Publications by authors named "Ingrid A Mayer"

126 Publications

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

J Natl Compr Canc Netw 2021 May 1;19(5):484-493. Epub 2021 May 1.

26Research Advocacy Network.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.
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http://dx.doi.org/10.6004/jnccn.2021.0023DOI Listing
May 2021

Reply to T. Shimoi et al and Y. Shimanuki et al.

J Clin Oncol 2021 Nov 23;39(31):3522-3524. Epub 2021 Sep 23.

Ingrid A. Mayer, MD, MSCI, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN; Fengmin Zhao, PhD, Dana-Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA; Carlos L. Arteaga, MD, UT Southwestern Simmons Cancer Center, Dallas, TX; William F. Symmans, MD, MD Anderson Cancer Center, Houston, TX; Ben H. Park, MD, PhD, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN; Brian L. Burnette, MD, Cancer Research of Wisconsin and Northern Michigan (CROWN) NCORP, Green Bay, WI; Amye J. Tevaarwerk, MD, University of Wisconsin Carbone Cancer Center, Madison, WI; Sofia F. Garcia, PhD, Northwestern University, Evanston, IL; Karen L. Smith, MD, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD; Della F. Makower, MD, Montefiore Medical Center, Bronx, NY; Margaret Block, MD, Alegent Health Bergan Mercy Medical Center, Omaha, NE; Kimberly A. Morley, MD, Saint Joseph Mercy Hospital, Ann Arbor, MI; Chirag R. Jani, MD, Phoebe Putney Memorial Hospital, Albany, GA; Craig Mescher, MD, Metro-Minnesota Community Oncology Research Consortium, St Louis Park, MN; Shabana J. Dewani, MD, Columbus Oncology and Hematology Associates Inc, Columbus, OH; Bernard Tawfik, MD, University of New Mexico Cancer Center, Albuquerque, NM; Lisa E. Flaum, MD, Northwestern University, Evanston, IL; Erica L. Mayer, MD, Dana-Farber Cancer Institute, Boston, MA; William M. Sikov, MD, Women and Infants Hospital of Rhode Island, Providence, RI; Eve T. Rodler, MD, University of California, Davis, Davis, CA; Lynne I. Wagner, PhD, Wake Forest University Health Sciences, Winston-Salem, NC; Angela M. DeMichele, MD, University of Pennsylvania/Abramson Cancer Center, Philadelphia, PA; Joseph A. Sparano, MD, Montefiore Medical Center, Bronx, NY; Antonio C. Wolff, MD, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD; and Kathy D. Miller, MD, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN.

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http://dx.doi.org/10.1200/JCO.21.01905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547907PMC
November 2021

Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.

JNCI Cancer Spectr 2021 Oct 28;5(5):pkab066. Epub 2021 Jul 28.

Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada and University of Toronto, Toronto, ON, Canada.

Background: Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer.

Methods: A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided.

Results: Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, <.001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all >.11).

Conclusions: Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.
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http://dx.doi.org/10.1093/jncics/pkab066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410139PMC
October 2021

New targets in endocrine-resistant hormone receptor-positive breast cancer.

Clin Adv Hematol Oncol 2021 Aug;19(8):511-521

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Endocrine-based treatments are the backbone of initial therapy for advanced hormone receptor-positive breast cancers. Developing new therapeutic strategies to address resistance to endocrine therapy is an area of active research. In this review, we discuss targeted therapies that are currently the standard of care, as well as agents that are at present under investigation as potential treatments for advanced hormone receptor-positive breast cancer.
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August 2021

Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases.

Front Genet 2021 28;12:707836. Epub 2021 Jul 28.

Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States.

Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study-a powerful regression method for generating hypotheses about new indications for an approved drug-with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, "go-no go" decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.
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http://dx.doi.org/10.3389/fgene.2021.707836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355705PMC
July 2021

Impact of molecular subtype and race on HR+, HER2- breast cancer survival.

Breast Cancer Res Treat 2021 Oct 31;189(3):845-852. Epub 2021 Jul 31.

Vanderbilt University Medical Center (VUMC)/Vanderbilt-Ingram Cancer Center (VICC), 2220 Pierce Ave. 777 PRB, Nashville, TN, 37232, USA.

Purpose: There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2- breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2- breast cancer by race.

