translational and clinical observations highlighting the foundational hypotheses that chronic stress-induced ß-AR signaling promotes a pro-tumoral immunophenotype and that blockade of these pathways may augment the therapeutic response of immune checkpoint inhibition within the scope of melanoma.

Systemic infusion of TLR3-ligand and IFN-α in patients with breast cancer reprograms local tumor microenvironments for selective CTL influx.

BACKGROUND: Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts the effectiveness of cancer immunotherapies. The ability of toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory T cell (Treg)-attractants) in the TME, but not in healthy tissues, observed in our preclinical studies, suggested that their systemic application can reprogram local TMEs. METHODS: Six evaluable patients (33-69 years) with metastatic triple-negative breast cancer received six doses of systemic chemokine-modulating (CKM) regimen composed of TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m2; intravenous) and COX2 inhibitor (celecoxib; 2×200 mg; oral) over 2 weeks. The predetermined primary endpoint was the intratumoral change in the expression of CTL marker, CD8α, in the post-CKM versus pre-CKM tumor biopsies. Patients received follow-up pembrolizumab (200 mg, intravenously, every 3 weeks), starting 3-8 days after completion of CKM. RESULTS: Post-CKM biopsies showed selectively increased CTL markers CD8α (average 10.2-fold, median 5.5-fold, p=0.034) and granzyme B (GZMB; 6.1-fold, median 5.8-fold, p=0.02), but not FOXP3 (Treg marker) relative to HPRT1 expression, resulting in the increases in average CD8α/FOXP3 ratio and GZMB/FOXP3 ratio. CKM increased intratumoral CTL-attractants CCL5 and CXCL10, but not Treg-attractants CCL22 or CXCL12. In contrast, CD8+ T cells and their CXCR3+ subset showed transient decreases in blood. One clinical response (breast tumor autoamputation) and three stable diseases were observed. The patient with clinical response remains disease free, with a follow-up of 46 months as of data cut-off. CONCLUSIONS: Short-term systemic CKM selectively increases CTL numbers and CTL/Treg ratios in the TME, while transiently decreasing CTL numbers in the blood. Transient effects of CKM suggest that its simultaneous application with checkpoint blockade and other forms of immunotherapy may be needed for optimal outcomes.

Racial and Ethnic Disparity in Preoperative Chemosensitivity and Survival in Patients With Early-Stage Breast Cancer.

Importance: It remains unclear what survival benefit is associated with preoperative chemosensitivity after receiving neoadjuvant chemotherapy (NACT) among patients with resectable breast cancer from diverse racial and ethnic backgrounds. Objective: To investigate racial and ethnic disparities in chemosensitivity and association with survival in patients with early-stage breast cancer. Design, Setting, and Participants: This retrospective cohort study queried data from the National Cancer Database (NCDB) between calendar years 2010 and 2018. Participants included patients with breast cancer with clinical stage I to III disease treated with NACT. Preoperative chemosensitivity was defined as very sensitive (ypT0N0), sensitive (pathologic TNM stage less than clinical stage, excluding ypT0N0), and refractory (pathologic stage greater than or equal to clinical stage). Data were analyzed in November 2022. Exposure: Receipt of NACT and clinicopathologic and treatment factors contributing to racial and ethnic disparities in survival. Main Outcomes and Measures: Overall survival of patients from diverse racial and ethnic backgrounds who received NACT. Results: This study included 103 605 patients (median age, 53 [IQR, 44-62] years, 99.5% [n = 103 060] women, and 68.7% [n = 71 203] White race). Among them, breast cancer was refractory in 43.2% (n = 44 796), sensitive in 34.4% (n = 35 638), and very sensitive in 22.4% (n = 23 171) of patients. In the hormone receptor-positive ERBB2 negative (formerly HER2 negative) group, patients had more refractory disease regardless of race or ethnicity (all races and ethnicities refractory: 54%-59%; P < .001). Among ERBB2 positive disease, Black patients had a lower percentage of very sensitive disease (32% vs 37%-40%; P < .001) and among triple-negative breast cancer, more refractory disease was seen among Black patients compared with other races and ethnicities (38% vs 30%-35%; P < .001). In refractory (hazard ratio [HR], 1.53; 95% CI, 1.47-1.60; P < .001) and sensitive (HR, 1.25; 95% CI, 1.17-1.33; P < .001) disease, Black patients had a higher mortality risk compared with White patients in the overall cohort. Asian patients had a lower mortality risk compared with White patients in refractory (HR, 0.71; 95% CI, 0.63-0.80; P < .001), sensitive (HR, 0.58; 95% CI, 0.49-0.69; P < .001), and very sensitive (HR, 0.60; 95% CI, 0.43-0.82; P < .001) disease groups in the overall cohort. Conclusions and Relevance: In this cohort study, Black patients had a higher mortality risk compared with White patients among those with residual disease after NACT. This highlights the need for personalized treatment strategies for Black patients to help them attain pathologic complete response.

