bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis according to prognostic factors in patients (pts) treated with first-line bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic breast cancer (mBC) in a routine oncology practice study.
Authors: Schrader Iris , Foerster Frank Gerhard , Schneeweiss Andreas , Geberth Matthias , Hahn Lars , Schumacher Claudia , Hertz-Eichenrode Martin Michael , Schoenegg Winfried , Wolfgarten Matthias Kim , Kutscheidt Andreas , Schmidt Marcus , Aktas Bahriye
Published: March 2020

1077

Background: 1st-line BEV combined with weekly PAC significantly improves progression-free survival (PFS) and response rate (RR) vs PAC alone in HER2-negative mBC, as shown in E2100. We analyzed data from a German routine oncology practice study of 1st-line BEV–PAC according to prognostic factors. Methods: Pts who had received no prior chemotherapy for mBC received BEV–PAC according to the European label. Efficacy and safety were documented for up to 1 y (or until progression, death, or BEV discontinuation if earlier) with additional long-term follow-up. Efficacy was analyzed in clinically important subgroups. Results: Efficacy data were available for 818 pts. The median duration of follow-up was 11.4 mo. The composition of the pt population with respect to the subgroups below was generally similar to the population treated in E2100, except for a higher proportion of pts with visceral disease or metastases in <3 organs. RR was very similar across all subgroups analyzed. Differences in median PFS and OS were generally in line with the differing prognoses according to clinical characteristics. Conclusions: These data suggest that 1st-line BEV–PAC is typically associated with median PFS >9 mo in the real-life setting, irrespective of baseline characteristics. [Table: see text]
Trends in the use of breast-conserving surgery and adjuvant radiation therapy in patients with DCIS: A U.S. population-based analysis from 1996 to 2007.
Authors: Nishimura Jennifer , Choi Audrey , Kim Sharon , Kim Julian
Published: March 2020

1031

Background: The treatment for patients with DCIS remains controversial. Current guidelines based upon best available evidence suggest that breast conserving surgery (BCS) followed by adjuvant radiation therapy (RT) result in acceptable local control and breast cancer specific survival. The purpose of this study was to analyze trends in patterns of care as well as identify factors associated with surgery type and use of adjuvant radiation therapy in a select cohort of patients enrolled into the SEER database. Methods: The study included females 18 years and older with focal DCIS and known tumor size of 5 cm or less diagnosed between 1996 and 2007. The Cochran-Armitage trend test was applied to identify trends in the use of BCS and RT over time. Multivariate logistic regression analyses were used to determine factors associated with receiving BCS vs. mastectomy and BCS plus RT vs. BCS alone. Cox proportional hazard model was used to determine associations with breast cancer-specific mortality. Results: Of the 34,233 women with DCIS, 76.59% were treated with BCS. 66.36% of BCS patients received adjuvant RT over the study period. The proportion of women receiving BCS increased from 71.5% in 1996 to 76.9% in 2007 (p<0.0001). Additionally, the proportion of women who underwent BCS and received adjuvant radiation therapy over the same time period increased from 55.3% to 69.7% (p<0.0001). Multivariate analysis demonstrated that year of diagnosis, race, marital status, geographic region, tumor size, tumor grade and comedo necrosis all were significantly associated with the use of adjuvant radiation therapy, but age was not. Cox proportional hazards models did not associate either surgery type or use of adjuvant radiation in patients undergoing BCS with breast cancer-specific mortality. Conclusions: Based upon reporting within the SEER database, the proportion of DCIS patients undergoing BCS and the BCS patients receiving adjuvant radiation increased over the study time period. Surgery type and use of adjuvant radiation therapy in patients with BCS was not associated with decreased risk of breast-cancer specific death in this cohort.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) as early imaging biomarker of axillary sentinel lymph node (SLN) status in locally advanced node-positive breast cancer (NPBC) patients (pts) receiving neoadjuvant chemotherapy (NACT).
Authors: Dockx Yanina , Huizing Manon Thirza , Van Den Wyngaert Tim , Altintas Sevilay , Huyghe Ivan , Geboers Inge , Vervliet Johan , Molderez Christoph , van Goethem Mireille , van Marck Veerle , Sonnemans Hetty , Tjalma Wiebren
Published: March 2020

