Publications by authors named "Andres Forero"

86 Publications

Less Toxic Chemotherapy in Locally Advanced Breast Cancer.

South Med J 2020 11;113(11):559-563

From the Division of Hematology/Oncology, the Department of Radiation Oncology, the Department of Surgery, the Division of Preventive Medicine, and the UAB Comprehensive Cancer, University of Alabama at Birmingham, Birmingham.

Objectives: Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab.

Methods: Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m, paclitaxel 175 mg/m, and cyclophosphamide 600 mg/m, with concurrent bevacizumab every 2 weeks without growth factor support.

Results: Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive.

Conclusions: The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.
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http://dx.doi.org/10.14423/SMJ.0000000000001169DOI Listing
November 2020

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

Breast Cancer Res Treat 2020 Jun 6;181(3):623-633. Epub 2020 May 6.

The University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA.

Purpose: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool.

Methods: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint.

Results: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10), representing a previously unidentified mechanism for HFS.

Conclusions: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.
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http://dx.doi.org/10.1007/s10549-020-05603-8DOI Listing
June 2020

Histone deacetylase inhibition promotes intratumoral CD8 T-cell responses, sensitizing murine breast tumors to anti-PD1.

Cancer Immunol Immunother 2019 Dec 12;68(12):2081-2094. Epub 2019 Nov 12.

Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1720 2nd AVE S, Birmingham, AL, 35294, USA.

Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8 T cells and IFNγ. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8 T cells and by sensitizing tumor cells to T-cell recognition.
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http://dx.doi.org/10.1007/s00262-019-02430-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879872PMC
December 2019

TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer.

Clin Cancer Res 2020 02 29;26(4):821-827. Epub 2019 Oct 29.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR.

Patients And Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR.

Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1-2 diarrhea and acneiform rash being the most common toxicities.

Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0851DOI Listing
February 2020

Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer.

JAMA Oncol 2019 Jun 13. Epub 2019 Jun 13.

Department of Medical Oncology, Stanford University School of Medicine, Stanford, California.

Importance: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC).

Objective: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC.

Design, Setting, And Participants: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019.

Interventions: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.

Main Outcomes And Measures: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival.

Results: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected.

Conclusions And Relevance: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT02657889.
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http://dx.doi.org/10.1001/jamaoncol.2019.1029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567845PMC
June 2019

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade.

J Natl Cancer Inst 2020 01;112(1):46-54

Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.

Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.

Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).

Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
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http://dx.doi.org/10.1093/jnci/djz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850037PMC
January 2020

Visualization of Sequential Treatments in Metastatic Breast Cancer.

JCO Clin Cancer Inform 2019 03;3:1-8

University of Alabama at Birmingham, Birmingham, AL.

Purpose: Treatment sequencing of metastatic breast cancer (MBC) is heterogeneous. The primary objective of this study was to develop a visualization technique to understand population-level treatment sequencing for MBC. Secondary outcomes were to describe the heterogeneity of MBC treatment sequencing, as measured by the proportion of patients with a rare sequence, and to generate hypotheses about the impact of sequencing on overall survival.

Methods: This retrospective review evaluated treatment sequencing for patients with MBC in the SEER-Medicare database. Patients with either de novo MBC or International Classification of Diseases, Ninth Revision, diagnosis codes for secondary metastasis (197.XX-198.XX) on two separate dates, excluding breast (198.81, 198.82, 198.2) and lymph nodes (196.XX), were included. Complete Medicare Parts A, B, and D coverage was required. A treatment sequence that fewer than 11 patients received was considered rare. A graphic was created with each nonrare treatment-sequence grouping on the y-axis and time on the x-axis. Bars representing time on hormonal therapy, chemotherapy, human epidermal growth factor receptor 2-targeted therapy, and other targeted therapies were color coded. Kaplan-Meier-like curves were overlaid on treatment maps, using estimated median survival for each sequence.

Results: Of 6,639 patients with MBC, 56% received a treatment sequence that fewer than 11 other patients received, with 2,985 other unique, rare sequences were identified. Sequence visualization demonstrated differential survival, with longer median survival for those initially receiving hormonal therapy. The median time receiving initial treatment was similar for patients receiving first-line chemotherapy.

Conclusion: Treatment-sequence visualization can enhance the capacity to effectively conceptualize treatment patterns and patient outcomes.
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http://dx.doi.org/10.1200/CCI.18.00095DOI Listing
March 2019

The antitumor effects of entinostat in ovarian cancer require adaptive immunity.

Cancer 2018 12 13;124(24):4657-4666. Epub 2018 Nov 13.

Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. In the current study, they evaluated whether entinostat treatment and resultant MHCII expression would enhance beneficial immune responses and impair tumor growth in mice with ovarian cancer.

Methods: C57BL/6 mice bearing intraperitoneal ID8 tumors were randomized to receive entinostat 20 mg/kg daily versus control. Changes in messenger RNA (mRNA) expression of 46 genes important for antitumor immunity were evaluated using NanoString analysis, and multicolor flow cytometry was used to measure changes in protein expression and tumor-infiltrating immune cells.

Results: Entinostat treatment decreased the growth of both subcutaneously and omental ID8 tumors and prolonged survival in immunocompetent C57BL/6 mice. NanoString analysis revealed significant changes in mRNA expression in 21 of 46 genes, including increased expression of the MHCI pathway, the MHCII transactivator (CIITA), interferon γ, and granzyme B. C57BL/6 mice that received entinostat had increased MHCII expression on omental tumor cells and a higher frequency of tumor-infiltrating, CD8-positive T cells by flow cytometry. In immunocompromised mice, treatment with entinostat had no effect on tumor size and did not increase MHCII expression.

Conclusions: In the current murine ovarian cancer model, entinostat treatment enhances beneficial immune responses. Moreover, these antitumor effects of entinostat are dependent on an intact immune system. Future studies combining entinostat with checkpoint inhibitors or other immunomodulatory agents may achieve more durable antitumor responses in patients with ovarian cancer.
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http://dx.doi.org/10.1002/cncr.31761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294677PMC
December 2018

CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma.

N Engl J Med 2018 Nov;379(18):1711-1721

From Stanford University, Stanford (R.A., T.T., R.M., I.L.W.), City of Hope, Duarte (L.P.), and Forty Seven, Menlo Park (J.L., J.Y.C., J.-P.V., B.A., J.H., R.M., I.L.W., C.H.T., M.P.C.) - all in California; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.F.); University of Alabama at Birmingham, Birmingham (A.F.); Washington University in St. Louis, St. Louis (N.L.B.); Levine Cancer Institute-Atrium Health, Charlotte, NC (N.G.); University of Chicago, Chicago (J.K., S.M.S.); National Cancer Institute, Rockville, MD (M.R.); Dana-Farber Cancer Institute, Boston (A.L.); and University of Oxford, Oxford, United Kingdom (G.P.C.).

Background: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.

Methods: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.

Results: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.

Conclusions: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).
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http://dx.doi.org/10.1056/NEJMoa1807315DOI Listing
November 2018

The expression of MHC class II molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth.

Cancer Immunol Immunother 2019 Feb 17;68(2):175-188. Epub 2018 Oct 17.

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 1720 2nd AVE S, SHEL 507, Birmingham, AL, 35294, USA.

The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4 and CD8 T cells. In addition, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8 T cells in tumors depended on CD4 T cells. However, both CD4 and CD8 T cells eventually became exhausted, even in MHCII-expressing tumors. Treatment with anti-CTLA4, but not anti-PD-1 or anti-TIM-3, promoted complete eradication of MHCII-expressing tumors. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4 T cells, indirectly helps the activation and expansion of CD8 T cells, and, in combination with the appropriate checkpoint inhibitor, promotes tumor regression.
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http://dx.doi.org/10.1007/s00262-018-2262-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504180PMC
February 2019

Concordance with NCCN treatment guidelines: Relations with health care utilization, cost, and mortality in breast cancer patients with secondary metastasis.

Cancer 2018 11 14;124(21):4231-4240. Epub 2018 Oct 14.

Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.

Background: The impact of National Comprehensive Cancer Network (NCCN) treatment guideline concordance on costs, health care utilization, and mortality for patients with breast cancer and secondary metastases is unknown.

Methods: From 2007 to 2013, women with early-stage breast cancer who received treatment for secondary metastases (n = 5651) were evaluated for first recorded systemic therapy concordance with NCCN guidelines within the Surveillance, Epidemiology, and End Results Program-Medicare linked database. Generalized linear and mixed effects models evaluated factors associated with nonconcordance and the relation between concordance status and health care utilization and costs. Mortality risk was estimated with Cox regression.

