bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal function after treatment for childhood cancer: A report from the St. Jude Lifetime Cohort Study.
Authors: Green Daniel M. , Wang Mingjuan , Krasin Matthew J. , Srivastava Deokumar , Howell Carrie R. , Jay Dennis W. , Ness Kirsten K. , Greene William , Lanctot Jennifer Q. , Shelton Kyla C. , Davidoff Andrew M. , Ehrhardt Matthew J. , Mulrooney Daniel A. , Robison Leslie L. , Hudson Melissa M.
Published: May 2019

10048

Background: We assessed renal function in a large, clinically assessed cohort of childhood cancer survivors. Methods: Creatinine and qualitative urine protein was measured in 2753 survivors (>10 years (years) post-diagnosis, age ≥18 years). Renal function was graded per the Kidney Disease International Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). Multivariable logistic regression was used to estimate associations between demographics, treatment exposures, and CKD (grades 1-5 and 3-5). Radiation treatment was expressed as percentage of total kidney volume treated with 5 (V5), 10 (V10), 15 (V15) and 20 (V20) Gray. Results: Among 2753 survivors, 48.7% were female and 82.5% non-Hispanic white. Median age at diagnosis - 7.3 years (interquartile range [IQR]=3.3-13.2), median age at evaluation - 31.4 years (IQR=25.8-37.8), and median time from diagnosis to evaluation - 23.2 years (IQR=17.6-29.7). Prevalence of grades 1-5 and 3-5 CKD was 7.4% and 2.1%, respectively (grade 1=113, grade 2=30, grade 3=44, grade 4=5, and grade 5=8). Individual and cumulative aminoglycoside doses and treatment with high-dose methotrexate were not associated with CKD (data not shown). Cumulative number of doses of ambisome/abelcet and of amphotericin B were significant risk factors for grades 1-5 and grades 3-5 CKD in models for V15 and V20 (data not shown). The multivariable results for V10 are shown in the Table. Conclusions: In addition to nephrotoxic antineoplastic and supportive care therapy, race, ethnicity, and body composition contribute to risk of CKD in long-term survivors. These novel results inform late effects reduction strategies for future treatment protocols and identify survivors at highest risk for CKD. [Table: see text]
Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Veiga Lene H. S. , Curtis Rochelle E. , Morton Lindsay M. , Withrow Diana , Howell Rebecca M. , Smith Susan A , Weathers Rita , Oeffinger Kevin C. , Moskowitz Chaya S. , Henderson Tara O. , Arnold Michael A. , Gibson Todd M. , Leisenring Wendy , Neglia Joseph Philip , Turcotte Lucie Marie , Whitton John , Robison Leslie L. , Inskip Peter , Armstrong Gregory T. , Berrington de González Amy
Published: May 2019

10053

Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p < 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend < 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- < 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.
Long-term health status of high-risk neuroblastoma survivors treated with high-dose chemotherapy and hematopoietic stem cell transplantation.
Authors: Haghiri Sandrine , Fayech Chiraz , Dufour Christelle , Pasqualini Claudia , Bolle Stephanie , Boumaraf Amel , Belhout Amel , Journy Neige , Souchard Vincent , Vu-Bezin Giao , Veres Cristina , Haddy Nadia , De Vathaire Florent , Valteau-Couanet Dominique , Fresneau Brice
Published: May 2019

10054

Background: Current treatment strategies including high-dose chemotherapy with stem cell transplantation rescue (HDC-SCT) have improved 5-year event-free survival for high-risk neuroblastoma (HRNB) patients, but with an increased risk of late treatment-related toxicities. Methods: Between 1980 and 2012, 439 children were treated for HRNB with HDC-SCT in Gustave Roussy (GR), among which 145 were alive and disease-free at 5-year post-SCT. Long-term health data have been collected for those 145 patients, prospectively within the long-term follow-up clinic in GR or retrospectively from pediatric consultations. Results: With a median follow-up post-SCT of 15 years (range 5-34), we observed 6 late relapses, 11 second cancers (including 3 papillary thyroid carcinomas; median delay = 20 years post-SCT [18-22]) and 9 deaths. Event-free and overall survival at 20-year post-SCT were 82% (95%CI = 70–90) and 89% (95%CI = 78–95), respectively. A second health event was observed in 135 patients (median = 3/patient), including 103 patients with at least 1 severe event (median = 1/patient). Cumulative incidence at 15-year post-SCT for second cancers is 4%, cardiac diseases 8%, thyroid 11%, renal 7%, hepatic focal nodular hyperplasia 14%, dental mal-development 70%, and severe hearing loss 20%. Height-for-age z-score was ≤-2 for 30 patients (21%) and ≤-3 for 12 patients (8%). After Busulfan-Melphalan conditioning regimen, 40/43 females and 33/35 males had a gonadal insufficiency. Conclusions: Long-term consequences of HRNB treatment including HDC are frequent and disabling, mainly due to hearing loss and gonadal insufficiency.
Cardiac events in survivors of childhood cancer treated in more recent eras: A report from the Childhood Cancer Survivor Study.
Authors: Mulrooney Daniel A. , Hyun Geehong , Ness Kirsten K. , Ehrhardt Matthew J. , Yasui Yutaka , Duprez Daniel , Howell Rebecca M. , Leisenring Wendy , Constine Louis S. , Oeffinger Kevin C. , Gibson Todd M. , Tonorezos Emily S. , Robison Leslie L. , Hudson Melissa M. , Armstrong Gregory T.
Published: May 2019