1129

Background: Use of FDG-PET in the early evaluation of NACT for NPBC is currently under investigation. The aim of this study is to assess FDG-PET in NPBC pts receiving NACT in order to identify a subset of pts that can be spared axillary lymph node dissection (ALND) in case of response. Methods: All pts (period 2009-2011) had [cT2 (≥3cm)-T4, pN1-3], and no prior BC treatment. All pts received 8 cycles (cy) of NACT +/- trastuzumab. FDG-PET was performed at baseline and after 2 cy. After NACT, mastectomy with SLN and ALND was peformed. As primary endpoint, the change in maximum standardized uptake value (SUVmax) in the primary tumor (PT) and ALNs was compared with pathological response (Jonckheere-Terpstra test). Logistic regression was used to determine the predictive value of a 50% reduction in SUVmax on pathological response and SLN status. Results: Forty-one pts were evaluable for the primary endpoint and 31 pts had successful SN procedures. The median age was 49.8 years (range 27-75). Overall, 9.8% (4/41; 95% CI 2.7 – 23.1) of pts had progressive disease (PD), 7.3% (3/41 ; 95% CI 1.5 – 19.9 ) stable disease (SD), 53.7% (22/41; 95% CI 37.4 – 69.3) partial response (PR), and 21.9% (9/41; 95% CI 10.6 – 37.6) a complete pathological response (pCR). A linear trend existed between pCR and higher decreases in SUVmax of the PT site (p=0.008), but not with lymph node SUVmax (p=0.294). The odds of achieving a pCR, increased significantly when SUVmax of the PT decreased with >50% (OR 10.7; 95% CI 1.2 - 98.0; p=0.03), but not lymph node SUVmax (OR 4.75; 95% CI 0.82 - 27.5; p=0.08). Achieving a true negative SLN status was more likely with >50% reductions in PT SUVmax (OR 41.2; 95% CI 4.0 - 421.9; p= 0.002). A reduction of >50% in nodal SUVmax was not predictive of negative SLN status (OR 3.33; 95% CI 0.66 - 16.8; p=0.1). Conclusions: Early changes in PT metabolism imaged with FDG-PET after only 2 cy of NACT is a promising biomarker in the management of the axilla in NPBC. Molecular imaging of PT biology and to a lesser extent of axillary lymph nodes using FDG-PET warrants further study.
Use of clinical history (CH) for Lynch syndrome (LS) risk assessment: An economic decision analysis.
Authors: Sadeghi Sarmad , Barzi Afsaneh , Kattan Michael W. , Meropol Neal J.
Published: March 2020

1514

Background: Previous studies comparing screening strategies (STs) for LS concluded that immunohistochemistry (IHC)-based STs are most cost effective. However, these analyses generally exclude clinical history (CH)-based criteria due to concerns for reliability, e.g. Amsterdam (Ams), Bethesda (Beth), MMRpro (Mpro), MMRpredict (Mpre) and PREMM (PRE). We conducted a comprehensive comparison of all STs. Methods: Using assumptions from published reports we performed a cost effectiveness analysis (CEA) with a societal viewpoint using TreeAge software. 20 STs for proband (Pd) and general population (GP) screening in a cohort of 100,000 assumed a 3% LS prevalence (Prev) in Pd and 0.23% in GP, 5 first degree relatives (FDRs) per LS diagnosis (Dx), 50% LS Prev in FDRs, and 90% genetic testing (GT) compliance in Pds and GP and 52% in FDRs. We used the number of LS Dxs as effectiveness measure (EM). Sensitivity, accuracy, and incremental cost effectiveness ratios (ICERs) were calculated. Results: The ST of Mpro followed by GT is highly sensitive and has an accuracy of .997. Assuming 1-1.4 life years saved per Dx based on prior studies, this strategy is also cost effective. Strategies with greater sensitivity were dominated or not cost effective. Table shows results in order of increasing cost per Dx. Conclusions: This comprehensive comparison suggests that Mpro is an appropriate first step in screening for LS in Pds, and its routine use may be considered as a quality measure in the management of colorectal cancer. IHC + BRAF, GT should be reserved for Pds where CH is incomplete. [Table: see text]
PTEN germline mutations in patients first tested for other hereditary cancer syndromes: Would use of risk assessment tools have reduced health care costs?
Authors: Mester Jessica , Moore Rebekah , Eng Charis
Published: March 2020

1516

Background: PTEN Hamartoma Tumor Syndrome (PHTS) includes patients with Cowden (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) with germline PTEN mutation. Breast, colon, endometrial cancer and GI polyposis are associated, creating overlap with Hereditary Breast and Ovarian Cancer (HBOC), Lynch (LS) and adenomatous polyposis syndromes (APS). We reviewed our PHTS patient series to find how often testing criteria for these syndromes were met or testing was pursued before PTEN. Methods: Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation; mutations were identified by mutation scanning or MLPA analysis and confirmed by sequencing or quantitative PCR, respectively. Families were excluded if diagnosed with CS or BRRS before 1998, family history was unavailable, or proband was <18 yrs. Pedigree, genetic testing reports, and medical records were reviewed to determine if patients met HBOC testing criteria, Amsterdam II or Bethesda 2004 criteria, or had adenomatous polyps. Risk assessment was conducted for BRCA1/2 via the BRCAPRO, Myriad II, and Penn II models; for MLH1/MSH2/MSH6 via the PREMM1,2,6 and MMRPro models; and for PTEN via the Cleveland Clinic (CC) PTEN Risk Calculator. Results: 115 PTEN mutation-positive adult probands were identified among 3,405 patients. 53 (46.1%) met testing criteria for HBOC or LS and 34 (29.6%) underwent previous testing for HBOC, LS or APS. Average risk for BRCA1/2 and MLH1/MSH2/MSH6 mutations in tested patients were 7.5-16.9% and 33.1-41.4%, respectively; whereas PTEN mutation risks were 35.9% and 79.7%. No patient tested for APS (average PTEN mutation risk 73%) had >5 adenomas. An estimated $89,700 was spent on negative analyses for HBOC, LS and APS among patients ultimately found to have germline PTEN mutations. Conclusions: PHTS should be part of the differential diagnosis for patients referred for question of HBOC, LS or APS. Pathology review is key for patients with polyposis. Using the CC PTEN risk calculator enables clinicians to understand when PTEN mutation risk is high, allowing testing to proceed in a step-wise and cost-saving manner.
Alcohol and breast cancer risk in postmenopausal women: The PLCO experience.
Authors: Falk Roni , Maas Paige , Schairer Catherine , Buys Saundra S. , Chatterjee Nilanjan , Lee Theresa , Ziegler Regina G , Isaacs Claudine
Published: March 2020

