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Background: The prognosis for advanced/metastatic triple negative breast cancer (TNBC) remains poor and novel therapeutic strategies are urgently needed to improve outcomes. Insulin resistance and obesity contribute to cancer progression and are independent predictors of worse survival after TNBC diagnosis. Chemotherapy worsens insulin resistance, body mass index, and multiple other metabolic parameters which can paradoxically limit treatment efficacy and survival. Methionine aminopeptidase 2 (MetAP2/p67) is overexpressed in many tumor types and MetAP2 inhibitors exhibit broad anti-tumor activity. Additionally, MetAP2 inhibitors improve insulin resistance, reduce adiposity, and normalize levels of adipokines, attenuating the effects of metabolic dysfunction on tumor growth. Evexomostat (SDX-7320) is a second-generation MetAP2 inhibitor designed to improve drug-like properties and minimize central nervous system toxicities. Evexomostat improved insulin sensitivity, reduced fat mass and normalized adipokine levels in preclinical models of obesity, and reduced tumor growth in preclinical models of TNBC. In phase 1 trials, MetAP2 inhibition combined with chemotherapy was safe and well tolerated, while evexomostat monotherapy partially restored insulin sensitivity, reduced angiogenic factors as well as adipokines and showed anti-metastatic effects in patients with advanced solid tumors. The goal of this phase 2 study is to test whether evexomostat in combination with eribulin chemotherapy prevents worsening of insulin resistance and augments tumor response in patients with metastatic TNBC and concomitant metabolic dysfunction. Methods: This is a single-center, placebo-controlled phase 2 randomized control trial of evexomostat, a MetAP2 inhibitor, in combination with eribulin chemotherapy. Eligible patients must have histologically confirmed metastatic TNBC, measurable disease or ≥1 predominantly lytic bone lesion, baseline metabolic dysfunction defined as hemoglobin A1c >5.5% and/or BMI ≥30 kg/m2, have received ≤2 prior lines of therapy in the advanced/metastatic setting, have ECOG performance status ≤1, and adequate organ function. Patients with uncontrolled or insulin-dependent type II diabetes, or who require combination antihyperglycemic therapy are excluded. During the safety run-in period, 15 patients will be assigned to receive evexomostat 49 mg/m2 every 2 weeks in combination with eribulin 1.4 mg/m2 administered on days 1 and 8 of a 21-day cycle. Upon safety confirmation, an additional 40 patients will be randomized 2:1 to receive evexomostat or placebo in combination with eribulin. The primary endpoint is metabolic efficacy assessed by change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Secondary endpoints include objective response rate, progression-free survival, duration of response, safety and tolerability, patient-reported outcomes, changes in metabolic markers, and changes in body composition parameters. Historically, HOMA-IR scores double during chemotherapy, and this trial will test whether evexomostat will attenuate the expected rise in HOMA-IR. Specifically, the trial will have >90% power to detect a difference between a 1.5-fold change in HOMA-IR in the control arm versus no change in the investigational arm while controlling the Type I error at 5%. This trial opened to accrual in July 2022. A total accrual of 61 patients is planned with a goal of 55 evaluable patients. For any inquiries/questions, please contact Sherry Shen at shens1@mskcc.org. Clinical trial registry number: pending Funding, study drug evexomostat and other support provided by: SynDevRx, Inc. Citation Format: Sherry Shen, Anna Whalen, Mark E. Robson, Larry Norton, Tiffany A. Traina, Neil M. Iyengar. The ARETHA Study: A phase 2 randomized control trial of Eribulin with Evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer and metabolic dysfunction [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-17-02.