Results: Eighteen percent of the patients received nonconcordant therapy, with the most common being single-agent, human epidermal growth factor receptor 2 (HER2)-targeted therapy (36%), therapy mismatched with the estrogen receptor/HER2 status (11%), unapproved bevacizumab regimens (10%), and adjuvant regimens in a metastatic setting (6%). A younger age, a hormone receptor-negative status, and a HER2-positive status were associated with nonconcordance (P < .05). Nonconcordance was associated with 22% and 21% increased rates of emergency department visits and hospitalizations, respectively, and $1765 higher average monthly Medicare costs. Differences in adjusted mortality risk were noted by the category of nonconcordance; single-agent, HER2-targeted therapy was associated with decreased mortality risk (hazard ratio [HR], 0.66; 95% confidence limit [CL], 0.57-0.76), and increased mortality risk was observed with unapproved bevacizumab use (HR, 1.40; 95% CL, 1.13-1.74).

Conclusions: Most patients (82%) received treatment consistent with NCCN guidelines. Nonconcordant treatment was associated with higher health care utilization and costs, with mortality differences observed by the type of guideline deviation. Consideration of both patient and financial outcomes will be important as health systems increase the emphasis on guideline-based care.
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http://dx.doi.org/10.1002/cncr.31694DOI Listing
November 2018

Impact of Nonconcordance With NCCN Guidelines on Resource Utilization, Cost, and Mortality in De Novo Metastatic Breast Cancer.

J Natl Compr Canc Netw 2018 09;16(9):1084-1091

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) have directed the care of patients with cancer for >20 years. Payers are implementing guideline-based pathway programs that restrict reimbursement for non-guideline-based care to control costs, yet evidence regarding impact of guidelines on outcomes, including mortality, Medicare costs, and healthcare utilization, is limited. This analysis evaluated concordance of first treatment with NCCN Guidelines for women with de novo stage IV metastatic breast cancer (MBC) included within the SEER-Medicare linked database and diagnosed between 2007 and 2013. Cox proportional hazards models were used to evaluate the association between mortality and guideline concordance. Linear mixed-effects and generalized linear models were used to evaluate total cost to Medicare and rates of healthcare utilization by concordance status. : We found that 19% of patients (188/988) with de novo MBC received nonconcordant treatment. Patients receiving nonconcordant treatment were more likely to be younger and have hormone receptor-negative and HER2-positive MBC. The most common category of nonconcordant treatment was use of adjuvant regimens in the metastatic setting (40%). Adjusted mortality risk was similar for patients receiving concordant and nonconcordant treatments (hazard ratio [HR], 0.85; 95% confidence limit [CL], 0.69, 1.05). When considering category of nonconcordance, patients receiving adjuvant regimens in the metastatic setting had a decreased risk of mortality (HR, 0.60; 95% CL, 0.43, 0.84). Nonconcordant treatments were associated with $1,867 higher average Medicare costs per month compared with concordant treatments (95% CL, $918, $2,817). Single-agent HER2-targeted therapy was the highest costing category of nonconcordance at $3,008 (95% CL, $1,014, $5,001). Healthcare utilization rates were similar for patients receiving concordant and nonconcordant treatments. : Despite a lack of survival benefit, concordant care was associated with lower costs, suggesting potential benefit to increasing standardization of care. These findings may influence policy decisions regarding implementation of pathway programs as health systems transition to value-based models.
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http://dx.doi.org/10.6004/jnccn.2018.7036DOI Listing
September 2018

Impact of Guideline-Discordant Treatment on Cost and Health Care Utilization in Older Adults with Early-Stage Breast Cancer.

Oncologist 2019 01 17;24(1):31-37. Epub 2018 Aug 17.

Divisions of Hematology & Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: National Comprehensive Cancer Network (NCCN) guideline-based treatment is a marker of high-quality care. The impact of guideline discordance on cost and health care utilization is unclear.

Materials And Methods: This retrospective cohort study of Medicare claims data from 2012 to 2015 included women age ≥65 with stage I-III breast cancer receiving care within the University of Alabama at Birmingham Cancer Community Network. Concordance with NCCN guidelines was assessed for treatment regimens. Costs to Medicare and health care utilization were identified from start of cancer treatment until death or available follow-up. Adjusted monthly cost and utilization rates were estimated using linear mixed effect and generalized linear models.

Results: Of 1,177 patients, 16% received guideline-discordant treatment, which was associated with nonwhite race, estrogen receptor/progesterone receptor negative, human epidermal growth receptor 2 (HER2) positive, and later-stage cancer. Discordant therapy was primarily related to reduced-intensity treatments (single-agent chemotherapy, HER2-targeted therapy without chemotherapy, bevacizumab without chemotherapy, platinum combinations without anthracyclines). In adjusted models, average monthly costs for guideline-discordant patients were $936 higher compared with concordant (95% confidence limits $611, $1,260). For guideline-discordant patients, adjusted rates of emergency department visits and hospitalizations per thousand observations were 25% higher (49.9 vs. 39.9) and 19% higher (24.0 vs. 20.1) per month than concordant patients, respectively.