Methods: Women with localized, HR+, HER2- breast cancer diagnosed between 2002 and 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2- breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates.

Results: In this study, 318 women with localized, HR+, HER2- breast cancer were included-227 Black (71%) and 91 NHW (29%). Young Black women (age ≤ 50) had the highest proportion of HR+, non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+, non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage, and income (HR 4.21 for Blacks, 95% CI 1.74-10.18 and HR 3.44 for NHW, 95% CI 1.31-9.03). Among HR+, non-luminal A subtypes there was, however, no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI 0.58-2.58).

Conclusion: Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2- breast cancer. Among women with HR+, HER2- breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype.
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http://dx.doi.org/10.1007/s10549-021-06342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511072PMC
October 2021

Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial.

NPJ Breast Cancer 2021 Jun 8;7(1):74. Epub 2021 Jun 8.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m (metformin) and 27.3 kg/m (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.
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http://dx.doi.org/10.1038/s41523-021-00275-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187713PMC
June 2021

Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131.

J Clin Oncol 2021 08 6;39(23):2539-2551. Epub 2021 Jun 6.

Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN.

Purpose: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine.

Patients And Methods: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine.

Results: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum.

Conclusion: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.
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http://dx.doi.org/10.1200/JCO.21.00976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577688PMC
August 2021

Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA.

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.

Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS.

Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8 T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8 T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8 T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors.

Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
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http://dx.doi.org/10.3390/ijms22105207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156389PMC
May 2021

Subjective cognition and mood in persistent chemotherapy-related cognitive impairment.

J Cancer Surviv 2021 May 11. Epub 2021 May 11.

Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, 1601 23rd Ave. South, Nashville, TN, 37212, USA.

Purpose: Persistent chemotherapy-related cognitive impairment (CRCI) is commonly reported following cancer treatment and negatively affects quality of life. While past research has focused on potential pathophysiological mechanisms underlying this relationship, the role of psychological factors, such as mood, stress, and anxiety, in the development of persistent CRCI has received less attention. As an additional analysis of data from a trial investigating the effects of transdermal nicotine patches on cognitive performance in patients with persistent CRCI, we examined whether change in mood was associated with changes in subjective and objective cognitive functioning.

Methods: Participants were randomized to either placebo (n = 11) or transdermal nicotine (n = 11) for 6 weeks, followed by 2 weeks of treatment withdrawal for a total of 8 weeks. Participants were assessed using behavioral, subjective, and objective measures of cognitive functioning and mood at five visits before, during, and after treatment.

Results: Although we did not detect an effect of treatment assignment on mood, over the course of the study, we observed a significant improvement on measures of mood that correlated with improvement in subjective and objective cognitive performance.

Conclusions: We observed improvement in objective and subjective cognitive performance measures. These changes were associated with improvement in subsyndromal mood symptoms, likely resulting from participation in the trial itself.

Implications For Cancer Survivors: These results suggest that women with persistent CRCI may benefit from support and validation of their cognitive complaints, cognitive rehabilitation/therapies into their post-cancer care.

Trial Registration: The study was registered with clinicaltrials.gov (trial registration: NCT02312943).
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http://dx.doi.org/10.1007/s11764-021-01055-1DOI Listing
May 2021

Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab.

Cancer Discov 2021 Oct 3;11(10):2474-2487. Epub 2021 May 3.

Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 () heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group ( < 0.0001, adjusted for hormone receptor status). Single-cell FISH analysis of cellular heterogeneity identified the fraction of nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. SIGNIFICANCE: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598376PMC
October 2021

Patient-Reported Outcomes in Patients With -Mutated Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From SOLAR-1.

J Clin Oncol 2021 06 29;39(18):2005-2015. Epub 2021 Mar 29.

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Purpose: In the phase III SOLAR-1 trial (NCT02437318), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ()-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients.

Materials And Methods: In the -mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively.

Results: Global Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], -3.50 [-8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [-4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (-3.77; 95% CI, -8.35 to 0.80; = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% 32%, week 24; = .090).

Conclusion: In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative -mutated advanced breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210974PMC
June 2021

Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis.