Background: Diet is a modifiable risk factor for breast cancer risk and mortality. Current guidelines recommend a diet that provides a diverse array of nutrients, comprised predominantly of fruits/vegetables and whole grains, with limited added sugar. The Healthy Living Program (HLP) is a clinical program at Memorial Sloan Kettering Cancer Center for patients with early-stage breast cancer that offers longitudinal, personalized lifestyle management starting at the time of diagnosis. Here, we report dietary patterns among the HLP cohort and association with baseline body mass index (BMI). Methods: We included all patients enrolled in the HLP from September 2020-February 2022. At the time of enrollment, participants complete a survey containing the National Cancer Institute (NCI) Dietary Screener Questionnaire (DSQ), which consists of consumption frequency questions for 26 food items over the past month. Total daily intake equivalents are calculated for foods from every diet factor group according to standard NCI DSQ scoring as follows: 1) Total daily cup equivalents of fruits/vegetables, which includes fruit, fruit juice, salad, potatoes, beans, other vegetables, tomato sauce, salsa, and pizza; 2) Total daily ounce equivalents of whole grains, which includes cereal, whole grain bread, whole grain rice, and popcorn; 3) Total teaspoon (tsp) equivalents of added sugars from candy, doughnuts, cookies/cake/pie, cereal, ice cream, and sugar-sweetened beverages including soda, fruit drinks, and sugar/honey in coffee/tea. Adherence to recommended daily intake of fruits/vegetables, whole grains, and added sugars was assessed as per the 2020-2025 Dietary Guidelines, the American Institute for Cancer Research, and the World Health Organization guidelines. Patient and tumor characteristics were abstracted from medical records. Results: Among the 399 patients included, the median age at diagnosis was 58 and median baseline BMI was 26.1 kg/m2. 45 patients had carcinoma in situ (11.3%), 296 had stage I disease (74.2%), 51 had stage II disease (12.8%), and 7 had stage III disease (1.8%). 316 had hormone-receptor positive disease (89.3%), 24 had HER2-positive disease (6.8%), and 26 had triple-negative disease (7.3%). 106 participants (27%) met the guideline recommendation of ≥4-5 cup equivalents of fruits/vegetables daily and 3 participants (0.8%) met the guideline recommendation of ≥3 ounces equivalents of whole grains daily. All patients in the cohort met the guideline recommendation of < 6 tsp equivalents of added sugars daily. Only 2 patients (0.5%) met guidelines for all three diet factors. Baseline BMI was significantly higher among patients who did not meet the recommended fruit/vegetable intake than among those who did (26.9 kg/m2 vs. 24.5 kg/m2, p=0.016). There were no significant differences in BMI between those who did and did not adhere to the other diet factor guidelines and no significant association between tumor stage or histology and dietary guideline adherence. Conclusion: Most patients with early-stage breast cancer did not meet the recommended daily intake of fruits/vegetables or whole grains. Participants who did not meet the fruit and vegetable intake guideline had significantly higher BMI at diagnosis. These findings indicate that lifestyle assessment near the time of breast cancer diagnosis identifies patients that could benefit from personalized dietary interventions to optimize prognostic factors such as BMI. Citation Format: Bethina Liu, Sherry Shen, Erica Salehi, Yuan Chen, Nicolas Toumbacaris, Johnny Allsop, Cara Anselmo, Stacie Corcoran, Bridget Kelly, Rocco Magnoli, Andrea Smith, Melissa Emerzian, Julia Brockway-Marchello, Doreen Bacotti, Mark E. Robson, Neil M. Iyengar. Dietary patterns among women with early-stage breast cancer from the Healthy Living Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-07.

A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC.Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods.WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p .05). WAT inflammation was associated with greater body mass index (p .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue.WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Mitochondria-rich brown adipocytes dissipate cellular fuel as heat by thermogenic energy expenditure (TEE). Prolonged nutrient excess or cold exposure impair TEE and contribute to the pathogenesis of obesity, but the mechanisms remain incompletely understood. Here we report that stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes a group of proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. We further determine a smaller subset that correlates with obesity in human subcutaneous adipose tissue. We go on to show that the top factor on this short list, acyl-CoA thioesterase 9 (ACOT9), migrates from the IM into the matrix upon stress where it enzymatically deactivates and prevents the utilization of acetyl-CoA in TEE. The loss of ACOT9 protects mice against the complications of obesity by maintaining unobstructed TEE. Overall, our results introduce aberrant protein translocation as a strategy to identify pathogenic factors.One-Sentence SummaryThermogenic stress impairs mitochondrial energy utilization by forcing translocation of IM-bound proteins into the matrix.

Supplementary Tables S1, S2, and S3

Figure S1. Breast SIRT1 levels correlate with adiposity. SIRT1 expression in the breast inversely correlated with (A) BMI, (B) adipocyte diameter, (C) total fat percentage, and (D) trunk fat percentage.

Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina patients with breast cancer, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina patients with breast cancer who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 IHC in nontumor breast tissue. BWATi severity was quantified as number of CLS-B/cm2. Adipocyte diameter was measured using hematoxylin and eosin-stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5–2), overweight (25.0–2), class I obesity (30.0–2), and class II–III obesity (35.0 kg/m2 or above). Patient charts were abstracted to record clinicopathologic features and liver function tests Ptrend 0.27 CLS-B/cm2) was associated with higher BMI (Ptrend = 0.046) and greater adipocyte diameter (P = 0.04). Adjusting for BMI, neoadjuvant chemotherapy, and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all P < 0.05). BWATi was associated with higher BMI in Hispanic/Latina patients with breast cancer, consistent with previously described associations in other populations.