Conclusion: One in six patients with early-stage breast cancer received guideline-discordant care, predominantly related to undertreatment, which was associated with higher costs and rates of health care utilization. Additional randomized trials are needed to test lower-toxicity regimens and guide clinicians in treatment for older breast cancer patients.

Implications For Practice: Previous studies lack details about types of deviations from chemotherapy guidelines that occur in older early-stage breast cancer patients. Understanding the patterns of guideline discordance and its impact on patient outcomes will be particularly important for these patients. This study found 16% received guideline-discordant care, predominantly related to reduced intensity treatment and associated with higher costs and rates of health care utilization. Increasing older adult participation in clinical trials should be a priority in order to fill the knowledge gap about how to treat older, less fit patients with breast cancer.
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http://dx.doi.org/10.1634/theoncologist.2018-0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324646PMC
January 2019

Trastuzumab-Resistant HER2 Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition.

Mol Cancer Ther 2018 05 28;17(5):921-930. Epub 2018 Mar 28.

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)-deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2 trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival and tumor growth of HER2 TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-κB-regulated genes. In particular, silencing PARP-1 inhibited NF-κB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2 breast cancer cells and support the testing of PARPi in patients with HER2 breast cancer resistant to trastuzumab. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932278PMC
May 2018

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 Mar;16(3):310-320

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
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http://dx.doi.org/10.6004/jnccn.2018.0012DOI Listing
March 2018

NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018.

J Natl Compr Canc Netw 2018 Mar;16(3):245-254

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.
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http://dx.doi.org/10.6004/jnccn.2018.0013DOI Listing
March 2018

Modulation of antitumor immunity with histone deacetylase inhibitors.

Immunotherapy 2017 12;9(16):1359-1372

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA, 35233.

Histone deacetylase inhibitors possess a broad array of antitumor activities; however, their net impact on the evolving antitumor immune response is highly dependent on the inhibitors used and the histone deacetylases they target. Herein, we sequentially focus on each stage of the antitumor immune response - from dendritic cell activation and migration, antigen uptake and presentation, T-cell activation and differentiation and the enactment of antitumor effector functions within the tumor microenvironment. In particular, we will discuss how various inhibitors have different effects depending on cellular activation, experimental design and specific histone deacetylases being targeted - and how these changes impact the outcome of an antitumor immune response. At last, we consider the impact these inhibitors may have on T-cell exhaustion and implications for combination with other immunomodulating therapies.
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http://dx.doi.org/10.2217/imt-2017-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077764PMC
December 2017

Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib.

Breast Cancer Res 2017 Nov 21;19(1):123. Epub 2017 Nov 21.

Division of Oncology, Section of Medical Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.

Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).

Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.

Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement.

Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.

Trial Registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.
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http://dx.doi.org/10.1186/s13058-017-0913-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699111PMC
November 2017

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.

Breast Cancer Res Treat 2018 02 7;167(3):731-740. Epub 2017 Nov 7.

Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.

Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.

Patients And Methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).

Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).

Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
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http://dx.doi.org/10.1007/s10549-017-4533-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821069PMC
February 2018

Neratinib Efficacy and Circulating Tumor DNA Detection of Mutations in Nonamplified Metastatic Breast Cancer.

Clin Cancer Res 2017 Oct 5;23(19):5687-5695. Epub 2017 Jul 5.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) detection. Tumor tissue positive for was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor ). Nine of 381 tumors (2.4%) sequenced centrally harbored (lobular 7.8% vs. ductal 1.6%; = 0.026). Thirteen additional cases were identified locally. Twenty-one of these 22 cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Neratinib is active in , nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with cancers for clinical trial participation. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746403PMC
October 2017

Physical Activity and Sleep Quality in Breast Cancer Survivors: A Randomized Trial.

Med Sci Sports Exerc 2017 Oct;49(10):2009-2015

1Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL; 2Faculty of Physical Education and Recreation, University of Alberta, Edmonton, Alberta, CANADA; 3Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; 4Department of Kinesiology, Southern Illinois University Carbondale, Carbondale, IL; 5Statistics and Research Informatics Core, Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL; and 6Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL.

