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Background Relatively little is known about the differences in prognostic factors for early vs late recurrence among women with early stage estrogen receptor–positive breast cancer. Methods We analyzed factors related to early (<5 years) vs late (≥5 years) recurrence in 2992 women with stage I-IIB estrogen receptor–positive breast cancer in the Pathways Study, a prospective cohort of women with breast cancer enrolled between 2006 and 2013, with ascertainment of recurrence and death through December 2021. Results After a median follow-up of 13.3 years, 341 (13.8%) women had recurrences, including 181 (53.7%) with late recurrence. Higher stage and grade were associated with recurrence regardless of timing, whereas progesterone receptor negativity was associated with early but not late recurrence. Receipt of endocrine therapy was associated with reduced risk of overall recurrence, but the length of endocrine therapy was not statistically significant in multivariable models. Minoritized racial and ethnic groups, including Asian, Black, and Hispanic women, had higher risk of early but not late recurrence compared to non-Hispanic White women. The trend of higher risk of early recurrence among these groups remained after adjustment for clinical, demographic, and socioeconomic factors but was statistically significant only in Asian women. Conclusions Our study revealed potentially important distinctions for early vs late recurrence, including the associations with progesterone receptor negativity and self-identified race and ethnicity. Possible higher risk of early recurrence among Asian, Black, and Hispanic women provides novel evidence for the existence of disparities in cancer outcomes, even within the breast cancer subtype indicative of generally good prognosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background There are few studies of social support and other social determinants of health after breast cancer diagnosis and their associations with mortality; results have been inconclusive. Further, it is not known if observed associations are specific to women with breast cancer diagnosis or if associations would be similar among healthy women. Methods Women with incident, pathologically confirmed invasive breast cancer, stage I-IV (n = 1012), and healthy frequency age-matched participants (n = 2036) answered a social support questionnaire in prospective follow-up of a population-based case-control study, the Western New York Exposures and Breast Cancer Study. At interview, all participants were aged 35-79 years and resident of 2 counties in Western New York State. Mortality status was ascertained from the National Death Index. Participants were queried regarding the number of their close friends, frequency of seeing them, household size, household income, and marital status. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer–specific mortality (breast cancer women only) and all-cause mortality were estimated. Results Lower household income was associated with higher all-cause mortality among women diagnosed with breast cancer (HR = 2.48, 95% CI = 1.24 to 4.97) and similarly among the healthy women (HR = 2.63, 95% CI = 1.25 to 5.53). Number and frequency of seeing friends, marital status, and household size were not associated with mortality, either among breast cancer patients or among healthy women. Conclusion Among those diagnosed with breast cancer and healthy women, lower income was associated with more than twice the mortality. Marital status, household size, and number or frequency of meeting friends were not associated with survival. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is a heterogenous disease that disproportionately affects Black women. TNBC outcomes among Black women are dismal secondary to multiple factors, such as poor healthcare accessibility resulting in delays in diagnosis, and aggressive disease biology in addition to a pro-tumor immune microenvironment (TME). Black women with breast cancer exhibit elevated levels of serum pro-inflammatory cytokines, and a pro-tumorigenic TME with higher immunosuppressive regulatory T cells (Tregs), M2 macrophages and exhausted CD8+ T cells. We have shown that the combined use of toll-like receptor 3 (TLR3) ligands with interferon-α (chemokine modulation: CKM) is able to enrich the tumor with CD8+ T cells, while not increasing immunosuppressive cells. Recent clinical trials have revealed the efficacy of immune checkpoint inhibitors (ICI) in rejuvenizing exhausted CD8+ T cells. We hypothesize that strategies to modulate the TME by enriching chemokines that attract CD8+T cells followed by reversal of CD8+ T cell exhaustion (ICI), when added to standard treatment, could potentially improve clinical outcomes, and mitigate the racial disparities in TNBC outcomes between Black and White Women. [ABSTRACT FROM AUTHOR]