10058

Background: Contemporary cancer protocols have incorporated modifications to minimize cardiotoxic exposures and preserve long-term health. We investigated the impact of these changes on late cardiac outcomes in a large cohort of adult survivors of childhood cancer. Methods: Congestive heart failure (CHF), myocardial infarction (MI), valvular disease, pericardial disease, and arrhythmias were graded by the National Cancer Institute’s Common Terminology Criteria for Adverse Events among 23,462 five-year cancer survivors [6,193 (26%) treated in the 1970s, 9,363 (40%) in the 1980s, and 7,906 (34%) in the 1990s] and 5,057 siblings. Cumulative incidence and 95% confidence intervals (95% CI) were estimated by treatment decade. Adjusted multivariable subdistribution hazard models were used to estimate hazard ratios (HR) and 95% CI for cardiac outcomes by decade. Mediation analysis examined risks with and without cardiotoxic exposures. Results: For survivors [median age 6 years (range: 0-21) at diagnosis, 28 years (8.2-58) at follow-up], cardiac radiation (RT) exposure declined from 77% of those treated in the 1970s to 55% and 40% in the 1980s and 1990s. Anthracycline exposure increased from 28% to 50% to 64%. The 20-year cumulative incidence of CHF (0.69% for those treated in 1970s, 0.74% in the 1980s, 0.54% in the 1990s) and MI (0.38%, 0.24%, 0.19%) declined in more recent treatment eras (p < 0.01). This change was not seen for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%) or arrhythmias (0.08%, 0.09%, 0.13%). Compared to survivors diagnosed in the 1970s, the risk of CHF, MI, and valvular disease decreased in the 1980s and 1990s, but only significantly for MI (HR 0.64 95% CI 0.47-0.89 and 0.52 95% CI 0.32-0.83). The overall MI risk was attenuated by adjustment for cardiac RT exposure (HR 0.94 95% CI 0.80-1.11), mostly among Hodgkin lymphoma (HL) survivors (HR 0.82 95% CI 0.69-0.98 [unadjusted for RT]; 1.03 95% CI 0.83-1.28 [adjusted for RT]). Conclusions: Reductions in exposure to cardiotoxic cancer therapies have resulted in declines in adverse cardiac outcomes, particularly for the RT-associated risk of myocardial infarction among HL survivors.
Genomic correlates of response to adjuvant trastuzumab (H) and pertuzumab (P) in HER2+ breast cancer (BC): Biomarker analysis of the APHINITY trial.
Authors: Krop Ian E. , Paulson Joseph , Campbell Christine , Kiermaier Astrid Christina , Andre Fabrice , Fumagalli Debora , de Haas Sanne , Salgado Roberto , Denkert Carsten , Loibl Sibylle , Bailey Andrew , Lewis Phillips Gail , Frank Elizabeth , Piccart Martine , Viale Giuseppe , Loi Sherene
Published: May 2019

1012

Background: We conducted a comprehensive genomic and immune-marker based analysis to identify prognostic and predictive biomarkers beyond clinical parameters (eg nodal status) in the setting of HP-based therapy. Methods: APHINITY, a phase III study, randomized 4805 pt with HER2+ BC to adjuvant chemo/H, plus P or placebo. Tumor Infiltrating Lymphocytes (TILs) were analysed using published methods. A nested case-control design with 1023 pt samples (3 controls matched to 1 distant relapse) underwent DNA (targeted) and RNA sequencing. Inverse probability weighting with Kaplan-Meier estimator weights, and models adjusted for treatment, hormone receptor, nodal status, age and chemotherapy type were used. Results are reported descriptively with 95% CIs. Interaction p-values are unadjusted for multiplicity. Results: DNA-seq, RNA-seq and TIL analyses were successful in 940/1023 (92%), 974/1023 (95%), and 4313/4804 (90%) samples, respectively. Prognosis (arms pooled): PI3K/PTEN/AKT alterations (HR 1.35; CI 1.01-1.79), MYC (HR 1.61; CI 1.16-2.23) or ZNF703 amplification (HR 1.62; CI 1.07-2.47) suggest poorer prognosis while TOP2A amplification (HR 0.49; CI, 0.32-0.74) suggests better prognosis independent of anthracycline use. Higher mRNA expression of an immune signature (IFNG, PD-L1, CXCL9 (HR 0.68; CI 0.52-0.89)) and TILs (HR 0.91; CI 0.86-0.96) also suggest better outcomes. Predictive effects: Table shows the HR for H+P benefit versus H for selected markers. PAM50 subtype did not predict benefit. Conclusions: In this comprehensive biomarker analysis, higher levels of immune markers and HER2 appeared to be associated with better prognosis and greater H+P benefit. Clinical trial information: NCT01358877. [Table: see text]
End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).
Authors: Swain Sandra M. , Miles David , Kim Sung-Bae , Im Young-Hyuck , Im Seock-Ah , Semiglazov Vladimir , Ciruelos Eva , Schneeweiss Andreas , Monturus Estefania , Clark Emma , Knott Adam , Restuccia Eleonora , Benyunes Mark , Cortes Javier
Published: May 2019