1521

Background: Moderate alcohol consumption is an established breast cancer (BC) risk factor. Invasive BC is a heterogeneous disease comprised of several histological subtypes with distinct biological features that suggest etiologic differences. Several studies show the alcohol link may be stronger for estrogen receptor-positive tumors (ER+/PR+ and ER+/PR-) and for lobular BC. Few have evaluated the role of alcohol consumption by BC histology and hormone receptor status combined. Methods: We evaluated the risk of BC by baseline alcohol consumption in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort (54649 participants, 1786 incident invasive breast cancers) by histology and hormone receptor status. Histologic subtype-specific associations were evaluated using a recently developed Cox proportional hazards model to calculate multivariate hazards ratios (HR) and 95% confidence intervals (CI). Results: 1444 ductal (81%), 233 lobular (13%) and 109 mixed ductal lobular (6%) cases were identified. The majority were ER+/PR+ (ductal: 959 ER+/PR+, 136 ER+/PR-, 229 ER-/PR-; lobular: 179 ER+/PR+, 37 ER+/PR-, 6 ER-/PR-; mixed ductal/lobular: 88 ER+/PR+, 6 ER+/PR-, 5 ER-/PR-). For ductal and lobular BC, risks for alcohol consumption were modestly elevated; compared to never drinkers, women consuming 7-14 drinks/week had a 40% increase in HR in both histologic subtypes. Risks for mixed ductal lobular cancer were significantly higher, particularly for women consuming 7-14 drinks per week (HR=3.0; 95% CI=1.5, 6.1). For all histologies combined, alcohol risks were confined to ER+/PR+ cancers with HR=1. 6 (95% CI=1.3, 2.1) for women consuming 7-14 drinks/ week; p trend=0.0005. Similarly, for each histologic subtype, the risk for alcohol consumption was limited to ER+/PR+ tumors, and notably, very few cases with pure lobular or mixed ductal lobular cancer were either ER+/PR- or ER-/PR-. Conclusions: Moderate alcohol consumption is associated with risk of ER+/PR+ BC in each of the predominant histologic subtypes, but not with hormone receptor-negative cancer. Unlike other studies, we did not find a link between alcohol consumption and ER+/PR- BC.
Cancer screening in France: 3rd edition of the EDIFICE survey.
Authors: Viguier Jérôme , Eisinger Francois , Coscas Yvan , Morere Jean F. , Blay Jean-Yves , Roussel Claire , Pivot Xavier B.
Published: March 2020

1568

Background: The EDIFICE survey program started in 2005 and was aimed at providing a better understanding of the participation of the French population in cancer screening programs and assess the evolution over time. The EDIFICE 3 survey was conducted in 2011, following EDIFICE 1 (2005) and EDIFICE 2 (2008), and focused on colorectal, breast and prostate cancer. Methods: This third nationwide observational study, EDIFICE 3, was conducted by phone interviews among a representative sample of 1603 subjects aged between 40 and 75 years, using the quota method. The analysis focused on the target population of the national screening programs for breast and colorectal cancer (50-74 years). The same population was analysed for prostate cancer screening behaviours. Results: For breast cancer, the rate of women attending at least one screening test was 93%/94%/95% in 2005/2008/2011 respectively. A mammography had been performed as recommended within the last two years for 75%/83%/83% among them. We observed an increase in timing compliance between 2005 and 2011, significant for women aged 65-74. For colorectal cancer, the rate of subjects attending at least one screening test was 25%/38%/59%. A fecal test or colonoscopy had been performed according to the recommended timing for NA/30%/51% among them. Colorectal cancer screening has increased significantly in all age groups, especially between 65 and 69 years, and for both genders. For prostate cancer, the rate of men having performed at least one screening test (PSA and/or rectal examination) was 36%/49%/50%.This rate have significantly decreased in men aged 50-59 between 2008 and 2011(44% vs 37%, p<0.05). Conclusions: For National Programs, the attendance rate remains high for breast cancer screening and is improving for colorectal cancer screening. However, the European guideline objective rate of participation for colorectal cancer screening has not yet been reached. Despite the absence of recommendations, prostate cancer screening is frequently carried out and stable overall.
Association of a history of autoimmunity or hypersensitivity with overall survival in breast cancer.
Authors: Olsson Hakan Lars , Kogler Ulrika , Einefors Rickard , Ellberg Carolina
Published: March 2020