Oncotype Dx Score, HER2 Low Expression, and Clinical Outcomes in Early-Stage Breast Cancer: A National Cancer Database Analysis.

BACKGROUND: The interaction between HER2-low expression, oncotype recurrence score (RS), and their influence on the prognosis of HR+/HER2- breast cancer (BC) is not very well studied. METHODS: We conducted a retrospective cohort study of patients diagnosed with resectable HER2-low and HER2-zero BC from the National Cancer Database. The primary outcome was overall survival (OS), and the association of RS with the clinical outcomes in HR+/HER2- BC was analyzed as an exploratory endpoint. RESULTS: The distribution of RS was comparable between HER2-low and HER2-zero groups; however, the RSs of HER2-low tumors were more likely to be 16-25. Women with HER2-low tumors had longer 5-year OS than women with HER2-zero tumors in the HR-negative (84.3% vs. 83.9%; p < 0.001, HR: 0.87 (0.84-0.90), p < 0.001) but not in the HR-positive group (94.0% vs. 94.0%; p = 0.38, HR: 0.97 (0.95-0.99), p = 0.01). The survival advantage was observed in patients who received adjuvant/neoadjuvant chemotherapy (p-interaction (chemo vs. no chemo) < 0.001). Among those who received adjuvant chemotherapy in the group with higher RSs (26-100), those with HER2-low BC had higher 5-year OS than HER2-zero BC. CONCLUSIONS: Resectable HER2-low BC had a better prognosis than HER2-zero BC. Among those who received adjuvant chemotherapy in the higher oncotype RS group, those with HER2-low tumors had better survival.

Novel Biomarkers to Guide Immunotherapy De-Escalation in the Neoadjuvant Setting in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has the highest incidence of disease recurrence and distant metastases among breast cancer subtypes, leading to significant rates of morbidity and mortality [...].

Effect of neighborhood deprivation index on breast cancer survival in the United States.

PURPOSE: To analyze the association between the Neighborhood Deprivation Index (NDI) and clinical outcomes of locoregional breast cancer (BC). METHODS: Surveillance, Epidemiology and End Results (SEER) database is queried to evaluate overall survival (OS) and disease-specific survival (DSS) of early- stage BC patients diagnosed between 2010 and 2016. Cox multivariate regression was performed to measure the association between NDI (Quintiles corresponding to most deprivation (Q1), above average deprivation (Q2), average deprivation (Q3), below average deprivation (Q4), least deprivation (Q5)) and OS/DSS. RESULTS: Of the 88,572 locoregional BC patients, 27.4% (n = 24,307) were in the Q1 quintile, 26.5% (n = 23,447) were in the Q3 quintile, 17% (n = 15,035) were in the Q2 quintile, 13.5% (n = 11,945) were in the Q4 quintile, and 15.6% (n = 13,838) were in the Q5 quintile. There was a predominance of racial minorities in the Q1 and Q2 quintiles with Black women being 13-15% and Hispanic women being 15% compared to only 8% Black women and 6% Hispanic women in the Q5 quintile (p < 0.001). In multivariate analysis, in the overall cohort, those who live in Q2 and Q1 quintile have inferior OS and DSS compared to those who live in Q5 quintile (OS:- Q2: Hazard Ratio (HR) 1.28, Q1: HR 1.2; DSS:- Q2: HR 1.33, Q1: HR 1.25, all p < 0.001). CONCLUSION: Locoregional BC patients from areas with worse NDI have poor OS and DSS. Investments to improve the socioeconomic status of areas with high deprivation may help to reduce healthcare disparities and improve breast cancer outcomes.

Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

A review of treatment options in HER2-low breast cancer and proposed treatment sequencing algorithm.

The expansion of the spectrum of human epidermal growth factor receptor 2 (HER2)-status to HER2-low, defined as HER2 expression of 1+ by immunohistochemistry (IHC) or 2+ by IHC without gene amplification, has made a major impact in the field of oncology. The HER2-low expression has emerged as a targetable biomarker, and anti-HER2 antibody-drug conjugate trastuzumab deruxtecan has shown significant survival benefit in pretreated metastatic HER2-low breast cancer (BC). With these recent data, the treatment algorithm for hormone receptor-positive and triple-negative BC needs to be reconsidered, as approximately half of these BCs are HER2-low. Although there are different therapeutic agents for hormone receptor-positive and hormone receptor-negative HER2-low BCs, there is no consensus regarding the sequencing of these agents. In this article, the treatment options for HER2-low BC are enumerated and a treatment sequencing algorithm based on the current clinical evidence proposed.

Effect of Neighborhood Deprivation Index on Breast Cancer Survival in the United States.

Purpose To analyze the association between the Neighborhood Deprivation Index (NDI) and clinical outcomes of early-stage breast cancer (BC). Methods Surveillance, Epidemiology and End Results (SEER) database is queried to evaluate overall survival (OS) and disease-specific survival (DSS) of early- stage BC patients diagnosed between 2010-2016. Cox multivariate regression was performed to measure the association between NDI (Quintiles corresponding to most deprivation (Q1), above average deprivation (Q2), average deprivation (Q3), below average deprivation (Q4), least deprivation (Q5)) and OS/DSS. Results Of the 88,572 early-stage BC patients, 27.4% (n = 24,307) were in the Q1 quintile, 26.5% (n = 23,447) were in the Q3 quintile, 17% (n = 15,035) were in the Q2 quintile, 13.5% (n = 11,945) were in the Q4 quintile, and 15.6% (n = 13,838) were in the Q5 quintile. There was a predominance of racial minorities in the Q1 and Q2 quintiles with Black women being 13-15% and Hispanic women being 15% compared to only 8% Black women and 6% Hispanic women in the Q5 quintile (p < 0.001). In multivariate analysis, in the overall cohort, those who live in Q2 and Q1 quintile have inferior OS and DSS compared to those who live in Q5 quintile (OS:- Q2: Hazard Ratio (HR) 1.28, Q1: HR 1.2; DSS:- Q2: HR 1.33, Q1: HR 1.25, all p < 0.001). Conclusion Early-stage BC patients from areas with worse NDI have poor OS and DSS. Investments to improve the socioeconomic status of areas with high deprivation may help to reduce healthcare disparities and improve breast cancer outcomes.

Impact of Environmental Temperature on the Pathological Complete Response and Survival Outcomes of Breast Cancer: A NCDB and SEER study.