1020

Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p < .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.
Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: Report of phase IB safety cohort.
Authors: Shagisultanova Elena , Chalasani Pavani , Brown-Glaberman Ursa Abigail , Gradishar William John , Brenner Andrew Jacob , Stopeck Alison , Gao Dexiang , McSpadden Tessa , Kabos Peter , Borges Virginia F. ,   on behalf of Academic Breast Cancer Research Consortium
Published: May 2019

1029

Background: Based on preclinical synergy, we are conducting a phase IB/II clinical trial of tucatinib (HER2 small molecule inhibitor, T), palbociclib (CDK4/6 inhibitor, P) and letrozole (aromatase inhibitor, L) in HR+/HER2+ metastatic breast cancer (MBC). Methods: Post-menopausal, or pre-menopausal women on ovarian suppression, with prior ≥2 HER2 inhibitors at any time of disease; ≥1 HER2 inhibitor for MBC or front line bone/soft tissue only disease are eligible provided ≤2 endocrine agents for MBC. Prior CDK4/6 or HER2 small molecule inhibitors are not allowed. Treatment entails T 300 mg BID, P 125 mg/day 21 days on, 7 days off, and L 2.5 mg/day. Safety was assessed using CTCAE v.4.03 with standard definitions for dose limiting toxicity (DLT). Dose reductions of T and / or P for DLTs, and discontinuation of either P or L for toxicity were allowed at any time during the study. Safety thresholds were set as DLTs in ≤7/20 pts for T, ≤15/20 pts for P, or ≤14/20 pts attributable to both T and P. Results: Phase Ib enrolled 20 pts from 11/16/17 to 12/5/18. The median age is 53y (22-70y), median number of prior lines of MBC therapy is 2 (0-5). 70% of pts have visceral disease and 45% CNS disease. Prior treatment includes 100% of pts with trastuzumab and pertuzumab, and 45% of pts with prior TDM-1. One pt required dose reduction of T; 9 (45%) had dose reduction and 2 (10%) discontinued P for DLTs. One pt discontinued L. Safety boundaries were not crossed. The most common grade (G) ≥3 toxicities were neutropenia (G3 55%, G4 15%), diarrhea (G3 20%), infections (G3 20%), thrombocytopenia (G3 10%) and mucositis (G3 10%). The frequency and type of toxicities were consistent with those previously reported for each single agent. PK analysis showed no interaction between P and T. As of 1/4/19, 14 pts (70%) remain on study (5 pts for ≥6 months) and 6 pts removed for progression. No withdrawals for toxicity and no deaths on study. The longest time on study (ongoing) is 10 months for pts without CNS disease, and 6 months for pts with CNS disease. Conclusions: T, P, L combination showed an acceptable safety profile and encouraging antitumor activity. RP2D of T is 300mg PO BID in combination with full doses of P and L. Enrollment in phase II cohort is ongoing. Clinical trial information: NCT03054363.
High frequency of HER2-specific immunity observed in patients (pts) with HER2+ cancers treated with margetuximab (M), an Fc-enhanced anti-HER2 monoclonal antibody (mAb).
Authors: Nordstrom Jeffrey L. , Muth John , Erskine Courtney L. , Sanders Catherine , Yusko Erik C. , Emerson Ryan O , Lee Min-Jung , Lee Sunmin , Trepel Jane B , Im Seock-Ah , Bang Yung-Jue , Giaccone Giuseppe , Bauer Todd Michael , Burris Howard A. , Baughman Jan E. , Rock Edwin P. , Moore Paul A. , Bonvini Ezio , Knutson Keith L
Published: May 2019