Sup Fig 1

BACKGROUND: Regular physical activity is associated with improved symptom control in patients with breast cancer but its association with chemotherapy completion or response is unclear. METHODS: Using a prospective design, 1075 breast cancer patients receiving neoadjuvant chemotherapy between March 2012 and February 2017 were studied. Physical activity was assessed using the Global Physical Activity Questionnaire [GPAQ-16], quantified in standardised MET-h/wk. Chemotherapy completion was defined as the proportion of patients completing planned treatment course, requiring dose reduction, or requiring dose delay. Response was evaluated by pathologic complete response (pCR). Associations between physical activity and primary outcomes were assessed using multivariable logistic regression models. RESULTS: There was no differences between any chemotherapy completion outcome on the basis of physical activity classification. The percent of patients not completing planned treatment was 5.7% for ≦0.33 MET-h/wk, compared with 6.8% for 0.34–16.65 MET-h/wk, and 4.6% for ≥16.6 MET-h/wk (p = 0.52). No significant relationships were observed between physical activity dose classification and pCR for the overall cohort or upon stratification by clinical subtype. CONCLUSION: Future studies are required to further investigate the relationship between pre-treatment levels of physical activity and function on treatment completion and response in breast and other cancer populations. CLINICAL TRIAL REGISTRATION: NCT01993498.

Background: Elevated bodyweight is a risk factor for breast cancer development in women who carry a mutation in the DNA repair enzymes BRCA1 and BRCA2. However, the mechanistic basis for this association is unknown. Breast adipose tissue undergoes significant changes in the setting of weight gain and obesity, including elevation in aromatase expression which leads to the increased biosynthesis of estrogens. Given that estrogens and estrogen metabolites have known pro-proliferative and genotoxic effects, we hypothesized that in BRCA1/2 mutation carriers, obesity may be positively associated with breast epithelial cell DNA damage, thereby increasing the risk of tumorigenesis. Furthermore, we examined the impact of inhibiting estrogen signaling or production on breast epithelium DNA damage in BRCA1/2 mutation carriers. Methods: Tissue microarrays were generated from non-cancerous breast tissue derived from 72 women carrying a mutation in BRCA1 or BRCA2 with known body mass index (BMI, kg/m2). Breast epithelium DNA damage was quantified by immunofluorescence (IF) staining of the DNA damage marker γH2AX. RNA-Seq was performed on breast organoids to assess differences in gene expression in relation to BMI. Associations between DNA damage and biomarkers of estrogen biosynthesis and bioavailability, including aromatase expression in the breast and circulating steroid hormone binding globulin (SHBG), were also evaluated. To explore the effect of blocking estrogen signaling or production on DNA damage, non-tumorous breast tissue explants from BRCA1/2 mutation carriers were cultured with fulvestrant, an estrogen receptor degrader, or metformin, an anti-diabetic drug that also reduces aromatase expression in the breast. Breast epithelial cell DNA damage was measured in control vs treated explants by γH2AX IF staining after 24 hours of treatment. Results: BMI was positively correlated with DNA damage in the breast epithelium of BRCA1/2 mutation carriers. Upstream analysis of gene expression in organoids derived from women with a BMI ≥ 30 compared to Citation Format: Priya Bhardwaj, Neil M. Iyengar, Sofya Oshchepkova, Phoebe Piloco, Rohan Bareja, Olivier Elemento, Dilip D. Giri, Michael Pollak, Monica Morrow, Jason A. Spector, Kristy A. Brown. Obesity is associated with DNA damage in the breast epithelium of BRCA1 and BRCA2 mutation carriers: A role for estrogens & strategies for prevention [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-06-03.

Background: Chemotherapy remains the mainstay of treatment for early-stage triple negative breast cancer (TNBC), yet targetable drivers of interest are under investigation. A subset of TNBCs express the androgen receptor (AR) and exhibit androgen-dependent growth. The AR-antagonist enzalutamide (ENZA) has shown activity in patients with metastatic AR+ TNBC. In this study, the feasibility of adjuvant ENZA in early-stage, AR+ TNBC was assessed (NCT02750358). As reported previously, this study met its primary endpoint of feasibility (Traina et al., ASCO 2019). Here we report secondary survival endpoints. Methods: In this single-arm, open-label, multi-center trial, patients with stage I-III, AR≥1% TNBC (ER/PR Citation Format: Elaine M Walsh, Ayca Gucalp, Sujata Patil, Marcia Edelweiss, Dara S Ross, Pedram Razavi, Shanu Modi, Neil M Iyengar, Rachel Sanford, Tiffany Troso-Sandoval, Mila Gorsky, Jackie Bromberg, Pamela Drullinsky, Diana Lake, Serena Wong, Patricia DeFusco, Nicholas Lamparella, Ranja Gupta, Tasmila Tabassum, Leigh Ann Boyle, Artavazd Arumov, Tiffany A Traina. Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple negative breast cancer: A feasibility study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-14-03.