Purpose: Data from large randomized controlled trials confirming sleep quality improvements with aerobic physical activity have heretofore been lacking for post-primary treatment breast cancer survivors. Our primary purpose for this report was to determine the effects of a physical activity behavior change intervention, previously reported to significantly increase physical activity behavior, on sleep quality in post-primary treatment breast cancer survivors.

Methods: Post-primary treatment breast cancer survivors (n = 222) were randomized to a 3-month physical activity behavior change intervention (Better Exercise Adherence after Treatment for Cancer [BEAT Cancer]) or usual care. Self-report (Pittsburgh Sleep Quality Index [PSQI]) and actigraphy (latency and efficiency) sleep outcomes were measured at baseline, 3 months (M3), and 6 months (M6).

Results: After adjusting for covariates, BEAT Cancer significantly improved PSQI global sleep quality when compared with usual care at M3 (mean between-group difference [M] = -1.4, 95% confidence interval [CI] = -2.1 to -0.7, P < 0.001) and M6 (M = -1.0, 95% CI = -1.7 to -0.2, P = 0.01). BEAT Cancer improved several PSQI subscales at M3 (sleep quality M = -0.3, 95% CI = -0.4 to -0.1, P = 0.002; sleep disturbances M = -0.2, 95% CI = -0.3 to -0.03, P = 0.016; daytime dysfunction M = -0.2, 95% CI = -0.4 to -0.02, P = 0.027) but not M6. A nonsignificant increase in percent of participants classified as good sleepers occurred. No significant between-group difference was noted for accelerometer latency or efficiency.

Conclusion: A physical activity intervention significantly reduced perceived global sleep dysfunction at 3 and 6 months, primarily because of improvements in sleep quality aspects not detected with accelerometer.
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http://dx.doi.org/10.1249/MSS.0000000000001327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600650PMC
October 2017

Epigenetic modifiers upregulate MHC II and impede ovarian cancer tumor growth.

Oncotarget 2017 Jul;8(27):44159-44170

Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA.

Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators - histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry. Treatment with entinostat and azacytidine of ID8 cells in vitro increased mRNA levels of Cd74, Ciita, and H2-Aa, H2-Eb1. MHC II and CD74 protein expression were increased after treatment with either agent. A dose dependent response in mRNA and protein expression was seen with entinostat. Combination treatment showed higher MHC II protein expression than with single agent treatment. In patient derived xenografts, CIITA, CD74, and MHC II mRNA transcripts were significantly increased after combination treatment. Expression of MHC II on ovarian tumors in MISIIR-Tag mice was increased with both agents relative to control. Combination treatment significantly reduced ID8 tumor growth in immune-competent mice. Epigenetic treatment increases expression of MHC II on ovarian cancer cells and impedes tumor growth. This approach warrants further study in ovarian cancer patients.
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http://dx.doi.org/10.18632/oncotarget.17395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546470PMC
July 2017

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 05;15(5):608-638

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.
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http://dx.doi.org/10.6004/jnccn.2017.0064DOI Listing
May 2017

NCCN Guidelines Insights: Breast Cancer, Version 1.2017.

J Natl Compr Canc Netw 2017 04;15(4):433-451

National Comprehensive Cancer Network

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.
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http://dx.doi.org/10.6004/jnccn.2017.0044DOI Listing
April 2017

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.

Clin Cancer Res 2017 Aug 7;23(15):4055-4065. Epub 2017 Mar 7.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Eligible patients with clinical stage II/III ER/HER2 breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-3206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555232PMC
August 2017

First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors.

Invest New Drugs 2017 06 3;35(3):298-306. Epub 2017 Jan 3.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety. Results Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects. Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.
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http://dx.doi.org/10.1007/s10637-016-0420-1DOI Listing
June 2017

The landscape of new drugs in lymphoma.

Nat Rev Clin Oncol 2017 Jun 29;14(6):335-346. Epub 2016 Dec 29.

UNMC Oncology/Haematology Division, 987680 Nebraska Medical Center, Omaha, Nebraska 681980-7680, USA.

The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.
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http://dx.doi.org/10.1038/nrclinonc.2016.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611863PMC
June 2017

Genomic regulation of invasion by STAT3 in triple negative breast cancer.

Oncotarget 2017 Jan;8(5):8226-8238

HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.

Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as "triple negative breast cancer" (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 5 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.
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http://dx.doi.org/10.18632/oncotarget.14153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352396PMC
January 2017

Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody.

Clin Cancer Res 2017 Jun 13;23(12):2942-2950. Epub 2016 Dec 13.

The Wistar Institute, Philadelphia, Pennsylvania.

Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs. The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated. The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies. Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468499PMC
June 2017