1030

Background: Previous studies have shown that 44-71% of trastuzumab (T)-treated pts develop HER2-specific immunity (Clin Cancer Res 2007, 13:5133; Cancer Res 2016, 76:3702; Breast Cancer Res 2018, 20:52). M is an Fc-engineered mAb that shares similar HER2 binding and antiproliferative activity as T. The Fc region of M has been engineered for increased affinity to the activating FcγRIIIA (CD16A) and lower binding to the inhibitory FcγRIIB (CD32B), attributes that may enhance the mAb’s immune function, such as antigen presentation. Methods: HER2+ cancer pts who progressed on prior therapy received M (0.1-6 mg/kg QW for 3 of every 4 weeks [N = 34]; or 10-18 mg/kg Q3W [N = 32]) in phase 1 trial NCT01148849. PBMC and plasma were collected pre-dose and 50 days post-dose for 46 pts and > 4 years for 3 pts on long-term treatment. Response to HER2 or control antigens (Ag) was assessed by IFNγ ELISpot and antibody (Ab) ELISA. In 14 pts, T-cell antigen receptor (TCR) repertoire was assessed by immunosequencing. Results: Following M treatment, mean frequencies of IFNγ-producing T cells specific for intra- or extracellular fragments of HER2 increased by 2.5 to 6-fold (p < 0.0027, paired t test). Most (95%) of subjects responded to ≥2 of 6 (median = 5) HER2 Ag. Mean HER2-specific Ab concentration increased by 19-54% (p < 0.0001), with all subjects responding to ≥2 (median = 5) of the 6 Ag. A small 1.6-fold increase in IFNγ response to control CMV/EBV/Flu (but not tetanus or cyclin D1) peptides was observed; no increase in Ab response to control Ag was noted. Subsets of HER2-specific T-cell and Ab responses persisted during long-term treatment. Median TCR clonality increased by 54% (p = 0.003), with an average of 125 unique clones expanding, while overall TCR diversity remained unchanged (p = 0.19). Conclusions: Treatment of HER2+ cancer with M was associated with enhanced HER2-specific T-cell and Ab responses together with increased TCR clonality, indicative of a more focused T-cell repertoire. The high frequency of HER2-specific immunity in M-treated patients ( > 95%) is consistent with its enhanced Fc region contributing to linkage of innate and adaptive immune responses.
Elevated serum activin A and PD-L1 and survival in the CCTG MA.31 phase III trial (trastuzumab vs. lapatinib) in first-line HER2+ metastatic breast cancer.
Authors: Moku Prashanth Reddy , Shepherd Lois E. , Ali Suhail , Leitzel Kim , Parulekar Wendy R. , Zhu Liting , Virk Shakeel , Nomikos Dora , Aparicio Samuel , Gelmon Karen A. , Drabick Joseph , Cream Leah , Halstead Scott , Polimera Hyma Vani , Maddukuri Ashok , Ali Aamnah , Poulose Joyson , Spiegel Howard , Chen Bingshu E. , Lipton Allan
Published: May 2019

1031

Background: In MA.31 the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2+ metastatic breast cancer (MBC). In MA.31 we previously reported the prognostic/predictive utility of pretreatment serum PD-L1 (SABCS 2018, PD3-10) and serum activin A (SABCS 2016, P6-07-06) separately; here we evaluate them combined. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients, and pretreatment serum was available for 382 patients (184 in trastuzumab arm, 198 in lapatinib arm). The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1, and ELISA for activin A (R&D Systems, Minneapolis, MN). Results: In correlation analysis, pretreatment serum PD-L1 was moderately correlated with serum activin A (r = 0.21, p = 0.004). In univariate analysis for OS, the combination of higher serum PD-L1 and higher serum activin A (median cutpoints) (vs. both low) was significant for shorter OS in the trastuzumab arm (HR 6.62, p=0.0005) and in the lapatinib arm (HR 3.25, p=0.0003)(table). In multivariate analysis for OS (17 covariates included), elevated serum activin A/PD-L1 combination remained the most significant independent covariate in the trastuzumab arm (HR 12.40, p=0.001), and in the lapatinib arm (HR 5.2, p=0.0001). Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum activin A (TGF-B superfamily) and PD-L1 was associated with a shorter OS to HER2-targeted treatment. Multiple mechanisms, including immune evasion, may decrease the effectiveness of HER2-targeted therapy. Elevated serum activin A and PD-L1 may identify HER2-positive MBC patients who would benefit from inhibitors of the HER2, PD-1, and activin A pathways. [Table: see text]
Comparison of outcomes in a population-based cohort of women with metastatic breast cancer receiving anti-HER2 therapy with clinical trial outcomes.
Authors: Gong Inna Y. , Yan Andrew T , Trudeau Maureen E. , Eisen Andrea , Earle Craig , Chan Kelvin K.
Published: May 2019