Background: The presence of white adipose tissue inflammation (WATi) in the breast has been associated with increased breast cancer risk and a worse clinical course. Elevated body mass index (BMI) and the post-menopausal state are both associated with breast WATi. Breast WATi has also been associated with increased expression of aromatase, the rate-limiting enzyme for estrogen biosynthesis. Currently, WATi is diagnosed in surgical samples of breast tissue by the identification of crown-like structures (CLS), which are comprised of a dead or dying adipocyte enveloped by macrophages. In contrast to surgical specimens, core biopsies have been shown to be inadequate for assessing WATi. Hence, there is an unmet need for strategies to non-invasively diagnose WATi. Here we used a novel lipidomics platform to identify potential non-invasive blood signatures of breast WATi. Methods: We conducted a cross-sectional study which included 100 patients who underwent mastectomy for breast cancer treatment or risk reduction. WATi was detected by CD68 immunohistochemistry to identify CLS. Breast aromatase expression levels were measured by qPCR. Clinicopathologic data were abstracted from electronic medical records. Lipidomic data were measured from blood plasma in collaboration with Waters Technologies Corporation. Lipid levels in association with breast WATi (presence/absence) and levels of aromatase expression (high/low) in non-tumorous breast tissue were examined using Welch’s t-test. P-values were adjusted for multiple comparisons by controlling the false discovery rate (FDR) using the Benjamini-Hochberg method. A logistic regression model was used to develop predictive models that evaluated potential lipid biomarkers of the presence of breast WATi and high breast aromatase expression levels. Stepwise regression was used for variable selection. AUC of the ROC curves was used to evaluate the performance of the predictive models. Results: Among 140 lipids analyzed, 13 were identified to be associated with breast WATi (P0.3). Specifically, 8 lipids had lower levels, and 6 lipids had higher levels in patients with breast WATi compared to those without. Levels of 7 lipids were significantly higher in patients with an increased level of aromatase (P0.3). After variable selection, LPE(22:6) (P=0.018), LPE(20:3) ES-(P=0.006), along with menopausal status and BMI provided an 86.0% (95% CI, 77.6%-94.5%) accuracy in predicting higher breast aromatase levels. Combining the effect of two lipids improved the accuracy by 10.4%(P=0.030) compared to the model only using menopausal status and BMI. A model with 5 lipids and menopausal status provided an 88.8%(95% CI, 81.9%-95.8%) accuracy for predicting breast WATi. The model performance improved by 9.2% (P=0.026) compared to the model only using menopausal status and BMI. Conclusions: Our study identified several lipid species that showed significant changes in association with breast WATi and levels of aromatase expression. Further validation of these blood signatures could provide non-invasive assessment of WATi and aromatase levels. The availability of such a diagnostic algorithm could help, in turn, to both identify women at elevated risk for breast cancer and for monitoring the efficacy of interventions aimed at reducing inflammation and aromatase levels. Citation Format: Xiao Cai, Siqi Wei, Zizhuo Xu, Xi K Zhou, Andrew Peck, Steven Lai, Giorgis Isaac, Hernando Olivos, Nayasha Munjoma, Suraj Dhungana, Rob Plumb, Andrew J Dannenberg, Neil M Iyengar. Plasma lipidomics analysis to identify potential non-invasive biomarkers for breast white adipose inflammation and aromatase expression levels [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-05.

Supplementary Figure S1. White adipose tissue inflammation. A. CLS-B positive breast WAT. H&E (upper panel) and anti-CD68 immunostaining (lower panel); 40x (left panel) and 400x (right panel). Arrow indicates CLS-B. B. CLS-B negative breast WAT. H&E (upper panel) and anti-CD68 immunostaining (lower panel); 40x (left panel) and 400x (right panel). WAT, white adipose tissue; CLS-B, crown-like structures of the breast.

This file contains Supplementary Figure 1. Supplementary Figure 1 shows the staining pattern of tumoral PD-L1 staining.

This file contains Supplementary Figure 2. Supplementary Figure 2 shows tumoral PD-L1 staining in association with PD-1, CD8, and CD4 TILs.

This file contains Supplementary Figures 3-9. Supplementary Figure 3. Representative multi-color immunofluorescence staining shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 4. Representative multi-color immunofluorescence staining of a PD-L1 negative tumor shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 5. CD4+ T cells show markedly more specific PD-L1 localization in OTSCC tumors compared to CD8+ T cells. Supplementary Figure 6. Representative multi-color immunofluorescence staining of an OTSCC tumor shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 7. Higher magnification multi-color immunofluorescence staining of a representative OTSCC tumor stained with PD-L1, PD-1, CD4, and CD8. Supplementary Figure 8. Diffuse tumoral PD-L1 staining shows low infiltration of CD4+ and CD8+ T cells. Supplementary Figure 9. Representative multi-color immunofluorescence staining of FoxP3, PD1, and Ki67 in OTSCC.

PDF file - 339K, Flow cytometry histograms of serial levels of p-ERK and p-mTOR in patient samples.

This file contains Supplementary Table 1. Supplementary Table 1 shows the immunohistochemical staining for PD-L1, PD-1, CD4, and CD8 in the samples analyzed in the manuscript.