Cancer J 2021 Jan-Feb 01;27(1):2-7

Abstract: Triple-negative breast cancer (TNBC) is pathologically defined by lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 amplification and portends an aggressive clinical course with worse outcomes compared with other breast cancers. Until recently, standard treatment options consisted of sequential cytotoxic chemotherapies for both early and metastatic disease. Advances in sequencing technology have led to the identification of 4 main subtypes of TNBC based on recurrent genetic alterations, transcriptional patterns, and molecular features: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR). Frequent alterations found in DNA damage response pathways, germline and somatic BRCA1/2 genes, PI3K signaling pathways, and the presence of androgen receptors and infiltrating immune cells could serve as actionable targets to optimize treatments and improve outcomes for patients with TNBC. Recent approvals for immune checkpoint inhibitors and the antibody-drug conjugate, sacituzumab govitecan-hziy, for advanced TNBC illustrate the advances in treatment that can result from these molecular discoveries. This review will explore the molecular subtypes of TNBC and their distinct characteristics, as well as highlight the molecular features and potential "drivers" that have been identified as promising targets for new treatment strategies.
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http://dx.doi.org/10.1097/PPO.0000000000000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109153PMC
September 2021

Racial/Ethnic Disparities in All-Cause Mortality among Patients Diagnosed with Triple-Negative Breast Cancer.

Cancer Res 2021 02 3;81(4):1163-1170. Epub 2020 Dec 3.

Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

It is unclear whether racial/ethnic disparities in triple-negative breast cancer (TNBC) mortality remain after accounting for clinical characteristics, treatment, and access-to-care-related factors. In this study, women with a primary diagnosis of TNBC during 2010-2014 were identified from the National Cancer Database. Hazard ratios (HR) and 95% confidence intervals (CI) for 3- and 5-year all-cause mortality associated with race/ethnicity were estimated using Cox proportional hazards models with stepwise adjustments for age, clinical characteristics, treatment, and access-to-care-related factors. Of 78,708 patients, non-Hispanic (NH) black women had the lowest 3-year overall survival rates (79.4%), followed by NH-whites (83.1%), Hispanics (86.0%), and Asians (87.1%). After adjustment for clinical characteristics, NH-blacks had a 12% higher risk of dying 3 years post-diagnosis (HR, 1.12; 95% CI, 1.07-1.17), whereas Hispanics and Asians had a 24% (HR, 0.76; 95% CI, 0.70-0.83) and 17% (HR, 0.83; 95% CI, 0.73-0.94) lower risk than their NH-white counterparts. The black-white disparity became non-significant after combined adjustment for treatment and access-to-care-related factors (HR, 1.04; 95% CI, 0.99-1.09), whereas the white-Hispanic and white-Asian differences remained. Stratified analyses revealed that among women aged less than or equal to 50 with stage III cancer, the elevated risk among NH-blacks persisted (HR, 1.20; 95% CI, 1.04-1.39) after full adjustments. Similar results were seen for 5-year mortality. Overall, clinical characteristics, treatment, and access-to-care-related factors accounted for most of the white-black differences in all-cause mortality of TNBC but explained little about Hispanic- and Asian-white differences. SIGNIFICANCE: These findings highlight the need for equal healthcare to mitigate the black-white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3094DOI Listing
February 2021

Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial.

Clin Breast Cancer 2021 02 6;21(1):80-91.e7. Epub 2020 Oct 6.

Puma Biotechnology Inc., Los Angeles, CA.

Background: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2)/hormone receptor-positive (HR) early-stage breast cancer (eBC).

Patients And Methods: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2 eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR eBC who initiated treatment ≤ 1 year (HR/≤ 1-year) and > 1 year (HR/> 1-year) post-trastuzumab.

Results: HR/≤ 1-year and HR/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported.

Conclusion: Neratinib significantly improved iDFS in the HER2/HR/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.
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http://dx.doi.org/10.1016/j.clbc.2020.09.014DOI Listing
February 2021

At the Bedside: Profiling and treating patients with CXCR4-expressing cancers.

J Leukoc Biol 2021 05 22;109(5):953-967. Epub 2020 Oct 22.

Polyphor Ltd, Allschwil, Switzerland.

The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx-xx; 2020.
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http://dx.doi.org/10.1002/JLB.5BT1219-714RDOI Listing
May 2021

Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial.

Clin Infect Dis 2021 06;72(11):e835-e843

University of Minnesota, Minneapolis, Minnesota, USA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure.

Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19-compatible illness. We measured hydroxychloroquine whole-blood concentrations.