1037

Background: Little data exist for comparing cardiac safety and survival outcomes of anti-HER2 therapy with concurrent trastuzumab (T) and pertuzumab (P) or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs those in the real world. Furthermore, whether older patients have worse outcomes is unknown. Methods: This was a retrospective population-based cohort of all women with MBC treated with concurrent T with P or TDM1 in Ontario (between 2012 and 2017), identified from New Drug Funding Program and linked to Ontario Cancer Registry and other administrative datasets. Outcomes were incident heart failure (HF, defined as hospitalization or emergency room visit for HF) and overall survival (OS). RCT data were obtained from digitizing survival curves as per established methods and compared with cohort OS data using log-rank test. Age based comparison of outcomes was conducted for women ≥ 65 years old vs younger. Results: Our cohort composed of 833 (28% > 64 years old), and 397 (28% > 64 years old) women treated with P and TDM1, respectively, of which 46 and 30 had baseline HF, respectively. 49% and 99.5% of women received T prior to P and TDM1, respectively. Incident HF following P or TDM1 initiation was low (P 26 women, TDM1 8 women; Table). HF events was not more in women ≥ 65 years old compared to women < 65 treated with P (16 vs. 10, p = 0.23). Unadjusted OS was significantly worse than RCT OS (Table; P HR 1.67, 95% CI 1.37-2.03, p < 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p < 0.0001). Older women had worse OS than younger women for P (HR 1.54, 95% CI 1.22-1.96, p = 0.0003), but not for TDM1 (HR 1.08, 95% CI 0.81-1.43, p = 0.62). Conclusions: HF incidence during P or TDM1 therapy in this real world cohort was relatively low. Survival in this cohort was significantly worse compared to RCT, particularly for older women, suggesting importance of evaluating effectiveness in an unselected patient population to facilitate informed decision-making based on real-world risks and survival outcomes.[Table: see text]
Germline BRCA1and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: Data from the German PRAEGNANT registry.
Authors: Fasching Peter A. , Hu Chunling , Hart Steven , Hartkopf Andreas D. , Taran Florin A , Janni Wolfgang , Tesch Hans , Haeberle Lothar , Ettl Johannes , Overkamp Friedrich , Lux Michael P , Lüftner Diana , Wallwiener Markus , Mueller Volkmar , Kolberg Hans-Christian , Fehm Tanja N. , Wallwiener Diethelm , Brucker Sara , Schneeweiss Andreas , Couch Fergus ,   PRAEGNANT Study Group
Published: May 2019

1048

Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.
PIPA: A phase Ib study of β-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) and fulvestrant (FUL) in PIK3CA-mutant (mt) ER-positive and taselisib (T) plus palbociclib (P) in PIK3CA-mutant (mt) ER-negative advanced breast cancer.
Authors: Pascual Javier , MacPherson Iain R. , Armstrong Anne Caroline , Ward Sarah Emily , Parmar Mona , Turner Alison Joanne , Bye Hannah , Proszek Paula , Dodson Andrew , Garcia-Murillas Isaac , King Jenny , Hall Emma , Finneran Laura , Lopez Juanita Suzanne , Okines Alicia Frances Clare , Ring Alistair E. , Turner Nicholas C.
Published: May 2019

1051

Background: PI3K and CDK4/6 inhibitors synergise in ER+ve and –ve PIK3CA-mt breast cancer (BC) models. Escalation phase of this study set recommended phase 2 dose (RP2D) at P 125mg on a 3/1 scheme plus T 2mg daily ( Lim, ASCO 2017). Here we present the results of expansion cohorts for PIK3CA-mt BC patients (pts). Methods: The primary objective was to assess the confirmed objective response rate (ORR) of the P + T + FUL triplet in pts with measurable PIK3CA-mt ER+ve HER2-ve advanced BC, with up to two prior lines of chemotherapy for advanced disease. PIK3CA mutation was assessed in tissue or plasma DNA analysis. Exploratory objectives included assessment of efficacy of P + T in a cohort of pts with PIK3CA-mt advanced ER-ve BC. Safety is reported overall for 44 patients including an additional cohort of 7 PIK3CA-unknown ER+ve BC pts treated with P + T + letrozole (LET). For the P + T + FUL triplet a Simon minmax design was used, with 6 responses in 25 patients required to declare efficacy. Results: We recruited 24 assessable patients with PIK3CA-mt ER+ve HER2-ve advanced BC, median age 57 (42-74), median 3 (1-9) prior therapy lines for advance disease, with 24 (100%) receiving prior endocrine therapy and 23 (96%) prior aromatase inhibitor. ORR was 33% (8/24, 95% CI 16-55%), with median progression free survival (PFS) 7.9m (95% CI 5.6-11.8). For the 11 assessable PIK3CA-mt ER-ve pts (8 HER2-ve, 3 HER2+ve) receiving P + T, ORR was 0% (0/11), clinical benefit rate (CBR) 27% (3/11) and median PFS 4.3m (95% CI 1.8-6.1). Most common AEs across all cohorts were neutropenia (80%), fatigue (50%), mucositis (50%) and thrombocytopenia (30%). Most common grade 3/4 AEs were neutropenia (57%) and rash (11%). Translational research is ongoing. Conclusions: The triplet of P + T + FUL has promising efficacy in pre-treated PIK3CA-mt ER+ve advanced BC. A subset of patients with PIK3CA-mt ER-ve advanced BC had clinical benefit from P + T. The combination of P + T +/- FUL/LET was well tolerated with anticipated AEs. Clinical trial information: NCT02389842.
A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC).
Authors: Wander Seth Andrew , Zangardi Mark , Niemierko Andrzej , Kambadakone Avinash , Kim Leslie SL , Xi Jing , Pandey Apurva Kumari , Spring Laura , Stein Casey , Juric Dejan , Kuter Irene , Moy Beverly , Mulvey Therese Marie , Vidula Neelima , Isakoff Steven J. , Yuen Megan , Brufsky Adam , Ma Cynthia X. , O'Shaughnessy Joyce , Bardia Aditya
Published: May 2019