This file contains Supplementary Table 2. Supplementary Table 2 shows that the proliferative capacity of PD-1 expressing CD8, CD4, and FoxP3+ TILs are decreased compared to non-PD-1 expressing TILs in OTSCC.

This file contains the figure legends for supplementary figures 1-9. Supplementary Figure 1. Staining pattern of tumoral PD-L1 staining. Supplementary Figure 2. Tumoral PD-L1 staining in association with PD-1, CD8, and CD4 TILs. Supplementary Figure 3. Representative multi-color immunofluorescence staining shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 4. Representative multi-color immunofluorescence staining of a PD-L1 negative tumor shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 5. CD4+ T cells show markedly more specific PD-L1 localization in OTSCC tumors compared to CD8+ T cells. Supplementary Figure 6. Representative multi-color immunofluorescence staining of an OTSCC tumor shows that PD-1+CD4+ T cells demonstrate greater PD-1 expression than PD1+CD8+ T cells. Supplementary Figure 7. Higher magnification multi-color immunofluorescence staining of a representative OTSCC tumor stained with PD-L1, PD-1, CD4, and CD8. Supplementary Figure 8. Diffuse tumoral PD-L1 staining shows low infiltration of CD4+ and CD8+ T cells. Supplementary Figure 9. Representative multi-color immunofluorescence staining of FoxP3, PD1, and Ki67 in OTSCC.

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+, and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TILs. We found that CD4+ TILs were present in equal or greater frequencies than CD8+ TILs in 94% of OTSCC and that CD4+FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8+ TILs. Both CD4+PD1+ and CD8+PD1+ TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. Cancer Res; 77(22); 6365–74. ©2017 AACR.

This file contains Supplementary Table 3. Supplementary Table 3 shows the clinicopathological characteristics of the patient cohort.

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown.Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation.Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027).Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.

Purpose: Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance.Experimental Design: WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome–associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status.Results: In cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07–3.13) for patients with inflammation.Conclusions: WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283–9. ©2015 AACR.

PDF file - 50K, Primers for KIT gene mutation testing.

Microcalcifications, primarily biogenic apatite, occur in cancerous and benign breast pathologies and are key mammographic indicators. Outside the clinic, numerous microcalcification compositional metrics (e.g., carbonate and metal content) are linked to malignancy, yet microcalcification formation is dependent on microenvironmental conditions, which are notoriously heterogeneous in breast cancer. We interrogate multiscale heterogeneity in 93 calcifications from 21 breast cancer patients using an omics-inspired approach: For each microcalcification, we define a “biomineralogical signature” combining metrics derived from Raman microscopy and energy-dispersive spectroscopy. We observe that (i) calcifications cluster into physiologically relevant groups reflecting tissue type and local malignancy; (ii) carbonate content exhibits substantial intratumor heterogeneity; (iii) trace metals including zinc, iron, and aluminum are enhanced in malignant-localized calcifications; and (iv) the lipid-to-protein ratio within calcifications is lower in patients with poor composite outcome, suggesting that there is potential clinical value in expanding research on calcification diagnostic metrics to include “mineral-entrapped” organic matrix.

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1 +/− mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

PURPOSE Antibody-drug conjugates (ADCs) are a class of cancer drug wherein some are associated with corneal abnormalities, but there is a dearth of published information on refractive shifts in patients receiving ADCs. Here, we evaluated the dynamics of refractive error and keratometry readings in patients with ADC-related keratopathy and microcyst-like epithelial changes (MECs). METHODS This study is a retrospective case series including 58 eyes of 29 patients with ADC-related keratopathy from a single tertiary care cancer referral center (MSKCC). One eye (29 total) was randomly assigned for statistical analysis. In addition, a subset analysis of MEC location-refractive error correlation was performed on 20 eyes. Clinical records including slitlamp examination, indirect ophthalmoscopy, calculated spherical equivalence (SE), keratometry, and visual acuity were recorded at baseline, during, and off treatment. RESULTS A subset analysis of MEC location-refractive error correlation of 20 eyes revealed the following: Peripheral MECs were significantly associated with hyperopic shifts (P value < 0.001) and paracentral/central associated with myopic shifts (P value < 0.001). In the full cohort and on drug, the greatest change in SE from baseline was myopic (68%, as high as -4.75 D) and hyperopic (32%, as much as +3.75 D). Eighty-nine percent had a change in vision from baseline while on drug, but at the 3-month follow-up off drug, SE and vision returned to baseline in 33% and 82% of eyes. CONCLUSIONS Peripheral MECs were significantly associated with hyperopic shifts, and paracentral/central MECs were associated with myopic shifts. While on drug, most eyes had a myopic refractive shift, which corresponded with corneal steepening.