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a meta-analysis to understand the impact of adding immunotherapy to chemotherapy in treating patients with triple-negative breast cancer (TNBC). Combining immunotherapy with chemotherapy increased the chance of attaining complete pathological response in TNBC patients, regardless of their PD-L1 status. The combined therapy worked better for patients with better performance status and positive lymph nodes. Identifying patients who would respond well to this approach can improve treatment decisions and patient outcomes. However, more research is needed to identify biomarkers through which to better understand response and resistance to this therapy. Background: Multiple randomized controlled trials (RCTs) have investigated the impact of adding checkpoint inhibitors to neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) patients. However, there is a lack of biomarkers that can help identify patients who would benefit from combination therapy. Our research identifies response predictors and assesses the effectiveness of adding immunotherapy to neoadjuvant chemotherapy for TNBC patients. Methods: We identified eligible RCTs by searching PubMed, Cochrane CENTRAL, Embase, and oncological meetings. For this meta-analysis, we obtained odds ratios using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. Potential bias was assessed using a funnel plot and the corresponding Egger's test. Results: In total, 1637 patients with TNBC were included from five RCTs. Neoadjuvant chemoimmunotherapy significantly improved pCR when compared to neoadjuvant chemotherapy alone. In the subgroup analysis, neoadjuvant chemoimmunotherapy showed higher pCR rates in both Programmed death-ligand 1 (PD-L1)-positive and PD-L1-negative TNBC patients. An Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 correlated with increased pCRs (OR = 1.9, p < 0.001) in neoadjuvant chemoimmunotherapy vs. neoadjuvant chemotherapy, but no benefit was observed for patients with ECOG PS 1. Nodal positivity was significantly associated with pCR (OR = 2.52, p < 0.001), while neoadjuvant chemoimmunotherapy did not benefit patients with negative lymph nodes. Conclusions: Checkpoint inhibition and neoadjuvant chemotherapy significantly increased pCRs in TNBC patients, regardless of their PDL-1 status. Additional checkpoint inhibitors improved pCR rates, mainly for patients with ECOG PS 0 and lymph node-positive disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent animal studies have shown a correlation between environmental temperature and tumor growth. Based on these studies, we hypothesized that esophageal cancer and gastric cancer patients living in warmer climates have improved survival as compared to patients living in colder climates. We conducted a study using the SEER (Surveillance, Epidemiology, and End Results) database and analyzed the cancer outcomes with the county-level average annual temperature in which those patients resided. We analyzed 17,408 esophageal cancer and 20,533 gastric cancer patients. We noted for the first time that higher environmental temperatures were associated with significant improvements in survival in patients with esophageal and gastric cancers. Further confirmatory population-based studies as well as mechanistic-bench studies are needed to support our findings. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. The expansion of the spectrum of human epidermal growth factor receptor 2 (HER2)‐status to HER2‐low has made a major impact in the field of oncology. Because there is no consensus regarding the sequencing of the HER2‐targeting agents in HER2‐low breast cancers, the treatment options for HER2‐low breast cancer are enumerated and a treatment‐sequencing algorithm based on the current clinical evidence proposed. [ABSTRACT FROM AUTHOR]

Simple Summary: The relation between HER2-low status in breast cancer and the hormone receptor-positive breast cancer recurrence score—oncotype recurrence score—is not very well studied. We conducted a study to look at the utility of the oncotype recurrence score in HER2-low and HER2-zero breast cancer by using the data from the National Cancer Database. We found that the recurrence score of HER2-low breast cancer was slightly higher compared to HER2-zero breast cancer. Women with HER2-low breast cancer had better survival, especially for those with hormone receptor-negative breast cancer. Among those who received chemotherapy for breast cancer with a high recurrence score, those with HER2-low breast cancer had higher survival compared to HER2-zero breast cancer. 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. [ABSTRACT FROM AUTHOR]

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. Due to the absence of biomarkers capable of predicting who these 10-15% patients could be, the current clinical practice is to give immune checkpoint inhibitors to all patients, resulting in the overtreatment of a significant number of patients. It is increasingly clear that about 30-50% of patients can attain a pCR with NAC alone, with neoadjuvant checkpoint inhibition only helping another 10-15% patients to attain pCR. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background: It is critically important to study the real-world data of FDAapproved 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. [ABSTRACT FROM AUTHOR]