1057

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used for pts with HR+/HER2- MBC. The MONARCH-1 trial of abemaciclib monotherapy in pre-treated pts demonstrated a median progression free survival (PFS) of 6.0 months, leading to approval as monotherapy in a CDK4/6i-naïve population. There are no data on abemaciclib in HR+/HER2- MBC after progressive disease (PD) with CDK4/6i. Methods: We evaluated clinical outcomes in pts with HR+/HER2- MBC who received abemaciclib following PD on prior palbociclib or ribociclib at 4 US academic centers. We conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free/cfDNA) when available. Results: From 2/2015 through 1/2019, 58 pts with HR+/HER2- MBC received abemaciclib following PD on prior palbociclib. 20 pts (34%) received sequential courses of therapy, while 38 pts (66%) had at least one intervening non-CDK4/6i regimen. 14 pts (24%) received abemaciclib monotherapy and 44 pts (76%) received it in combination with an antiestrogen, including fulvestrant (52%), an aromatase inhibitor (22%), and tamoxifen (2%). 22 pts (38%) required dose reduction, while 7 (12%) discontinued due to toxicity. At data cutoff (1/23/2019), 20 pts (34%) had early PD (duration < 90 days), while 21 pts (36%) had treatment duration exceeding 6 months, including 10 who remain on treatment at interim analysis (range 181-413 days). The median PFS was 5.8 months (95%CI 3.4 – 8.0). Preliminary analysis of cfDNA revealed RB1 and FGFR1 alterations in pts with PD on abemaciclib. Additional analyses with mature clinical data and genomic sequencing will be provided at the meeting. Conclusions: This is the first multi-center experience to demonstrate that a substantial proportion of pts continue to derive clinical benefit with abemaciclib after prior CDK4/6i, highlighting the potential for its use following CDK4/6 blockade. A second subset had early progression, suggesting cross-resistance to CDK4/6i via common pathways. Future effort should be directed towards validating potential biomarkers to guide optimal utilization of continued CDK4/6 blockade in HR+/HER2- MBC.
Everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer patients previously treated with CDK4/6 inhibitor based therapies.
Authors: Cook Madeline , Al Rabadi Luai , Mitri Zahi Ibrahim
Published: May 2019

1058

Background: The combination of everolimus (EVE) and exemestane (EXE) is approved as second line endocrine therapy for metastatic hormone receptor positive breast cancer (mHRBC) patients who progressed on non-steroidal aromatase inhibitor (NSAI) therapy based on the BOLERO-2 trial. However, none of the patients in BOLERO-2 received prior CDK4/6 inhibitors, which have since become standard of care for metastatic HRBC. As such, the clinical benefit of EVE + EXE in mHRBC patients previously treated with CDK4/6 inhibitors remains unknown. Methods: We reviewed patients ≥18yo with mHRBC treated with EVE + EXE following NSAI alone or NSAI + CDK 4/6 inhibitor at our institution between 2012-2018. Data collected included patient and tumor characteristics, therapies in the metastatic setting, special interest adverse events, and clinical outcomes. The primary objective was comparing PFS for EVE + EXE therapy between patients who received prior CDK4/6 inhibitor therapy and those who did not. Secondary endpoints included overall survival (OS). Patient features were summarized with descriptive statistics and time-to-event measures were estimated using the Kaplan-Meier method. Differences between groups were tested with Fisher’s exact, Kruskal-Wallis, or log-rank test. Results: Thirty-three patients were included in the study; 17 had prior CDK4/6 inhibitor therapy and 16 did not. Subjects that took EVE + EXE for < 28 days were excluded. Patient characteristics, including prior therapies and sites of metastatic disease, were not significantly different. There was no significant difference in PFS (median 5.7 vs 4.7 months, p = 0.890) or OS (median 17.8 vs 11.4 months, p = 0.177) between patients who received prior CDK4/6 inhibitors and those who did not, respectively. Steroid mouthwash use was associated with a reduced incidence of stomatitis. Conclusions: EVE + EXE is well tolerated and shows similar efficacy in metastatic HRBC patients who received CDK4/6 inhibitor therapy and those who did not. There was a non-significant trend towards improved OS in the CDK4/6 inhibitor group that needs to be further evaluated in larger patient cohorts.
Effect of metformin on PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 expression in triple-negative breast cancer.
Authors: Han Ye , Li Chia-Wei
Published: May 2019