Results: We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44-1.16; P = .18) and for twice-weekly was .74 (95% CI, .46-1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19-compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08).

Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19-compatible illness among healthcare workers.

Clinical Trials Registration: Clinicaltrials.gov NCT04328467.
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http://dx.doi.org/10.1093/cid/ciaa1571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665393PMC
June 2021

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial.

medRxiv 2020 Sep 18. Epub 2020 Sep 18.

University of Minnesota, Minneapolis, Minnesota.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure.

Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations.

Results: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08).

Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.
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http://dx.doi.org/10.1101/2020.09.18.20197327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523161PMC
September 2020

Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial.

J Natl Cancer Inst 2021 04;113(4):390-399

Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment.

Methods: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided.

Results: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25.

Conclusions: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.
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http://dx.doi.org/10.1093/jnci/djaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599918PMC
April 2021

Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer.

Drugs 2020 Nov;80(16):1685-1697

Breast Cancer Program, Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232-6307, USA.

Approximately 70% of invasive breast cancers have some degree of dependence on the estrogen hormone for cell proliferation and growth. These tumors have estrogen and/or progesterone receptors (ER/PR+), generally referred to as hormone receptor positive (HR+) tumors, as indicated by the presence of positive staining and varying intensity levels of estrogen and/or progesterone receptors on immunohistochemistry. Therapies that inhibit ER signaling pathways, such as aromatase inhibitors (letrozole, anastrozole, exemestane), selective ER modulators (tamoxifen), and ER down-regulators (fulvestrant), are the mainstays of treatment for hormone-receptor-positive breast cancers. However, de novo or acquired resistance to ER targeted therapies is present in many tumors, leading to disease progression. The PI3K/AKT/mTOR pathway is implicated in sustaining endocrine resistance and has become the target of many new drugs for ER+ breast cancer. This article reviews the function of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and the various classes of PI3K pathway inhibitors that have been developed to disrupt this pathway signaling for the treatment of hormone-receptor-positive breast cancer.
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http://dx.doi.org/10.1007/s40265-020-01394-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572750PMC
November 2020

Radiotherapy after breast-conserving surgery for elderly patients with early-stage breast cancer: A national registry-based study.

Int J Cancer 2021 02 14;148(4):857-867. Epub 2020 Sep 14.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Considerable controversies exist regarding whether elderly patients with early-stage breast cancer receiving breast-conserving surgery (BCS) should forgo radiotherapy. We utilized the National Cancer Database to analyze data of 115 516 women aged ≥70 years, treated with BCS for T1-2N0-1M0 breast cancer between 2004 and 2014. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality 3, 5 and 10 years after 90 days of BCS associated with radiotherapy. Patients who received no radiotherapy had a higher mortality rate than those who received radiotherapy (5-year survival rate: 71.2% vs 83.8%), with multivariable-adjusted HRs of 1.65 (95% CI: 1.57-1.72) for 3-year mortality, 1.53 (1.47-1.58) for 5-year mortality and 1.43 (1.39-1.48) for 10-year mortality. The association held even for patients ≥90 years. This association was observed in all strata by reasons for radiotherapy omission, receipt of endocrine therapy or chemotherapy, calendar period and other clinical characteristics, with 40% to 65% increased 5-year mortality for patients without radiotherapy. This positive association persisted when analyses were restricted to patients with T1N0 and estrogen-receptor-positive disease who had received endocrine therapy (5-year mortality: HR 1.47 [1.39-1.57]) and in propensity score weighted analyses. Our study shows, in routine practice, elderly patients who received no post-BCS radiotherapy had higher total mortality than those who received radiotherapy. These findings suggest that the current recommendation of omission of post-BCS radiotherapy for elderly women with early-stage breast cancer may need to be reconsidered, particularly for those without contraindication.
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http://dx.doi.org/10.1002/ijc.33265DOI Listing
February 2021

Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer.

Clin Cancer Res 2020 11 21;26(21):5668-5681. Epub 2020 Aug 21.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Purpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).

Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1) CD8 peripheral T cells and examination of a cytolytic gene signature in whole blood.

Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.

Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642197PMC
November 2020

Correlative studies investigating effects of PI3K inhibition on peripheral leukocytes in metastatic breast cancer: potential implications for immunotherapy.