Purpose: Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients. Methods: A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups. Results: High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFβ, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts. Conclusion: PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical role of tumor-associated macrophages, including foamy (FM) and hemosiderin-laden macrophages (HLM) in the tumor bed (TB) of triple-negative breast cancer (TNBC) post-neoadjuvant chemotherapy (NACT). Methods: We conducted a pathologic review of 129 women, diagnosed with TNBC between 2002 and 2016 at our institute. The residual cancer burden (RCB) was calculated. We estimated the percentage of tumor-infiltrating lymphocytes (TILs) in the core needle biopsy (CNB), and FM, HLM, and TILs (in TB) [the combined cells are designated as tumor-associated mononuclear cells (TAMNC)]. The information on patient demographics, chemotherapy regimen, recurrence-free survival (RFS), and overall survival (OS) was extracted from the medical records. Results: Pathologic complete response (pCR) was achieved in 34.1% of the women. TILs (10% increment in CNB) only were associated with pCR in the multivariable analysis [odds ratio 1.04 (1.02, 1.06) (p = 0.0003)]. Immune cells associated with better OS included TAMNC (≤ 30%) [hazard ratio (HR) 4.32 (1.93, 9.66) (p = 0.0004)], and FM (0%) [HR 2.30 (1.06, 4.98) (p = 0.036)]. While increased HLM (10% increment) was statistically significant with HR 0.93 and 95% CI (0.88 to 0.98) (p = 0.0061), using a cutoff of 0%, HLM (0%: negative vs. ≥ 1%: positive) achieved only borderline significance with HR 2.05 (0.98, 4.31) (p = 0.058). Similarly, these immune cells were also associated with better RFS: TAMNC (≤ 30%) [HR 4.57 (2.04, 10.21) (p = 0.0002)], FM (0%) [HR 2.80 (1.23, 6.35) (p = 0.014)], and HLM (0%) [HR 2.34 (1.07, 5.11) (p = 0.03)]. TILs (in TB) were not associated with any clinical outcomes. Conclusions: Although TILs may play a role in the response to NACT, they may not be critical to the prognosis after NACT. Instead, FM and HLM may assume this role. More studies are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Reactive oxygen species (ROS) are oxygen-containing molecules that have high reactivity and play roles in protection or harm the cancer cells. We aimed to clarify the clinical relevance of ROS in breast cancer (BC) tumor microenvironment (TME). We hypothesized that it is associated with worse BC patient outcomes. Methods: ROS score was generated by Gene Set Variation Analysis of Hallmark ROS pathway gene set and a total of 6245 BC patients were analyzed. Results: High ROS BC significantly enriched cell proliferation-related gene sets (MYC targets v1 and v2, G2M checkpoint, E2F targets), pro-cancer-related gene sets (DNA repair, unfolded protein response, MTORC1 signaling, PI3K/AKT/MTOR signaling, glycolysis, and oxidative phosphorylation), immune-related gene sets (inflammatory response, allograft rejection, interferon-α and γ responses, complement, and IL6/JAK/STAT3 signaling), and infiltrated immune cells (CD4+ memory and CD8+ T cells, Th1 and Th2, dendritic cells, Tregs, M1 and M2 macrophages) and B cells, as well as elevated cytolytic activity consistently in both METABRIC and GSE96058 cohorts. Cancer cells were the major source of ROS in BC TME of single-cell sequence (GSE75688) cohort. High ROS was associated with intratumor heterogeneity, homologous recombination defects, mutation rates, and neoantigens, and with clinical aggressiveness in AJCC stage, Nottingham grade and Ki67 expression, as well as worse overall survival in both GSE96058 and METABRIC, and with worse disease-specific survival in METABRIC. Conclusion: Abundant ROS in BC patients is associated with abundant mutations, aggressive cancer biology, immune response, and worse survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor dormancy is a state in which some cancer cells are dormant by less cell proliferation, and are resistant to treatments, thus leading to late recurrence. As nuclear receptor subfamily 2 group F member 1 (NR2F1) is a biomarker of dormancy shown in experimental settings, we studied its clinical relevance by analyzing comprehensive gene expression profiles of approximately 7000 breast cancer patients using computational biological approaches. NR2F1 gene expression of bulk tumors correlated with the suppression of cell proliferation and metastasis-related pathways, but not with metastasis or survival. Using single-cell sequence cohorts, we found that NR2F1 was predominantly expressed in cancer-associated fibroblasts, particularly in inflammatory type, rather than in cancer cells. Further, NR2F1 expression in breast cancer cells did not consistently correlate with stem cell-like traits. Our findings suggest that the NR2F1 gene expression signal from a patient's bulk tumor is not from the cancer cells. Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGFβ signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: There have been growing interests in the roles of intratumoral innervation of the autonomic nervous system (ANS) as a mechanism linking psychosocial stress, β-adrenergic signaling pathways, and poor cancer outcomes, and a potential target for therapeutic purpose. Our current knowledge is being limited by the few cancer types where intratumoral ANS have been studied; it remains to be determined the extent of this mechanism existing in different cancer types. Our study provided the first pan-cancer characterization of intratumoral innervation across 32 cancer types, and further, their relationships with tumor histopathological and molecular characteristics and survival outcomes. We found wide variations in intratumoral ANS expression both within and across cancer types. The association of ANS signatures with tumor histopathological characteristics and survival outcomes also varied by cancer type. Our findings suggest that the potential benefits of cancer therapies targeting β-adrenergic receptor-mediated stress signaling pathways are likely dependent on cancer type. Over the past two decades, multiple studies have demonstrated the important role that the autonomic nervous system (ANS) plays in tumorigenesis and cancer progression. However, the mechanisms by which this process occurs have only recently begun to be elucidated. Further, the extent of autonomic innervation in various cancer types and its effects on tumor molecular, immunological, and histopathological features, as well as on patient outcomes, are not yet fully characterized. In this study, we analyzed intratumoral ANS gene expression signatures, including overall intratumoral neuron growth and sympathetic and parasympathetic markers, across 32 cancer types using tumor transcriptomic and clinical annotation data available from The Cancer Genome Atlas (TCGA). Our analysis revealed wide variations in intratumoral ANS expression both within and across cancer types. The association of ANS signatures with tumor histopathological characteristics and survival outcomes also varied by cancer type. We found intratumoral ANS expression to be commonly correlated with angiogenesis, TGF-β signaling, and immunosuppression in the tumor microenvironment of many cancer types, which provide mechanistic insights into the involvement of intratumoral innervation in cancer development and progression. Our findings suggest that the potential benefits of cancer therapies targeting β-adrenergic receptor-mediated stress signaling pathways are likely dependent on cancer type. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer is a life-threatening disease, even when identified at early stages. Recent advances have allowed the improvement of life expectancy via a personalized approach with the addition of newer chemotherapies, immunotherapies, and targeted therapies, but at the cost of added side effects. It has become increasingly clear that not all patients need such aggressive treatment. Here, we provide an overview of emerging opportunities to use less toxic therapies in patients at lower risk of recurrence or with mutations that can be effectively targeted using novel approaches. We provide a comprehensive review of completed and ongoing clinical trials with information on how to best stratify these patients for treatments to obtain maximum benefit without unnecessary toxicities. Early-stage triple negative breast cancer (TNBC) has been traditionally treated with surgery, radiation, and chemotherapy. The current standard of care systemic treatment of early-stage II and III TNBC involves the use of anthracycline-cyclophosphamide and carboplatin-paclitaxel with pembrolizumab in the neoadjuvant setting followed by adjuvant pembrolizumab per KEYNOTE-522. It is increasingly clear that not all patients with early-stage TNBC need this intensive treatment, thus paving the way for exploring opportunities for regimen de-escalation in selected subgroups. For T1a tumors (≤5 mm), chemotherapy is not used, and for tumors 6–10 mm (T1b) in size with negative lymph nodes, retrospective studies have failed to show a significant benefit with chemotherapy. In low-risk patients, anthracycline-free chemotherapy may be as effective as conventional therapy, as shown in some studies where replacing anthracyclines with carboplatin has shown non-inferior results for pathological complete response (pCR), which may form the backbone of future combination therapies. Recent advances in our understanding of TNBC heterogeneity, mutations, and surrogate markers of response such as pCR have enabled the development of multiple treatment options in the (neo)adjuvant setting in order to de-escalate treatment. These de-escalation studies based on tumor mutational status, such as using Poly ADP-ribose polymerase inhibitors (PARPi) in patients with BRCA mutations, and new immunotherapies such as PD1 blockade, have shown a promising impact on pCR. In addition, the investigational use of (bio)markers, such as high levels of tumor-infiltrating lymphocytes (TILs), low levels of tumor-associated macrophages (TAMs), and complete remission on imaging, also look promising. In this review, we cover the current standard of care systemic treatment of early TNBC and review the opportunities for treatment de-escalation based on clinical risk factors, biomarkers, mutational status, and molecular subtype. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence-free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). Methods: Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I–III TNBC (n = 171 including 124 NHW and 47 NHB) and HER2-positive (n = 161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000 to 2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. Results: There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54–2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36–3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. Conclusion: TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients' race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography, and clinical outcomes are warranted. [ABSTRACT FROM AUTHOR]