1063

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for BRCA-mutated cancers by blocking repair of DNA double-strand breaks. However, resistance to PARP inhibitors have been described in some patients lowering overall response rates. The mechanisms underlying PARP inhibitor (PARPi) resistance are an area of active investigation. Methods: PARPi adaptive resistant clones (MDA-MB-468, MDA-MB-231, HCC1806) were generated in triple-negative breast cancer cell lines. Through morphologic observation and functional analysis, we evaluated epithelial-mesenchymal transition (EMT) and changes in immune checkpoint programmed death-ligand 1 (PD-L1). We also downregulated the expression of PD-L1 by shRNA to study the role of PD-L1 in PARPi resistance. We evaluated the immunology sensitivity to cytotoxic T cell upon PD-L1 change using a murine ex-vivo CD8+ T cell killing assay and a comparison of total killing cells percentage per well. Results: We demonstrated that inhibition of PARP enhances EMT, which induces phosphorylation of Akt at S473. This in turn upregulates the expression of PD-L1 by 2-3 fold in triple-negative breast cancer cells. In addition, PARPi–induced EMT occurred independent of PD-L1 upregulation in triple-negative breast cancer cells. Metformin administration (10µM) was found to reverse EMT by blocking the p-Akt S473 axis through activation of AMPK, resulting in downregulation of PD-L1 expression and sensitizing PARPi-resistant cancer cells to T cell killing. Conclusions: In summary, we identified that induction of EMT is a new mechanism for PARP inhibitor resistance. Metformin was able to reverse EMT and therefore a combination of metformin and PARP inhibitors may be a promising therapeutic strategy to increase the efficacy of PARP inhibitors and tumor sensitivity to T cells.
A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC).
Authors: Chien Amy Jo , Rahmaputri Siti , Dittrich Heidi F , Majure Melanie Catherine , Rugo Hope S. , Melisko Michelle E. , Goga Andrei
Published: May 2019

1072

Background: Increased expression of the MYC transcriptional oncogene is found in 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC were enrolled. Pts received intravenous dina day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. Results: 22 pts were enrolled (median age 50, median 2 prior lines of therapy, 10 pts (45%) had disease which was previously ER+). Dina was dose escalated from 12 to 33 mg/m2 in 4 cohorts. No DLTs were observed. Of the first 5 patients in the 33 mg/m2 cohort, 2 pts required a dose reduction (1 pt due to recurrent grade (G) 3 fever and G2 chills; 1 pt due to recurrent G2 diarrhea, chills, fatigue), and 1 pt discontinued due to G3 hemolytic anemia. 4 additional pts were treated at 33 mg/m2 without DLT or dose reduction. G ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (36.3%), febrile ntp (13.6%), and fatigue (13.6%). Most common all-grade AEs included fatigue (73%), diarrhea (59%), nausea (50%), ntp (45%), mucositis (32%), anorexia (23%). Immune-related AEs included sinusitis (3 pts), hemolytic anemia (1 pt), pneumonitis (1pt), and rash (2 pts). Of 21 pts evaluable for response, 1 pt had complete response (4.8%), 2 pts had partial response (9.5%), and 5 pts had stable disease (23.8%). Dose expansion and correlative biomarker studies are ongoing. Conclusions: The recommended phase 2 dose of dinaciclib given in combination with pembrolizumab is 33 mg/m2 on D1, 8 of 21-day cycle. Toxicities are generally manageable with dose reduction and dose delay. Clinical trial information: NCT01676753.
Impact of a breast cancer (BC) polygenic risk score (PRS) on the decision to take preventive endocrine therapy (ET): The Genetic Risk Estimate (GENRE) trial.
Authors: Kim Julian Oliver , Schaid Daniel J. , Cooke Andrew , Kim Christina , Goldenberg Benjamin Adam , Highsmith W Edward , Grenier Debjani , Sinnwell Jason P. , Degnim Amy C. , Couch Fergus , Vachon Celine M , Pruthi Sandhya
Published: May 2019

1501

Background: Despite BC risk reduction of 50-65% by preventive endocrine therapy (ET), very few at-risk women choose to take them. A woman’s perceived BC risk correlates with uptake of ET. A PRS comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP) improves the accuracy of risk prediction for BC. We examined the impact of the addition of individualized PRS BC risk prediction to standard risk calculator estimates on intent to take BC prevention medication. Methods: Eligible women had ≥5% 10 yr BC Tyrer-Cuzick risk (IBIS) or 5 year Gail score ≥3%, with no history of BC or hereditary BC syndrome. Standard BC risk estimates (IBIS or Gail) were incorporated into the counselling on BC preventive ET. A self-reported questionnaire at baseline quantified intention to take ET and explored factors associated with this decision. Blood samples were obtained and genotyped for 77 SNPs, individualized PRS were calculated then incorporated into IBIS and Gail predictions for 5 yr, 10 yr, & lifetime BC risk. At a second visit, PRS risk & prevention recommendations were revisited. Post visit questionnaires assessed change in intent to take ET. Multivariable linear regression was performed to assess impact of baseline variables on change in intent to take medication. Results: From 2016 to 2017, 151 women in Canada & USA were enrolled, median age: 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian. Median 5yr, 10yr, & lifetime IBIS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). PRS increased BC risk estimates in 84 (55.6%) and reduced BC risk estimates in 67 (44%) women. After PRS risk counselling, intention to take ET significantly changed (p<0.001): 41.9% of those with increased PRS were more inclined, and 46.7% of women with decreased PRS were less inclined to take ET. On multivariable regression, increase in PRS (p<0.0001) and less concern about ET side effects (p<0.0001) were associated with greater intent to take ET. Conclusions: In high risk women, PRS significantly changed BC risk estimates & intent to take preventive ET. Further assessments of the impact of PRS scores on compliance with ET are warranted. Clinical trial information: NCT02517593.
Relative risks of prostate cancer associated with different family cancer histories.
Authors: Beebe-Dimmer Jennifer Lynn , Kapron Ashley , Fraser Alison M , Smith Ken R , Cooney Kathleen A.
Published: May 2019