Breast Cancer Res Treat 2020 Nov 7;184(2):357-364. Epub 2020 Aug 7.

Department of Veteran Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

Purpose: Patients with localized breast cancer have a 5-year survival rate > 99% compared to patients with metastatic breast cancer (MBC) that have a 5-year survival rate of ~ 27%. Unregulated PI3K/AKT signaling is a common characteristic of MBC, making it a desirable therapeutic target for tumors with activating mutations in this pathway. Interestingly, inhibition of the PI3K/AKT pathway can affect signaling in immune cells, which could potentially alter the immune phenotype of patients undergoing therapy with these drugs. The purpose of this study is to evaluate how PI3K inhibition affects the immune cells of MBC patients during treatment.

Methods: We investigated the effects of PI3K inhibition on the immune cell populations in peripheral blood of MBC patients enrolled in 4 different clinical trials utilizing PI3K inhibitors. Peripheral blood was drawn at different points in patient treatment cycles to record immune cell fluctuations in response to therapy.

Results: MBC patients who responded to treatment with a positive fold-change in cytotoxic T cell population, had an average duration of treatment response of 31.4 months. In contrast, MBC patients who responded to treatment with a negative fold-change in cytotoxic T-cell population, had an average duration of therapeutic response of 5 months. These data suggest that patients with a more robust, initial anti-tumor T cell response may have a longer therapeutic response compared to patients who do not have a robust, initial anti-tumor T cell response.

Conclusions: These results highlight the potential for PI3K inhibition to sensitize tumors to immune checkpoint inhibitors, thus providing additional therapeutic options for patients with MBC.
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http://dx.doi.org/10.1007/s10549-020-05846-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606736PMC
November 2020

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with -Mutant, ER-Positive Metastatic Breast Cancer.

Clin Cancer Res 2020 08 20;26(15):3947-3957. Epub 2020 Apr 20.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: The activating mutation occurs in approximately 7% of estrogen receptor-positive (ER) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with -mutant ER MBC.

Patients And Methods: Patients with an mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR). Biomarker analyses were conducted in the combination cohort.

Results: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].

Conclusions: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with -mutant ER MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415507PMC
August 2020

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.

PLoS One 2020 16;15(4):e0231711. Epub 2020 Apr 16.

Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies and Research, Meharry Medical College, Nashville, Tennessee, United States of America.

Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of breast cancer tissues revealed that compared to non-TNBC tumors, TNBC tumors express lower levels of AnxA6 and higher Ki67 expression. GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with residual tumor size following chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and GRF2 can delineate GRF2-low/AnxA6-high invasive from GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable biomarker for distant relapse-free survival and response of TNBC patients to chemotherapy, and that the reciprocal expression of AnxA6 and GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162501PMC
August 2020

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 04;18(4):452-478

O'Neal Comprehensive Cancer Center at UAB.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2020.0016DOI Listing
April 2020

Combining Adjuvant Radiotherapy With Capecitabine in Chemotherapy-resistant Breast Cancer: Feasibility, Safety, and Toxicity.

Clin Breast Cancer 2020 08 6;20(4):344-352.e1. Epub 2020 Mar 6.

Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Background: In a randomized trial (CREATE-X), patients with residual disease after standard neoadjuvant chemotherapy had improved survival with the addition of adjuvant capecitabine. For patients who required radiotherapy (RT), capecitabine was given sequentially. Concurrent capecitabine-RT might be more efficacious. We hypothesized that the safety, feasibility, and toxicity of adjuvant capecitabine-RT would not be significantly different compared with adjuvant RT alone.

Patient And Methods: We retrospectively studied the data from patients with stage I-III invasive mammary carcinoma. Patients who had received capecitabine-RT were matched 1:3 with control patients who had received RT alone. Logistic regression analysis was used to evaluate the predictors of radiation dermatitis.

Results: A total of 64 patients were enrolled, including 16 who had received capecitabine-RT and 48 who had received RT alone. The cohorts were balanced regarding the clinicopathologic factors. No treatment in either cohort resulted in hospitalization, short-term disability, or fatality. Most toxicities of capecitabine-RT were related to radiation dermatitis. Radiation dermatitis was not significantly different between the capecitabine-RT and RT cohort at either grade 2 (odds ratio [OR], 1.36; 95% confidence interval [CI], 0.38-4.93; P = .63) or grade 3 (OR, 3.00; 95% CI, 0.85-10.63; P = .09) or after multivariable analysis. However, the capecitabine-RT group was more likely to require modifications in the RT schedule, including treatment breaks or cancelled fractions (44% vs. 17%; OR, 3.89; 95% CI, 1.12-13.52; P = .03).