1594

Background: Antibody therapy of malignant melanoma with ipilimumab is associated with the development of an autoimmune disease. The aim was to investigate if preexisting autoimmune disorders or hypersensitivities, similar to the side effects of immunotherapy in malignant melanoma, gave a better overall survival for breast cancer (BC) patients, compared with patients without these disorders. Methods: A consecutive clinical material consisting of 1,705 breast cancer patients diagnosed between 1980 and 2010 was used. The patients were grouped according to preexisting autoimmune disease or hypersensitivities. The remaining BC patients were used as a reference group. All analyses were adjusted for age at diagnosis, T, N, M-status of the tumor, and ever-use of HRT simultaneously. A p value of less than 0.05 was considered significant. Results: One hundred and twenty-five (7.3%) patients had a history of autoimmunity and 72 (4.2%) patients had a history of hypersensitivity prior to BC diagnosis. Our main finding was that BC patients with a preexisting autoimmune disease or hypersensitivities with ER-negative tumors had a longer overall survival compared to patients without, HR 0.55, 95% CI 0.31-0.97. The risk was specifically low in BC patients with hypersensitivity and ER-negative tumors, HR 0.39, 95% CI 0.16-0.96. The risk was nonsignificantly lower in the autoimmune group, HR 0.78, 95% CI 0.37-1.61. Stratifying both on ER-status and menopausal status, similar results were seen in premenopausal BC patients with hypersensitivity. Postmenopausal BC patients with an ER-negative tumor and an autoimmune disease had a longer nonsignificant overall survival, HR 0.3, 95% CI 0.07-1.26. Conclusions: BC patients with an ER-negative tumor and/or diagnosed before menopause had a longer overall survival when previously diagnosed with hypersensitivity. For BC patients with an autoimmune disease, the prognostic benefit was seen when diagnosed postmenopausally with an ER-negative BC. Preexisting or induced autoimmunity or hypersensitivity may prolong life in breast cancer especially in young patients and those with ER-negative tumors.
Long-term survival and prognostic factors in neuroendocrine tumors: Results from a large multicenter study.
Authors: Faggiano Antongiulio , Grimaldi Franco , Manzoni Marco , Davi Maria Vittoria , Ferone Diego , Giuffrida Dario , Roiter Ignazio , Fanciulli Giuseppe , Papini Enrico , Martini Chiara , Franchi Giulia Maria , Fasola Giampiero , Albertelli Manuela , Crinò Lucio , Colao Annamaria , Ferolla Piero
Published: March 2020

1604

Background: The clinical behavior of neuroendocrine tumors (NET) is highly variable, but the only data available in literature on large series are mainly based on retrospective register data collected in 3-5 decades, focusing on short-term follow-up. These are clearly insufficient due to the frequent evolution in classification criteria, diagnostic techniques and the scarcity of clinical data. Methods: Data from a total of 1659 NET patient were collected from 12 Italian referral centers. A specific software was developed for the study. Only patients with histological diagnosis revised according to the WHO Classification in active long term follow-up in the period 1990-2010 were included in the study. Patients with incomplete diagnostic work-up, without clinical data or lost at follow-up were excluded. Cumulative survival were analyzed according to site of origin, histotype, grading, ki67 score, secreting pattern (functioning or not functioning) and staging. Results: At 2 yr cumulative survival do not differ between pancreatic (pNET 94.9%), gastrointestinal (GINET 94.4%) and lung NET (TNET 94.6%), functioning (93.5 %) and non functioning (93.9%), while was significantly different between T1N0M0 (98%), T1N1M0 (92.9%), T1N1M1 (90.2%) and grading (G1 98%, G2 96.8%, G3 84.1%). At 5, 10 and 15 yr, cumulative survival were respectively 90.9, 77.1, 62.7% for pNET, 88.7, 83.5, 62.7% for GINET 90.3, 80.2, 67.9% for TNET. 88.4, 77.0, 59.0% in functioning and 89.8, 79.1, 64.6% in not functioning. 96.1, 89.5 and 77.0% for T1N0M0, 88.2, 83.5, 70.4 for T1N1M0 and 82.0, 55.8 and 43.9 for T1N1M1, 93.1, 82.3, 75.4% for G1, 87.8, 64.8, 48.6% for G2, 81.4, 75.2, 40.1% for G3. Conclusions: Brief (2y) and very long term (15y) survival do not significantly differ between different site of NET origin. Functioning tumors have the same survival rate at 2 y but lower at 15 y. Staging and grading appear as the most significant prognostic factors particularly at 10 and 15 y. Long-term cumulative survival in NET results significantly higher than in historical series, probably due to the anticipation of the diagnosis and the availability of new therapeutic strategies.
Survival of elderly Medicare patients after standard chemotherapy for advanced lung and gastrointestinal cancers in the real world.
Authors: Lamont Elizabeth B. , He Yulei , Lan Lan , Joffe Steven
Published: March 2020