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are probably important for explaining the link between excess body fat, adipose inflammation and breast cancer. The first goal of this cross-sectional study of 196 women was to carry out transcriptome profiling to define the molecular changes that occur in the breast related to excess body fat and WAT inflammation. A second objective was to determine if commonly measured blood biomarkers of risk and prognosis reflect molecular changes in the breast. Breast WAT inflammation was assessed by immunohistochemistry. Bulk RNA-sequencing was carried out to assess gene expression in non-tumorous breast. Obesity and WAT inflammation were associated with a large number of differentially expressed genes and changes in multiple pathways linked to the development and progression of breast cancer. Altered pathways included inflammatory response, complement, KRAS signaling, tumor necrosis factor α signaling via NFkB, interleukin (IL)6-JAK-STAT3 signaling, epithelial mesenchymal transition, angiogenesis, interferon γ response and transforming growth factor (TGF)-β signaling. Increased expression of several drug targets such as aromatase, TGF-β1, IDO-1 and PD-1 were observed. Levels of various blood biomarkers including high sensitivity C-reactive protein, IL6, leptin, adiponectin, triglycerides, high-density lipoprotein cholesterol and insulin were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

ImportanceAs the incidence of cancer and metabolic disorders, such as obesity, concurrently rise, there has been increasing awareness of the pervasive effect of nutrition. The whole foods plant-based diet (WFPBD) and ketogenic diet (KD) have gained popularity in oncology, and this topic is increasingly permeating clinical dialogue.ObservationsDietary intake is associated with multiple pathways involved in carcinogenesis and tumor progression. Consumption of a plant-enriched diet is associated with reduced cancer incidence and is recommended by dietary guidelines for cancer prevention. Despite a starkly different nutrient composition, a WFPBD and KD can be associated with weight loss, decreased inflammation, and decreased insulin levels. In addition, a WFPBD is associated with increased fiber, phytochemicals, and butyrate levels and decreased insulin-like growth factor 1 levels, whereas a KD exerts potential anticancer effects by increasing β hydroxybutyrate levels. A KD may be of interest in select, less common settings, such as tumors treated with phosphatidylinositol 3-kinase inhibitors, which induce hyperinsulinemia and hyperglycemia. Completed interventional trials have focused on increasing fruit and vegetable intake or reducing fat intake but have not specifically tested WFPBD or KD for cancer prevention or treatment. Currently available data support plant-based diets as opposed to KD as part of a lifestyle associated with reduced cancer risk. In the postdiagnosis setting, there are currently no rigorously tested approaches that support the recommendation of any diet to treat cancer.Conclusions and RelevanceThe results of this review suggest that the collective evidence supports plant-enriched diets vs KD for the reduction of cancer risk and the improvement of metabolic disorders in survivors. Additional prospective randomized clinical trials are needed to encourage use of dietary modification across the cancer continuum. Rigorous trial designs that adapt classical oncologic end points may identify populations that are likely to benefit from starkly contrasting diets. Current data support prioritization of plant-based diets, and future data could further personalize dietary recommendations in cancer populations.

Hyperinsulinemia is an independent risk factor for cancer mortality. Insulin-lowering dietary strategies such as calorie restriction (CR), low-carbohydrate or ketogenic diets (KD), and intermittent fasting (IF) are aimed at reducing systemic stores of nutrients utilized by cancer cells, attenuating insulin-related growth signaling, and improving obesity-related metabolic parameters. In this narrative review, we searched the published literature for studies that tested various insulin-lowering diets in metastatic cancer in preclinical and clinical settings. A total of 23 studies were identified. Of these, 14 were preclinical studies of dietary strategies that demonstrated improvements in insulin levels, inhibition of metastasis, and/or reduction in metastatic disease burden in animal models. The remaining nine clinical studies tested carbohydrate restriction, KD, or IF strategies which appear to be safe and feasible in patients with metastatic cancer. These approaches have also been shown to improve serum insulin and other metabolic parameters. Though promising, the anti-cancer efficacy of these interventions, such as impact on tumor response, disease-specific-, and overall survival, have not yet been conclusively demonstrated. Studies that are adequately powered to evaluate whether insulin-lowering diets improve cancer outcomes are warranted.

Obesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P P P BRCA1/2 mutation carriers.

Obesity is an increasingly prevalent state of energy imbalance that contributes to breast cancer risk and outcomes. The effects of obesity differ by breast cancer subtype and menopause. While most studies have focused on postmenopausal hormone receptor-positive disease, less is known about the relationship between obesity and triple-negative breast cancer (TNBC). Here we will review the observations linking obesity to TNBC, the socioeconomic disparities that contribute to obesity-related TNBC, and putative biologic mechanisms. Finally, we will consider the impact of obesity on surgical and medical treatment of TNBC and novel strategies to improve energy balance after cancer diagnosis.