Endocrine therapy with or without CDK4/6 inhibitors is the most commonly used frontline treatment option for metastatic hormone receptor–positive breast cancer. Approximately, 25% to 30% of women may have resistance to endocrine therapy, especially in the setting of certain genomic mutations in the tumor. This prompts the need to identify those patients who may benefit from frontline chemotherapy over endocrine therapy. Here, we present a case of a patient who presented with a de novo metastatic hormone receptor–positive breast cancer with visceral involvement (including bone marrow) as well as multiple somatic genomic alterations. The patient was treated with upfront chemotherapy, resulting in clinical and radiographic response, but rapidly progressed when she was transitioned to hormonal therapy. This report focuses on the role of upfront chemotherapy in the setting of visceral crisis including bone marrow involvement, the role of genomic alterations in contributing to endocrine resistance, and the need for biomarker-driven treatment options for hormone receptor–positive breast cancer. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NAC) had been developed as a systematic approach before definitive surgery for the treatment of locally advanced or inoperable breast cancer such as inflammatory breast cancer in the past. In addition to its impact on surgery, the neoadjuvant setting has a benefit of providing the opportunity to monitor the individual drug response. Currently, the subject of NAC has expanded to include patients with early-stage, operable breast cancer because it is revealed that the achievement of a pathologic complete response (pCR) is associated with excellent long-term outcomes, especially in patients with aggressive phenotype breast cancer. In addition, this approach provides the unique opportunity to escalate adjuvant therapy in those with residual disease after NAC. Neoadjuvant chemotherapy in breast cancer is a rapidly evolving topic with tremendous interest in ongoing clinical trials. Here, we review the improvements and further challenges in the NAC setting in translational breast cancer research. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer diagnosed in women. It is associated with multiple symptoms in both patients and caregivers, such as stress, anxiety, depression, sleep disturbance, and fatigue. Stress appears to promote cancer progression via activation of the sympathetic nervous system releasing epinephrine and norepinephrine as well as activation of hypothalamic-pituitary-adrenal axis releasing cortisol. These stress hormones have been shown to promote the proliferation of cancer cells. This review focuses on stress-reducing strategies which may decrease cancer progression by abrogating these pathways, with a main focus on the β-adrenergic signaling pathway. Patients utilize both non-pharmacologic and pharmacologic strategies to reduce stress. Non-pharmacologic stress-reduction strategies include complementary and alternative medicine techniques, such as meditation, yoga, acupuncture, exercise, use of natural products, support groups and psychology counseling, herbal compounds, and multivitamins. Pharmacologic strategies include abrogating the β2-adrenergic receptor signaling pathway to antagonize epinephrine and norepinephrine action on tumor and immune cells. β-Blocker drugs may play a role in weakening the pro-migratory and pro-metastatic effects induced by stress hormones in cancer and strengthening the anti-tumor immune response. Preclinical models have shown that non-selective β1/2-blocker use is associated with a decrease in tumor growth and metastases and clinical studies have suggested their positive impact on decreasing breast cancer recurrence and mortality. Thus, non-pharmacological approaches, along with pharmacological therapies part of clinical trials are available to cancer patients to reduce stress, and have promise to break the cycle of cancer and stress. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-based immunotherapy (ICI) of breast cancer is currently efficacious in a fraction of triple negative breast cancers (TNBC) as these cancers generally carry high tumor mutation burden (TMB) and show increased tumor infiltration by CD8+ T cells. However, most estrogen receptor positive breast cancers (ERBC) have low TMB and/or are infiltrated with immunosuppressive regulatory T cells (Tregs) and thus fail to induce a significant anti-tumor immune response. Our understanding of the immune underpinning of the anti-tumor effects of CDK4/6 inhibitor (CDKi) treatment coupled with new knowledge about the mechanisms of tolerance to self-antigens suggests a way forward, specifically via characterizing and exploiting the repertoire of tumor antigens expressed by metastatic ERBC. These treatment-associated tumor antigens (TATA) may include the conventional tumor neoantigens (TNA) encoded by single nucleotide mutations, TNA encoded by tumor specific aberrant RNA transcription, splicing and DNA replication induced frameshift (FS) events as well as the shared tumor antigens. The latter may include the conventional tumor associated antigens (TAA), cancer-testis antigens (CTA) and antigens encoded by the endogenous retroviral (ERV) like sequences and repetitive DNA sequences induced by ET and CDKi treatment. An approach to identifying these antigens is outlined as this will support the development of a multi-antigen-based immunotherapy strategy for improved targeting of metastatic disease with potential for minimal autoimmune toxicity against normal tissues. [ABSTRACT FROM AUTHOR]

We report a case of a 37-year-old woman who developed a duodenal ulcer while receiving adjuvant neratinib for HER2 positive breast cancer. The clinical course of abdominal pain was strongly correlated with the use of neratinib. An esophagogastroduodenoscopy (EGD) was performed and confirmed the diagnosis of a large duodenal ulcer. Neratinib was stopped, and the patient was treated with a proton pump inhibitor. Repeat EGD performed 3 months later showed complete resolution of the duodenal ulcer. Given this unexpected serious adverse event and only modest benefit of neratinib in the adjuvant setting, the decision was made to forgo further treatment with neratinib. Physicians should be aware of the gastrointestinal (GI) side effects associated with neratinib and recognize that peptic ulcer disease may be another GI toxicity associated with neratinib use. [ABSTRACT FROM AUTHOR]

We report a case of a 37-year-old woman who developed a duodenal ulcer while receiving adjuvant neratinib for HER2 positive breast cancer. The clinical course of abdominal pain was strongly correlated with the use of neratinib. An esophagogastroduodenoscopy (EGD) was performed and confirmed the diagnosis of a large duodenal ulcer. Neratinib was stopped, and the patient was treated with a proton pump inhibitor. Repeat EGD performed 3 months later showed complete resolution of the duodenal ulcer. Given this unexpected serious adverse event and only modest benefit of neratinib in the adjuvant setting, the decision was made to forgo further treatment with neratinib. Physicians should be aware of the gastrointestinal (GI) side effects associated with neratinib and recognize that peptic ulcer disease may be another GI toxicity associated with neratinib use. [ABSTRACT FROM AUTHOR]

In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti- CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immunebased therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal. [ABSTRACT FROM AUTHOR]

Derangement of the phosphatidylinositol-3 kinase (PI3K) pathway is implicated in several subtypes of breast cancers. Mutation or upregulation of PI3K enhances cancer cells' survival, proliferation, and ability to metastasize, making it an attractive molecular target for systemic therapy. PI3K has four isoforms, and several drugs targeting individual isoforms or pan-PI3K have been or are currently being investigated in clinical trials. However, the search for an effective PI3K inhibitor with a robust therapeutic effect and reasonable safety profile for breast cancer treatment remains elusive. This review focuses on the recently completed and ongoing clinical trials involving PI3K inhibitors as mono- or combination therapy in breast cancer. We review the salient findings of clinical trials, the therapeutic efficacy of PI3K inhibitors, and reported adverse effects leading to treatment discontinuation. Lastly, we discuss the challenges and potential opportunities associated with adopting PI3K inhibitors in the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: Preclinical studies have shown that cold stress results in the activation of thermogenesis and an increased tumor growth rate in mice. This study aimed to investigate the clinical relevance of these laboratory findings in patients with triple-negative breast cancer using publicly available large cohorts. Triple-negative breast cancers with high thermogenesis were found to have a pro-tumorigenic immune microenvironment, which may explain the trend towards poor survival observed in this group. This study investigated thermogenesis as a biomarker to predict clinical outcomes, and may pave the way to test novel therapeutics to improve the outcomes of this breast cancer subtype. Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. "High" and "low" expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of 65-year-old African-American female who was diagnosed with lung adenocarcinoma and has been subjected to pemetrexed and carboplatin medication.