1605

Background: Elderly cancer patients are under-represented on clinical trials that determine standards of treatment, thus survival of such patients following standard treatment in the real world is not known. We describe unadjusted survivals for site, stage, and treatment-specific cohorts of elderly Medicare cancer patients who were treated in usual care settings. Methods: From SEER-Medicare data, we identified elderly Medicare patients with advanced lung or GI cancers who received specific standard chemotherapy regimens within six months of diagnosis. Of the 108,386 patients with the cancer sites and stages of interest, 39% (42,570/108,386) received some form of chemotherapy within six months of diagnosis. Only 32% (13,689/42,570) received one of the specific standard regimens we studied. Results: Median survival times and interquartile ranges (IQRs) varied according to cancer site, stage, and treatment. For 598 stage IV CRC patients on FOLFOX, the median survival was 19.4 mos (IQR 9.3-43.0); this is comparable to PRIME Study patients (19.7 mos). For 130 stage IV CRC patients on FOLFIRI, the median survival was 16.1 mos (IQR 5.6-30.0), which is lower than BICC-C Study patients (23.1 mos). For 3,815 advanced pancreatic cancer patients on gemcitabine, the median survival was 4.3 mos (IQR 2.0-8.7), which is slightly lower than CALGB 80303 patients (5.8 mos). For 8,040 stage IV NSC lung cancer patients on carboplatin and paclitaxel, the median survival was 7.0 mos (IQR 3.2-14.2); this is comparable to ECOG 1594 patients (7.8 mos). For 1,104 extensive stage SCLC patients on cisplatin and VP16, the median survival was 8.5 mos (IQR 4.7-12.9), which is slightly lower than CALGB 9732 patients (10.0 mos). Conclusions: The observed survival of cancer site, stage, and treatment-specific cohorts of elderly Medicare patients with advanced lung or GI cancers who were treated in real world settings with standard chemotherapy was, in general, similar to that of patients treated with nominally identical regimens on trials. Further analyses should explore the shorter survival for elderly Medicare patients with stage IV CRC treated with FOLFIRI in the usual care setting compared to patients treated on trials.
Impact of obesity and overweight in the prognosis of women diagnosed with non metastatic breast cancer in a Mexican cohort.
Authors: Aguilar José Luis , Martinez Itzel Anahi , Villarreal-Garza Cynthia Mayte , Lara Gisell Anaid , Medina Fernando Lara , Alvarado Miranda Alberto , De La Garza Jaime G. , Mohar Alejandro , Meneses Abelardo , Herrera Gomez Angel , Olvera-Caraza Daniela , Granados-Garcia Martin , Arrieta Oscar
Published: March 2020

1607

Background: Mexico positions right up at the top with U.S. in worldwide rankings of the most obese countries. In addition, breast cancer (BrCa) is the main type of cancer among women in this country. Studies have shown inconsistent results regarding obesity as a prognostic factor for worse outcome. Methods: Our aim is to identify if overweight and obesity confer poor prognosis in non-metastasic BrCa patients (pts). We identified 1799 Hispanic women with newly diagnosed BrCa who attended the National Cancer Institute in Mexico from 2004-2008 and compared clinical and pathological features and overall survival (OS) between pts with a body mass index (BMI) > or ≤ than 25. Results: The median age at diagnosis was 51 years. A BMI>25 was found in 71% of pts. Postmenopausal women comprised 52%, and had a greater proportion of cases with a BMI>25 than premenopausal pts (75% vs. 67%, p<0.0001). Pts with BMI>25 presented with more advanced TNM stages and nodal involvement than their counterparts (73% vs. 67%, p=0.005 and 76% vs. 71%, p=0.017; respectively). Overall prevalence of hormone-receptor (HR), triple-negative (TN) and HER2 positive disease was 62%, 23%, and 27%, respectively. Differences according to receptor status between pre and postmenopausal pts and BMI are shown in table. There was no difference in disease-free survival and OS according to overweight and obesity in the overall population, but when menopausal status was considered, premenopausal pts with BMI>25 had a worse OS compared to pts with BMI<25 (HR 1.6, p=0.037). This difference was not seen in the postmenopausal group. Conclusions: Obesity may influence BrCa outcomes via several hormonal and inflammatory mechanisms. In this study, overweight and obesity confer a poor prognosis in premenopausal patients, possibly related to excess estrogen availability and higher prevalence of TN BrCa. Therefore, overweight and obesity deserve additional attention to assess possible causal relationships that potentially could be modified to improve outcomes in premenopausal patients. [Table: see text]
Bevacizumab for recurrent WHO grade III anaplastic glioma (AG).
Authors: Delios Anna Maria , Brennan Cameron W , Huse Jason T. , Colevas Kara , Omuro Antonio Marcilio Padula
Published: March 2020

2028

Background: Salvage treatment with bevacizumab (BEV) has been increasingly used in grade III AG, but limited data are available, with conflicting results reported. Because of differences in molecular characteristics, angiogenesis mechanisms, growth rate and chemosensitivity, results observed in glioblastoma (GBM) treated with BEV may not apply to AG, and may differ between anaplastic astrocytomas (AA) and oligodendrogliomas (AO). Methods: IRB approved retrospective review of all pts with recurrent WHO grade III AG treated with BEV at MSKCC. Response and progression were determined by RANO criteria. Results: BEV was given to 39 pts with recurrent grade III AG (AA: 26; AO: 10; anaplastic oligoastrocytoma [AOA]: 3); median (med) age: 49 (range 20-75); med KPS: 80 (60-100). MGMT promoter methylation was determined in 17 pts (methylated 8, unmethylated 9). Amongst AO/AOA, 1p/19q co-deletion was present in 6 and absent in 5. IDH1/ IDH2 mutations were present in 3/5 tested tumors. Med time from diagnosis of AG to BEV treatment was 11.5m (3 – 112.5). The med number of previous recurrences was 1 (range 1-4). BEV was given as single agent to 16 pts and combined with a cytotoxic agent in 23. Objective response rate (ORR) was 41% (complete response: 5; partial: 11). The med progression-free survival (PFS) was 4.8m (6-m PFS: 35% [95% CI 20-50]). The med overall survival (OS) was 11.5 m (1y-OS: 45% [95% CI 29-61]). In pts achieving ORR, med OS was 13 m vs 4 m in pts with stable/progressive disease (P=0.02). Pts at first recurrence fared better than pts with more than one recurrence (med PFS: 6 vs 3.4 months, P=0.04). AO/AOA tended to fare worse than AA (med PFS 3 vs 5.5 m, P=0.07). There were no differences in PFS (P=0.8) or OS (P=0.4) between single agent vs BEV + cytotoxic agent. Toxicity included one grade 4 brain hemorrhage. Conclusions: In this relatively large series, BEV was associated with higher ORR and PFS as compared to historical controls, although improvements in those endpoints were of a lower magnitude than in GBM. While ORR predicted OS, improvements in OS were not apparent; results in AO were particularly disappointing. The use of BEV in this population requires reappraisal in a randomized study with adequate stratification for histology and number of previous recurrences.
Association of breast cancer in men with exposure to 5-α reductase inhibitors: A RADAR report.
Authors: Belknap Steven M , Godinez-Puig Victoria , Brannigan Robert E , Lin Simon M , Cashy John , Chowdhary Rajesh , Postelnick Michael J , Fotis Michael A , Irwig Michael , Khan Seema Ahsan , Gradishar William John , Garg Vishvas , Shen Xian , Raisch Dennis W , Nardone Beatrice , Rosen Steven T. , Edwards Beatrice J. , McKoy June M , Yarnold Paul R , West Dennis P.
Published: March 2020