Background: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate with an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates have higher odds of achieving pathologic complete response (pCR) and better survival outcomes than patients living in colder climates. Methods: A retrospective population-based analysis was conducted on Stage I-III breast cancer patients utilizing data from National Cancer Database (NCDB) from 2010-2018 with 892,092 patients and Surveillance, Epidemiology and End Results (SEER) from 1996-2017 with 270,496 patients. The average annual temperature (AAT) was calculated based on data from the National Centers for Environmental Information. Results: In the SEER cohort, patients residing at AAT ≥47.5°F had a 16% higher overall survival (OS) (HR 0.84, 95% CI 0.81-0.88, p <0.001) and 15% higher disease specific survival (DSS) (HR 0.85, 95% CI 0.80 - 0.90; p <0.001). Similarly, 4% higher OS (HR 0.96, 95% CI 0.95-0.97, p <0.001) and DSS (HR 0.96, 95% CI 0.94-0.97, p <0.001) was noted with every 5°F increment in AAT. In the NCDB cohort, patients in regions with AAT ≥ 60.9°F had 9% greater odds of achieving a pCR, odds ratio (OR 1.09, 95% CI 1.05, 1.13, p <0.001) and a 5% higher OS (HR 0.95, 95% CI 0.93 - 0.97, p<0.001). Conclusions: Higher environmental temperatures are associated with significantly better OS and DSS, as well as higher odds of achieving pCR in these patients. Future research is warranted to confirm this observation using large datasets, to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Facing the conundrum: which first-line therapy should be used for patients with metastatic triple-negative breast cancer carrying germline BRCA mutation?

Pembrolizumab combined with chemotherapy has been established as the preferred first-line therapy for treating metastatic triple-negative breast cancer (mTNBC) with programmed cell death ligand-1 (PD-L1)-positive disease since its approval for that indication. However, the optimal sequencing of therapy remains an unanswered question for a subset of mTNBC patients who harbor germline breast cancer gene 1/2 (BRCA1/2; gBRCA1/2) mutation. This article aims to offer insights into the optimal therapy sequencing for mTNBC patients with gBRCA1/2 mutations and its impact on clinical decision-making. The perspective offered is based on the best currently available data and propose a practical algorithm to guide the management of this subgroup in the frontline setting.

MEETING HIGHLIGHTS: THE THIRD MARIE SKLODOWSKA-CURIE SYMPOSIUM ON CANCER RESEARCH AND CARE AT ROSWELL PARK COMPREHENSIVE CANCER CENTER, BUFFALO, NY, SEPTEMBER 20-22, 2023.

Marie Sklodowska-Curie Symposia on Cancer Research and Care (MSCS-CRC) promote collaborations between cancer researchers and care providers in the United States, Canada and Central and Eastern European Countries (CEEC), to accelerate the development of new cancer therapies, advance early detection and prevention, increase cancer awareness, and improve cancer care and the quality of life of patients and their families. The third edition of MSCS-CRC, held at Roswell Park Comprehensive Cancer Center, Buffalo, NY, in September 2023, brought together 137 participants from 20 academic institutions in the US, Poland, Ukraine, Lithuania, Croatia and Hungary, together with 16 biotech and pharma entities. The key areas of collaborative opportunity identified during the meeting are a) creating of a database of available collaborative projects in the areas of early-phase clinical trials, preclinical development, and identification of early biomarkers; b) promoting awareness of cancer risks and efforts at cancer prevention; c) laboratory and clinical training; and d) sharing experience in cost-effective delivery of cancer care and improving the quality of life of cancer patients and their families. Examples of ongoing international collaborations in the above areas were discussed. Participation of the representatives of the Warsaw-based Medical Research Agency, National Cancer Institute (NCI) of the United States, National Cancer Research Institutes of Poland and Lithuania, New York State Empire State Development, Ministry of Health of Ukraine and Translational Research Cancer Center Consortium of 13 cancer centers from the US and Canada, facilitated the discussion of available governmental and non-governmental funding initiatives in the above areas.

A 47-Year-Old Woman with Confusion and Weakness.

A 47-Year-Old Woman with Confusion and WeaknessA 47-year-old woman with metastatic breast cancer presents with 3 months of confusion, memory loss, and lower-extremity weakness. How do you approach the evaluation, and what is the differential diagnosis?

Association between Environmental Temperature and Survival in Gastroesophageal Cancers: A Population Based Study.