Context Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. Evidence Acquisition Pubmed literature search using combinations of “obesity,” “breast cancer risk,” “diet,” “exercise,” “weight gain,” “weight loss,” “adipose tissue inflammation,” “crown-like structure,” “immune markers,” “metformin,” “gliflozins,” “SGLT-2i,” “GLP1-RA,” and related terms. Evidence Synthesis Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor–positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. Conclusion Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC.This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors.Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached.This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.

Maintaining a healthy weight is beneficial for cancer survivors. However, weight loss program effectiveness studies have primarily been in highly controlled settings. This is a retrospective study exploring real-world outcomes (weight loss and program engagement) after use of a digital commercial weight loss program (Noom) in cancer survivors and matched controls. All participants had voluntarily self-enrolled in Noom. Weight and engagement data were extracted from the program. Cancer-related quality of life was secondarily assessed in a one-time cross-sectional survey for survivors. Controls were a sample of Noom users with overweight/obesity who had no history of cancer but 0–1 chronic conditions. Primary outcomes were weight change at 16 weeks and program engagement over 16 weeks. Engagement included frequency of weight, food, and physical activity logging, as well as number of coach messages. Multiple regression controlling for baseline age, gender, engagement, and BMI showed that survivors lost less weight than controls (B = −2.40, s.e. = 0.97, p = 0.01). Survivors also weighed in less (survivors: 5.4 [2.3], controls: 5.7 [2.1], p = 0.01) and exercised less (survivors: 1.8 [3.2], controls: 3.2 [4.1], p &lt, 0.001) than controls. However, survivors sent more coach messages (survivors: 2.1 [2.4], controls: 1.7 [2.0], p &lt, 0.001). Despite controls losing more weight than cancer survivors (−7.0 kg vs. −5.3 kg), survivors lost significant weight in 4 months (M = −6.2%). Cancer survivors can have success on digital commercial programs available outside of a clinical trial. However, they may require additional support to engage in weight management behaviors.

Background Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. Materials and methods In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. Results From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. Conclusion With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. Implications for practice The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

Background Plasma cell disorders (PCDs) are chronic incurable conditions with an opportunity to positively impact outcomes with nutritional changes. Epidemiologic studies show that inflammatory/insulinemic diets are linked to PCDs (Lee IJC 2020), while vegetarians/vegans have a reduced risk (Key AJCN 2014). MGUS/SMM present a unique opportunity for early intervention, given the standard of care is observation. Though patients often inquire about the role of nutrition and whether they should alter habits to eat healthfully, their oncologists are frequently not prepared to address these concerns. The purpose of this survey was to provide insights into patient nutrition perceptions/practices and identify areas for further research. Methods We utilized HealthTree® Cure Hub (HealthTree® Foundation, Lehi, Utah, USA) and invited participants with PCDs to answer questions pertaining to their diet/nutrition and related experience with their oncologist in an online survey. De-identified aggregated responses were reviewed. Results Of 421 participants, 82% reported having dietary questions post-diagnosis, yet 23% stated this was not addressed by their oncologists despite asking. Among those who discussed it with their oncologist, 50% received no specific advice or were recommended a ‘balanced diet’ lacking details. Of the participants that received clear guidance from their oncologists, 88% attempted to follow it, reflecting the positive influence their oncologists can have. Lack of knowledge/conflicting advice were barriers to change for 23%. Although the American Institute of Cancer Research (AICR) has published dietary guidelines, only 34% were aware of them. Patients also more frequently reported following a healthier diet after diagnosis – 75% pre-diagnosis vs 88% post-diagnosis. 78% patients with unhealthy diets pre-diagnosis improved their diet post-diagnosis and 7% with healthy diets pre-diagnosis worsened their diet post-diagnosis. Post-diagnosis, more patients reported consuming whole fruits and vegetables ≥1 times/day and whole grains and seafood ≥3 times/week. Post-diagnosis dietary changes were based on online/media information and advice from non-medical friends in 47%, compared to advice from PCPs/oncologists/nutritionists in 22%. Conclusions Patients with PCDs are interested in dietary advice and make dietary changes when faced with a cancer diagnosis. Most patients currently receive this advice from non-medical sources and report barriers related to lack of consistent information. Oncologists who provide clear guidance can positively impact dietary changes among patients. Our results reflect a missed opportunity between patients’ need for dietary advice and the potential for oncologists to provide helpful counsel. Our findings highlight a need for further research into standardized guideline (AICR) implementation as well as for the development of PCD-specific guidelines. Further disease focused dietary studies are needed to fill this gap.