2532

Background: Breast cancers in men (BCM) account for <1% of all breast cancers. Dihydrotestosterone (DHT) inhibits proliferation of normal and neoplastic mammary tissue and constrains the effect of estrogens. Finasteride (F) and dutasteride (D) are 5-α reductase inhibitors (5-αRIs) that reduce systemic and local dihydrotestosterone and cause gynecomastia in 1–3% of men. The package inserts for F and D state, “the relationship between long-term use of (finasteride/dutasteride) and male breast neoplasia is currently unknown.” F and D are marketed for treatment of symptomatic benign-prostatic hyperplasia. F is marketed for treatment of androgenetic alopecia. Methods: To detect disproportionality in the FDA MedWatch dataset, we calculated the empiric Bayes geometric mean (EBGM) for association of BCM with F or D. We also calculated the attributable risk of BCM exposed to F or D among men at an urban academic hospital (Northwestern Memorial Hospital) and at a rural healthcare system (Marshfield Clinic). Results: In the MedWatch dataset, we identified 33 reports of F-associated BCM and 5 reports of D-associated BCM. For F–associated BCM, the EBGM was 58.95 (95% CI 24.47-81.76; p=0.0001). For D-associated BCM, the EBGM was 15.79 (95% CI 4.57-35.49; p=0.0001). The mean age for BCM after 5-αRI exposure was 70±11 years; 11/38 (29%) had gynecomastia. There were 38 cases of BCM associated with 5-αRI in the combined Northwestern and Marshfield cohort (see table below). Conclusions: We found a highly significant association between BCM and 5-αRI exposure in each of 6 separate analyses (3 sources X 2 drugs), with an estimated 1 extra BCM per 564 men exposed to 5-αRIs. We now plan to assess BRCA status and other risk factors. Given that 5-αRIs are marketed for control of lower urinary tract symptoms or for cosmetic purposes, it is not immediately obvious that use of finasteride or dutasteride for their labeled indications would provide any net benefit. [Table: see text]
Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.
Authors: Sheikh Nadeem A. , Wesley Johnna D. , Perdue Nikole , Stewart Frances P. , Fong Lawrence
Published: March 2020

2563

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects with localized prostate cancer. Methods: In this open-label, phase 2 study (NCT00715104), subjects with localized prostate cancer received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy (RP). Following RP, subjects were randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12 weeks post-RP. Cellular composition, antigen presenting cell (APC) activation, cytokines, and T and B cell activation were profiled before and after each culture with PA2024, the fusion protein containing prostatic acid phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T, and 15 subjects received a booster infusion. Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first (p<0.001). The expression of early T cell activation markers (CD134, CD137, CD278 and CD279) were increased in pre-culture cells obtained after the first infusion, and further increased after culture. Activated mature B cells (CD20+CD27+IgD+CD86+) increased following culture in all 3 products (p<0.01); memory B cells (CD20+CD27+IgD-CD86+) were progressively increased following the first infusion (p<0.05 third vs. first product). TNF-α, IFN-γ, IL-2 were secreted at higher levels during culture of the second and third products (all p<0.001). The observed increases in CD54 upregulation, early T cell activation markers, and memory and activated mature B cells were maintained at booster treatment. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that was consistent with boosting of an immune response primed with the first infusion. Immune activation was maintained at the booster infusion 3 months following initial sipuleucel-T treatment.
Is cigarette smoke associated with increased catabolism of gemcitabine in patients with advanced solid tumors?
Authors: O'Malley Meaghan Working , Daignault Stephanie , Healy Patrick N. , Schmidt Lindsay A. , Ramnath Nithya
Published: March 2020