BACKGROUND: Cold stress suppresses antitumor response in animal models, leading to tumor growth. Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved survival outcomes than those living in colder climates. METHODS: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. We retrieved the National Centers for Environmental Information data to calculate the county-level AAT. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan-Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS: A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were males and 21% were females. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with an AAT > 53.5 °F had an 11% improvement in OS [HR 0.89 (95% CI 0.86-0.92), p < 0.0001] and 13% in DSS [HR 0.87 (95% CI 0.84-0.90), p < 0.0001]. When the temperature was analyzed in 5 °F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96-0.98), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95-0.97), p < 0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with an AAT > 53.5 had a 13% improvement in OS [HR 0.87 (95% CI 0.85-0.90), p < 0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83-0.89), p < 0.0001]. When analyzed in 5 °F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.952-0.971), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.945-0.965), p < 0.0001]. CONCLUSION: We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancers, notwithstanding the limitations of a retrospective database analysis. Further confirmatory and mechanistic studies are required to implement specific interventional strategies.

Clinical outcomes of de novo metastatic HER2-low breast cancer: a National Cancer Database Analysis.

The development of novel anti-HER2 drugs opens new treatment options for women with breast cancers, including lower expression of HER2. The epidemiology and clinical outcome of metastatic HER2-low breast cancer remain not well described. We designed a retrospective cohort study of the 2010-2017 National Cancer Database (NCDB) was designed to compare the overall survival of HER2-low and HER2-zero de novo metastatic breast cancer with systemic therapy. Multivariable Cox regression models were performed to estimate hazard ratios (HR), adjusting for sociodemographic and clinical factors. A total of 20,636 of 30,929 (66.7%) patients were HER2-low and 10,293 (33.3%) were HER2-zero. When stratified by hormonal receptor status, HER2-low tumors account for 18,066 (69.7%) cases in HR+/HER2- population and 2570 (51.4%) cases in HR-/HER2- population. The prevalence of HER2-low tumors was similar across racial groups with a slightly lower prevalence among the Hispanic population. Women with HER2-low tumors had longer overall survival (OS) than women with Her2-zero tumors in both HR-positive (median OS 39.0 months vs. 37.1 months; adjusted HR: 0.95, 95%CI (0.91-0.98)) and HR-negative groups (median OS 15.8 months vs. 14.1 months; adjusted HR: 0.92 95%CI (0.86-0.98)). The survival advantage was primarily observed in patients who received chemotherapy as their first line of treatment (HR 0.92 95%CI (0.88-0.96) vs. 0.99 95%CI (0.94-1.04), p-interaction = 0.04). In summary, HER2-low tumors, irrespective of hormone receptor status, have better survival than HER2-zero tumors in the de-novo metastatic setting. The survival advantage was primarily observed in patients who received chemotherapy in the first line.

Real world outcomes with alpelisib in metastatic hormone receptor-positive breast cancer patients: A single institution experience.