12100 Background: Rash associated with increased peripheral eosinophils develops in approximately 50% of metastatic breast cancer patients receiving alpelisib. Antihistamines and corticosteroids have limited benefit. Refractory rash may lead to decreased dose intensity and affect clinical outcome. Benralizumab is an anti-IL-5Rα chimeric monoclonal antibody that depletes peripheral eosinophils and has demonstrated benefit in eosinophilic asthma and hypereosinophilic syndrome. We investigate the efficacy and safety of benralizumab for the treatment of alpelisib rash. Methods: We performed a single-center, single-arm, prospective phase 2 study to evaluate the efficacy and safety of benralizumab in cancer patients who developed CTCAE grade 2/3 skin events resulting from immunotherapy or targeted therapies with absolute blood eosinophil counts of ≥300/mcl. While remaining on culprit drugs, patients were treated with benralizumab 30mg once every 4 weeks for the first 3 doses followed by once every 8 weeks for 3 additional doses (approved dosing for eosinophilic asthma). Primary endpoint was clinical response measured as reduction in CTCAE grade 2/3 skin event to grade ≤1 by week 4. Secondary endpoints were patient quality of life (QoL) measured by skindex16, safety data, need for supportive oral corticosteroids, and changes in cytokines and eosinophil biomarkers. This interim analysis focuses on patients with PIK3CA-mutant metastatic breast cancer receiving alpelisib. Results: Between September 16th 2020 and January 1st 2022, we enrolled 10 metastatic breast cancer patients with grade 2/3 rash attributed to alpelisib (5 pts with G3). All patients had a reduction of rash to grade ≤1 (n = 10, p < 0.0001), and a decrease in peripheral absolute eosinophils (mean 500/mcl to 0, p < 0.0001). Of these, 6 patients had been on prophylactic oral antihistamines and 2 had oral steroid coadministration. QoL significantly improved (Skindex16 mean score 58 to 16, p = 0.0001) and eosinophils in skin histology decreased per HPF (mean 6.25 to 0.25, n = 8, p = 0.2) by week 4. An increase in IL-5 > 600% and reduction IL-6 and TNF-α > 50% were reported by week 4 and 8. Grade 1/2 mucositis in 4 patients were reported as adverse events. Conclusions: Our findings suggest that benralizumab is safe and effective for the treatment of grade 2/3 rash with eosinophilia related to alpelisib in patients with breast cancer. A reduction in rash severity was evidenced in all patients, along with improved QoL. Larger controlled studies are in development to evaluate the efficacy of benralizumab for the prevention of alpelisib rash. Clinical trial information: NCT04552288.

TPS1113 Background: Breast cancer is the most common malignancy among women in the U.S. and is a leading cause of cancer-related death. Among women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, 45% harbor activating mutations in the PIK3CA gene , which induces hyperactivation of phosphatidylinositol 3-kinase (PI3K) and drives cell growth and survival. The SOLAR-1 trial found that the combination of alpelisib, a PI3K inhibitor, and fulvestrant, an endocrine therapy, significantly improved progression-free survival compared to fulvestrant alone, leading to Food and Drug Administration approval in PIK3CA-mutated metastatic breast cancer. While PI3K inhibition induces apoptosis of cancer cells, inhibition of this pathway in the liver and skeletal muscle impairs physiologic insulin signaling leading to hyperglycemia. This affects > 60% of patients, results in grade 3-4 hyperglycemia in 36% of patients, and is a major cause of interrupted/reduced dosing or discontinuation. In preclinical models, application of a very low carbohydrate (ketogenic) diet or a sodium-glucose cotransporter 2 inhibitor (SGLT2i), a commonly used diabetes medication, minimized hyperglycemia and improved the anti-tumor efficacy of PI3K inhibition. These interventions are safe and feasible in cancer patients but have not been studied for the prevention of PI3K inhibitor-associated hyperglycemia. Methods: We are conducting a multicenter phase II clinical trial (NCT05090358) in patients receiving standard-of-care alpelisib plus fulvestrant to test the efficacy of three interventions (n = 106): 1) ketogenic diet, 2) low-carbohydrate diet, or 3) canagliflozin (a SGLT2i) in preventing alpelisib-associated hyperglycemia. The goal of this study is to mitigate a major toxicity of PI3K inhibitors and maximize their clinical efficacy. Eligible patients must be postmenopausal and have histologically confirmed HR-positive, HER2-negative metastatic breast cancer, ≥1 activating PIK3CA mutations, measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion, recurrence or progression during or after endocrine-based therapy, ECOG performance status of 0-1, hemoglobin A1c < 8%, and fasting blood glucose < = 140mg/dL. Prior CDK4/6 inhibitor use is allowed. The primary endpoint is the grade 3-4 hyperglycemia-free rate at 12 weeks. Secondary endpoints include the 6- and 12-month overall response rate, 6- and 12-month progression-free survival, alpelisib adherence, changes in systemic hormones and metabolites related to glucose homeostasis, changes in body composition, and quality of life. The first patient was enrolled on October 15, 2021. Participating sites include Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, and the Ohio State University Wexner Medical Center. Clinical trial information: NCT05090358.