2602

Background: Cigarette smoking can accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent. Reduced drug levels may lead to undertreatment in smokers and, conversely, increased treatment-related neutropenia in nonsmokers. Methods: An IRB-approved retrospective chart review was performed on 151 patients with solid tumor malignancies who received gemcitabine alone or in combination with oral chemotherapy agents from July 1, 2009 to June 30, 2011 at the University of Michigan. Using logistic regression, we compared toxicity, including neutropenia, and smoking history measured in pack-years in smokers vs. nonsmokers to ascertain whether cigarette smoking is an independent factor predictive of toxicity to gemcitabine. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary (15.2%). Most patients had advanced disease (stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; n=107), 77.6% patients had stage III-IV disease. Within the PB cohort, most patients were “ever” smokers as compared to “never” smokers (60.7% vs. 39.3%). Logistic regression of this cohort showed that current smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers (OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with higher pack-year history: smokers with >50 pack-years had even less neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-1.699]). Further statistical analysis of subgroups was not performed due to small sample size. Conclusions: Smokers with pancreatobiliary malignancies receiving gemcitabine had less treatment-related neutropenia as compared to never smokers, a finding that was more pronounced as pack-years increased. Decreased toxicity, including neutropenia, may be due to increased metabolism and drug clearance as a result of smoking. This may lead to potential undertreatment of smokers and, conversely, increased treatment-related toxicity in never smokers. A prospective clinical trial is needed to further elucidate this correlation, and is currently being designed.
Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts.
Authors: Lotze Michael T. , Appleman Leonard Joseph , Ramanathan Ramesh K. , Tolcher Anthony W. , Beeram Muralidhar , Papadopoulos Kyriakos P. , Rasco Drew Warren , Weiss Glen J. , Mountz James M , Toledo Frederico G.S. , Alvarez Rene J , Oborski Matthew J , Rajagopalan Prabhu , Jeffers Michael , Roth Diane , Dubowy Ronald L. , Patnaik Amita
Published: March 2020

3019

Background: BAY 80-6946 (BAY) is a potent and highly selective reversible pan-Class I PI3K inhibitor, previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg on days 1, 8 and 15 every 28 days (MTD). Additional pts were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected tumor types, as well as safety in Type 2 diabetics. Methods: To date, 23 nondiabetic pts with solid tumors and 5 with follicular lymphoma (FL) received BAY at the MTD, until disease progression or unacceptable toxicity. Tumor types were selected for high frequency of PIK3CA mutation, including breast cancer (BC; 16), endometrial (3), gastric (2), GU transitional cell (1) and ovarian clear cell (1). Partial enrichment for PIK3CA mutation was achieved by analysis of plasma DNA. 3 diabetic pts have been enrolled, at starting dose of 0.4 mg/kg. PK was done after the 1st and 3rd doses. FDG-PET/CT scans were done at baseline and 48 hrs after the 1st dose for pharmacodynamic assessment. Results: Safety and tolerability assessments confirmed MTD. There were no 1st cycle DLTs. Almost all nondiabetic pts had acute Grade 2/3 hyperglycemia (HG) following each dose; at least 10 of them received insulin for 1-3 days post dose. Hypertension (HTN) lasting < 24 hrs was common in pts with preexisting HTN, and manageable. 2 FL pts developed interstitial pneumonitis (IP) after cycles 2 and 3, both responsive to steroids. Diabetic pts tolerated 0.4 mg/kg. Tumor SUVmax consistently fell at 48 hrs. 3 of 4 FL pts had partial response (PR) after 2 cycles, with 2 confirmed PR pts on BAY for 10+ and 8+ mos. 2 BC pts showed PR , 1 confirmed. PIK3CA mutation (n=7) does not appear to correlate with response. Average T1/2 was 36 hrs. Observation of high Cmax in very obese pts led to recommended maximum dose of 65 mg. Conclusions: BAY induced PRs in pts with BC and FL. The acute toxicities of HG in most pts and HTN in some are manageable, and IP has been limited to 2 lymphoma pts and is responsive to steroids. The observed clinical activity of BAY, along with its acceptable safety profile, provide a rationale for the ongoing development of BAY in combination with cytotoxic and targeted agents.
Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors.
Authors: Daniele Gennaro , Ranson Malcolm , Blanco-Codesido Montserrat , Dean Emma Jane , Shah Krunal Jitendrakumar , Krebs Matthew , Brunetto Andre , Greystoke Alastair , Johnston Claire , Kuznetsov Galina , Matijevic Mark , Mistry Bipin , de las Heras Begona , Molife L Rhoda
Published: March 2020

3030

Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. This phase 1 study was performed to determine the MTD, safety, PK, PD and preliminary activity of golvatinib. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, ≥ 18 years (yrs) and adequate organ function were eligible. Golvatinib was administered orally, once daily (QD), continuously. Blood samples for PK and PD analysis were collected at multiple time-points. Mandatory tumor biopsies for PD analysis were taken pre and post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n=15), lung (n=4), renal (n=4), esophageal (n=2), melanoma (n=2) and others (n=7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase (n=1; 200mg) and repeated Gr2 (n=1) and Gr3 (n=1) fatigue, both at 450mg. The MTD was determined to be 400 mg QD. Frequently occurring adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. Best response was stable disease in 6 pts lasting >84 days. PK showed high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated MET gene copy number, with c-Met overexpression and post treatment decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. Preliminary PD analysis demonstrated evidence of c-Met target modulation. Further evaluation will continue in phase 2 combination studies.
NRAS mutations in patients with advanced cancers treated with target-based therapies in early-phase clinical trials.
Authors: Madhusudanannair Vinu , Janku Filip , Falchook Gerald Steven , Hong David S. , Wheler Jennifer J. , Naing Aung , Fu Siqing , Piha-Paul Sarina Anne , El-Osta Hazem Edmond , Luthra Rajyalakshmi , Tsimberidou Apostolia Maria , Kurzrock Razelle
Published: March 2020