Background: It is critically important to study the real-world data of FDA-approved medications to understand the response rates and toxicities observed in the real-world population not represented in the clinical trials. Methods: We reviewed charts of patients diagnosed with metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 negative, PIK3CA-mutated breast cancer treated with alpelisib from May 2019 to January 2022. Clinical characteristics and treatment outcomes were collected. The association of clinical characteristics with responses and adverse events (AEs) was evaluated using the logistic regression model. Results: 27 patients were included. Median age at alpelisib initiation 67 years (range: 44, 77 years). Majority of patients had excellent performance status at time of alpelisib initiation. Most patients had chronic comorbidities, notably; 2 patients had controlled type 2 diabetes mellitus at time of alpelisib initiation. Majority had a median of three lines of therapy (range: 1, 7) before alpelisib. Clinical responses were determined using RECIST v1.1. 3/27 (11.11%) patients discontinued therapy before response assessment due to grade 3 AEs. Overall response rate was 12.5% (3/24), with all partial responses (PR). The median duration of response was 5.77 months (range: 5.54, 8.98). 14/27 (51.9%) of patients required dose interruption/reduction. Overall, 23/27 (85.19%) patients discontinued alpelisib of which 11 (47.83%) discontinued alpelisib due to AEs. Median duration of treatment was 2 months in patients who had grade 3 AEs (range: <1.00, 8.30) and 6.28 (1.15, 10.43) in those who did not. Any grade AEs were reported in 24/27 (88.9%) patients, namely, hyperglycemia 16/27 (59.3%), nausea 11/27 (40.7%), diarrhea 10/27 (37.0%), fatigue 7/27 (25.9%) and rash 6/27 (22.2%). Grade 3 AEs were reported in 13/27 patients (50%), namely, hyperglycemia in 7/27 (53.8%) patients followed by skin rash 4/27 (30.8%), GI side effects 3/27 (23.1%). Those with progressive disease as best response to alpelisib, had more non-metabolic comorbidities, higher number of liver metastases, PIK3CA E545K mutations, and shorter duration on therapy compared to those with PR and stable disease. Conclusion: Patients should be counseled about the toxicity and modest benefit observed with alpelisib in real-world clinical practice when used in later lines of therapy.

Development of a novel BRCAness score that predicts response to PARP inhibitors.

BACKGROUND: BRCAness is a characteristic feature of homologous recombination deficiency (HRD) mimicking BRCA gene mutation in breast cancer. We hypothesized that a measure to quantify BRCAness that causes synthetic lethality in BRCA mutated tumors will identify responders to PARP inhibitors. METHODS: A total of 6753 breast cancer patients from 3 large independent cohorts were analyzed. A score was generated by transcriptomic profiling using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. RESULTS: The score was significantly associated with BRCA1 mutation, high mutation load and intratumoral heterogeneity as expected, as well as with high HRD, DNA repair and MKi67 expression regardless of BRCA mutations. High BRCAness tumors enriched not only DNA repair, but also all five Hallmark cell proliferation-related gene sets. High BRCAness tumors were significantly associated with higher cytolytic activity and with higher anti-cancerous immune cell infiltration. Not only did the breast cancer cell lines with BRCA-mutation show high score, but even the other cells in human breast cancer tumor microenvironment were contributing to the score. The BRCAness score was the highest in triple-negative breast cancer consistently in all 3 cohorts. BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative and ER-positive/HER2-negative breast cancer. CONCLUSIONS: We established a novel BRCAness score using BRCA-mutation-related gene expressions and found that it associates with DNA repair and predicts response to PARP inhibitors regardless of BRCA mutation.

Left sided breast cancer is associated with aggressive biology and worse outcomes than right sided breast cancer.

Breast cancer is more common on the left side than the right side. We aim to evaluate differences in clinicopathological and genomic characteristics based on laterality. We analyzed survival outcomes and clinical characteristics of 881,320 patients recorded by the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer Genome Atlas (TCGA) was used to explore genomic and clinical features from 1,062 patients. Gene expression data was used to quantitate cytolytic activity and hallmark gene-sets were used for gene set enrichment analysis. An institutional retrospective review was conducted on 155 patients treated with neoadjuvant chemotherapy (NACT). Patient characteristics were summarized by pathological complete response (pCR). Left sided tumors were found to be more prevalent than right sided tumors. No major clinicopathological differences were noted by laterality. Left sided breast cancer demonstrated poorer outcomes versus right sided tumors (HR 1.05, 95% CI 1.01-1.08; p = 0.011). Cell proliferation gene sets, including E2F Targets, G2M Checkpoint, Mitotic spindle, and MYC Targets, were enriched on the left side compared to the right. Left sided tumors had lower pCR rates versus right sided tumors (15.4% versus 29.9%, p = 0.036). Our findings suggest that left sided breast cancer is associated with aggressive biology and worse outcomes compared to right sided breast cancer.

The clinical relevance of unfolded protein response signaling in breast cancer.

Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.