1505

Background: Recently developed clinical guidelines have suggested that men in families with Hereditary Prostate Cancer (HPC), Hereditary Breast and Ovarian Cancer (HBOC), and Lynch Syndrome (LS) be referred for consideration of genetic testing, especially in the setting of aggressive disease. However, while a family history (FH) of the same disease among close relatives is an established risk factor for prostate cancer (PC), a direct comparison of risk associated with specific FH, and particularly with respect to known familial cancer syndromes, in a single population is needed. Methods: The Utah Population Database was used to identify 569,320 men, 40+ years with a pedigree that included at least three consecutive generations. Each man was evaluated for FH of FPC, HPC, HBOC and LS, as well as their own PC status. PC cases (N=34,889) were identified from both the SEER Utah Cancer Registry and death certificates and classified into one or more subtypes: early-onset (EO [age of diagnosis <60 years]), lethal, and/or aggressive (Gleason Grade ≥7, metastatic, or lethal). Relative risks (RR) associated with each PC subtype, adjusted for important covariates, were calculated in STATA using a modified Poisson regression with robust error variances to obtain corresponding confidence intervals (CIs) for each FH definition. Results: A FH of HPC conveyed the greatest relative risk for all PC subtypes (RR=2.30; 95% CI 2.21-2.39), followed by HBOC and LS. Furthermore, the strongest risks associated with FH were generally observed for EO disease. No differences in risk by degree of FH were observed for either lethal or aggressive disease. Conclusions: In this large population-based family database, the risk of PC was shown to vary by cancer FH and was most strongly associated with EO disease. These results are critically valuable in understanding and targeting high-risk populations that would benefit from genetic screening and enhanced surveillance. [Table: see text]
Clonal hematopoiesis of indeterminate potential (CHIP) mutations in solid tumor malignancies.
Authors: Conces Madison , Ni Ying , Bazeley Peter , Patel Bhumika , Funchain Pauline , Carraway Hetty E
Published: May 2019

1507

Background: CHIP predisposes to a higher risk of developing hematological malignancies and cardiac events. Multiple germline mutations have been recognized as contributing to CHIP, most notably ASXL1, DNMT3A, and TET2. The frequency of CHIP mutations in solid tumor malignancies (STM) is unknown. We report the frequency and incidence of CHIP mutations in adult patients (pts) with STM. Methods: Data from 880 pts with STM who underwent next generation sequencing (NGS) at Foundation One from 2013-2017 was collected. This excluded two pts with known primary hematological malignancies who were removed. A list of CHIP mutations using NCCN guidelines as well as numerous original research articles was created, and tabulation of pathogenic or likely pathogenic mutations ( ASXL1, DNMT3A, TET2, JAK2, SF3B1, TP53, GNAS, N/KRAS) was performed. To date, only the lung, breast, and colorectal cancer pts have been annotated (N = 372) since these cancers have an overall higher incidence and prevalence in society. Results: Annotation of lung cancer pts (155/880), breast (118/880), and colorectal cancer pts (99/880) is collected and represents about 40% of all pts. At least one CHIP mutation was present in 44.5% (69/155) lung cancer pts, 32.2% (38/118) in breast cancer pts, and 7.1% (7/99) in colorectal cancer pts. Most common mutations found were TP53 and KRAS at 29.6% (110/372) and 28.0% (104/372), respectively. Mutations in genes not known to be somatic drivers for solid tumor malignancies, particularly SF3B1, DNMT3A, and JAK2, were found at very low frequencies 0.8% (3/372), 0.5% (2/372), and 0.3% (1/372), respectively. Notably, ASXL1 and TET2 mutations were not encountered in any pts. Conclusions: In tumor NGS testing, multiple CHIP mutations were noted to be present within the cohort of lung, breast, and colorectal cancers. There is a need to further understand clinical consequences of CHIP mutations incidentally found in pts with STM given known clinical implications of CHIP. We will report on clinical data (comorbidities), response/non-response to therapy, and identify specific molecular patterns of mutations to further understand the role of CHIP in pts with STM.