3106

Background: NRAS mutations in cancers increase MAPK signaling. It is plausible that NRAS mutations may be associated with sensitivity to drugs targeting the MAPK pathway. Methods: Tumors from 689 patients with advanced cancers referred to the Clinical Center for Targeted Therapy (phase I program) were screened in a CLIA-certified laboratory for NRAS mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN aberrations. Whenever possible, patients with NRAS mutations were treated with agents targeting the RAF-MEK pathway. Results: Of the 689 patients, 58 (8%) had NRAS mutations. NRAS mutations were most prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial (2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the tested head and neck squamous cell cancers (n = 44); sarcomas (n = 41) and breast cancers (n = 25). None (0/62, 0%) of the patients tested for KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%) tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58 patients with NRAS mutations, 14 (24%) were enrolled in trials that included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and 1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage >10% from baseline. In comparison, only 22/187 (12%) patients with wild-type/unknown NRAS, KRAS and BRAF treated on the same trials demonstrated tumor shrinkage >10% (p=0.086). Conclusions: NRAS mutations are diagnosed in variety of advanced cancers. Patients with NRAS mutations demonstrated a trend to better antitumor activity with MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF mutations. Further studies are warranted to delineate the role of NRAS mutations in patients treated with MEK axis inhibitors.
Use of next-generation sequencing (NGS) to detect a novel ALK fusion and a high frequency of other actionable alterations in colorectal cancer (CRC).
Authors: Ross Jeffrey S. , Lipson Doron , Sheehan Christine E , Otto Geoff , Yelensky Roman , Parker Alex , Jarosz Mirna , Juhn Frank , Brennan Tina , Downing Sean , Donahue Amy , Balasubramanian Sohail , Palmer Gary A. , Miller Vincent A. , Stephens Philip , Cronin Maureen T.
Published: March 2020

3533

Background: We hypothesized that NGS could identify genomic alterations that guide selection of targeted therapies and discover novel drug targets for primary and metastatic CRC. Methods: DNA was extracted and sequenced from 4 X 10 μ FFPE sections from 40 (32 primary and 8 metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage unknown) using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions (64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions (1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of CRCs respectively, with both mutated more frequently than reported in COSMIC. Alterations associated with potential sensitivity to targeted therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS (TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 Mb tandem duplication generated a novel C2orf44-ALK gene fusion starting at the canonical exon 20 recombination site previously reported for the majority of ALK gene fusions. cDNA sequencing identified an 90-fold increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results in ALK kinase domain overexpression and contains the same intracellular domain as other ALK fusions including the ALK inhibitor sensitive EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from FFPE CRC samples uncovered an unexpectedly high frequency of genomic alterations, many of which may be clinically actionable by informing treatment decisions, including a novel ALK gene fusion. This previously unrecognized subset of CRC patients may be candidates for clinical trials of crizotinib or other ALK inhibitors.
Phase I study of EMD 525797 (DI17E6), an antibody targeting ανβ integrins, in combination with cetuximab and irinotecan, as a second-line treatment for patients with k-ras wild-type metastatic colorectal cancer.
Authors: Elez Elena , Kocáková Ilona , Hoehler Thomas , Martens Uwe Marc , Bokemeyer Carsten , Van Cutsem Eric , Fram Robert J , Bernard Laurence , Tabernero Josep
Published: March 2020

3539

Background: EMD 525797 is a humanized monoclonal antibody that specifically targets all αν integrins, including ανβ1, ανβ3, ανβ5, ανβ6, and ανβ8. In colorectal cancer (CRC), ανβ3 is highly expressed on tumor-associated vessels, and ανβ5 is strongly expressed on tumor cells, vessels, and stromal cells. Overexpression of ανβ6 is associated with a significant reduction in median overall survival. Methods: Safety, tolerability, and anti-tumor activity of escalating doses of EMD525797 in combination with irinotecan and cetuximab were assessed in patients (pts) with metastatic CRC who had failed first-line fluoropyrimidine/oxaliplatin-containing chemotherapy. Pts received IV infusions over 1 hour of 250, 500, 750, and 1,000 mg EMD 525797 every 2 weeks in combination with irinotecan at 180 mg/m2 IV every 2 weeks and cetuximab at 400 mg/m2 on Cycle 1, Day 1 and then 250 mg/m2 IV weekly. A standard 3+3 trial design was used. Three pts were enrolled at each dose level and if no dose limiting toxicities (DLTs) were observed, pts were enrolled at the next dose level. An additional 3 pts were added if 1 of the initial 3 pts in the cohort experienced a DLT. Results: A total of 16 pts received treatment.No DLTs were observed at any dose of EMD 525797 in combination with irinotecan and cetuximab. Serious adverse events related to EMD 525797 included Grade 3 hypokalemia and tachyarrhythmia. Dosing was well tolerated over treatment intervals as long as 18 months. Objective responses included 1 partial response (PR) at 250 mg; 1 complete response and 1 PR at 750 mg; and 2 PRs at 1,000 mg. Two pts had prolonged stable disease lasting longer than 11 weeks at 750 mg. Anti-tumor activity was observed in pts who had failed anti-VEGF therapy in combination with first-line chemotherapy. Conclusions: The combination of EMD 525797 with irinotecan and cetuximab was well tolerated and has anti-tumor activity. Further evaluation of this regimen is warranted and is underway in an open-label, randomized phase II study of two doses of EMD 525797 (500 and 1,000 mg) combined with irinotecan and cetuximab that are compared with standard irinotecan and cetuximab.