Conclusion: Capecitabine-RT appears to be safe in the adjuvant treatment of breast cancer with comparable toxicity to RT alone. It might require more treatment adjustments. Prospective studies are needed to evaluate the safety and tolerability of this combination.
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http://dx.doi.org/10.1016/j.clbc.2020.02.010DOI Listing
August 2020

Disparities in BRCA counseling across providers in a diverse population of young breast cancer survivors.

Genet Med 2020 06 18;22(6):1088-1093. Epub 2020 Feb 18.

Vanderbilt University Medical Center, Nashville, TN, USA.

Purpose: All women diagnosed with breast cancer (BC) ≤age 50 should be referred for genetic counseling (GC) and testing. We sought to compare differences in provider practices and access across a racially and ethnically diverse population of young BC survivors.

Methods: A registry-based sample of women diagnosed with invasive BC ≤age 50 from 2009 to 2012 was recruited through the Florida Cancer Registry, and completed a questionnaire and medical record release. Differences were compared across those tested with or without the involvement of a board-certified or credentialed genetics health professional (GHP) in (1) clinical and demographic variables and (2) pretest GC elements.

Results: Of 1622 participants, there were 440 Blacks, 285 Hispanics, and 897 Non-Hispanic Whites. Of 831 participants with medical record verification of testing provider, 170 (20%) had documentation of GHP involvement. Among the 613 who recalled a pretest discussion and had GC elements collected, those with GHP involvement were significantly more likely to recall the seven recognized GC elements.

Conclusion: GHP involvement was associated with adherence to nationally recommended best practices. With the expanding importance of identifying inherited cancers, it is critical to ensure equitable access to best practices across all populations.
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http://dx.doi.org/10.1038/s41436-020-0762-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275890PMC
June 2020

Efficacy and Determinants of Response to HER Kinase Inhibition in -Mutant Metastatic Breast Cancer.

Cancer Discov 2020 02 5;10(2):198-213. Epub 2019 Dec 5.

Memorial Sloan Kettering Cancer Center, New York, New York.

mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with -mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating or alterations were associated with poor treatment outcome. Similarly, acquisition of multiple -activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both and acquired resistance to neratinib. SIGNIFICANCE: mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007377PMC
February 2020

Sex Disparity Observed for Oncotype DX Breast Recurrence Score in Predicting Mortality Among Patients with Early Stage ER-Positive Breast Cancer.

Clin Cancer Res 2020 01 20;26(1):101-109. Epub 2019 Nov 20.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Purpose: Prognostic value of Oncotype DX Breast Recurrence Score (RS) in male patients with breast cancer is understudied. We evaluated associations of RS with overall mortality in male patients with breast cancer and compared it with female counterparts.

Experimental Design: With a cohort of 848 male and 110,898 female patients with breast cancer identified from the National Cancer Database (2010-2014), we estimated HRs and 95% confidence intervals (CI) for overall mortality associated with RS using Cox regression models. RS was evaluated continuously, as well as by categorization following respective traditional (≤17, 18-30, and ≥31) and TAILORx (≤10, 11-25, and ≥26) cutoffs.

Results: RS was positively associated with mortality in male patients (HR = 1.13; 95% CI, 1.02-1.26 per unit RS increment) up to RS > 21, after which the risk plateaued. Among female patients, mortality began to increase with RS only when RS > 23 (HR = 1.02; 95% CI, 1.01-1.02 per unit of RS increment). The intermediate- (HR = 5.37; 95% CI, 1.79-16.11) and high-risk diseases (HR = 4.28; 95% CI, 1.22-14.97) defined by TAILORx, but not traditional cutoffs established for female patients, were associated with elevated mortality risk in men even after adjustment for demographic, clinical characteristics, and treatments, except chemotherapy.

Conclusions: RS is associated with mortality in male patients with breast cancer at a much lower threshold than that for female patients. Studies are needed to establish specific guidelines for RS thresholds for male patients with breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380510PMC
January 2020
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