tbuckley/cabot-search huggingface dataset:
Correlation between prostate cancer immunohistochemical stains (IHC) and survival in stage D2 patients(pts)
Authors: B. S. Kasimis, V. Chang, S. Gounder, D. Hoover, C. Finch-Cruz, J. Cogswell, M. L. Gonzalez, E. Morales, S. Srinivas, M. Blumenfrucht
Journal: Journal of Clinical Oncology (2008)

16093 Background: The expression of 9 signaling transduction pathways, important for angiogenesis and apoptosis was identified by IHC in archival prostate cancer biopsies and correlated with survival in pts with metastatic disease. All pts had androgen deprivation and were followed at 3 month intervals. Methods: In an IRB approved protocol, 42 pts with paraffin-embedded tissue collected between 1992 and 2006 at our Institution were identified for chart review. The most representative tumor tissue block was chosen for each of the 42 cases evaluated. IHC stains to detect tumor expression of S6 (ribosomal), p70s6, pTEN, AKT-1, BCL-1 (Cyclin D1), VEGF, c-KIT (CD117), PDGFR-alpha (C-20), and PDGFR-beta (P20) were done by US LABS (Irvine, CA). All results were independently evaluated by two pathologists. Immunoreactivity was scored using a semiquantitative system combining intensity of staining(0–3+) and percentage of cells staining positive(0–3+). The total score was obtained by adding the scores for intensity and the percentage of positive cells, then averaging the results obtained by each reader. A Cox regression survival model for each stain was developed with variables known to predict survival: Gleason score, Hemoglobin (Hgb), Alkaline Phosphatase (Alk Phos), Prostate Specific Antigen (PSA), Lactate Dehydrogenase (LDH) levels. Results: The medians were: age 70 yrs(56–92), Gleason score 8(6–10), LDH 171 IU/L(97–350), Hgb 12.9 gm/dl(6.8–16.3), PSA 188 ng/ml(2–5677), Alk Phos 139 U/L(60–1756), survival 851 days(163–6102). In univariate analysis, VEGF staining was predictive of D2 survival (p<0.037) but not in multivariate analysis. None of the other stains were predictive of survival. Conclusions: In this sample the overexpression of S6,p70s6,pTEN,AKT-1,BCL-1,VEGF,c-KIT,PDGFR-alpha and PDGFR-beta by IHC staining in archival tissue is not independent predictors of survival. The VEGF staining, however, was predictive for survival in univariate analysis. No significant financial relationships to disclose.
Prevalence of <i>BRCA1</i> and <i>BRCA2</i> mutations in women diagnosed with ductal carcinoma in situ.
Authors: N. Elsayegh, S. Bayraktar, A. M. Gutierrez-Barrera, H. Lin, H. M. Kuerer, K. I. Muse, K. Ready, J. K. Litton, F. Meric-Bernstam, G. N. Hortobagyi, B. Arun
Journal: Journal of Clinical Oncology (2011)

1512 Background: The frequency of a BRCA mutation among women with ductal carcinoma in situ (DCIS) has not been well described. Consequently, patients with DCIS were not historically considered ideal candidates for genetic testing even in the presence of a family history of breast and ovarian cancer. Therefore, we examined the prevalence of BRCA1/2 mutations in women diagnosed with DCIS. Methods: Patients with DCIS, who were referred for genetic counseling and underwent genetic testing, were included in the study. Patient characteristics were obtained from a prospectively maintained research database. This study was approved by institutional review board. The likelihood of carrying a BRCA mutation was calculated using the BRCAPRO model (Version 5.1). Chi-square analysis was used to determine the difference among mutations carriers vs. non-carriers with DCIS. Results: One hundred and twenty nine patients diagnosed with DCIS underwent genetic testing for BRCA mutations. Twenty-eight percent (37/129) of DCIS patients tested positive for a deleterious BRCA mutation (15 BRCA1, and 22 BRCA2). In addition, 6 were found to have a variant of uncertain significance (VUS). The average age of diagnosis was 46.2 yrs (30-69) in BRCA positive patients and 43.5 yrs (26-65) in BRCA negative patients (p =0.177). Patients who tested positive for the BRCA mutations had significantly more family history of breast and ovarian cancer (p=0.021, p=0.006 (respectively) than those who tested negative; as reflected by the BRCAPro calculation (p ≤0.0001). Fifty seven percent of BRCA positive patients had one breast removed for prophylactic reasons while only 28% BRCA negative patients did (p=0.004). This effect was significantly stronger for patients ≤40 (p=0.007). Conclusions: Patients with DCIS and a family history of breast and/or ovarian cancer have a high rate of BRCA positivity regardless of age. These findings suggest that patients with DCIS are appropriate candidates for genetic testing in the presence of family history and regardless of age even if they do not have invasive cancer.
KEYNOTE-177: First-line, open-label, randomized, phase III study of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma.
Authors: Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry Andre, Johanna C. Bendell, Yinghua Zhang, Baohoang Lam, Minori Koshiji, Dirk Jäger
Journal: Journal of Clinical Oncology (2016)

TPS789 Background: Mismatch repair deficient (dMMR) tumors are characterized by high mutational load and lymphocyte infiltration and may be good candidates for immune checkpoint blockade. Pembrolizumab is a monoclonal antibody against PD-1 that is designed to block its interaction with PD-L1 and PD-L2 and thus allow an antitumor immune response. In the KEYNOTE-016 proof-of-concept study, pembrolizumab showed promising antitumor activity against dMMR tumors in patients (pts) with treatment-refractory metastatic colorectal carcinoma (mCRC). KEYNOTE-177 is an international, randomized trial designed to evaluate the efficacy and safety of pembrolizumab compared with standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or microsatellite instability-high (MSI-H) mCRC. Methods: Key eligibility criteria include age ≥ 18 y, confirmed MSI-H or dMMR mCRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. Pts will be randomized 1:1 to receive either pembrolizumab 200 mg Q3W or investigator’s choice of SOC chemotherapy. Chemotherapy must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment will continue until PD, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembrolizumab only). Response will be evaluated every 9 wk per RECIST v1.1 by central review and per RECIST adapted for immunotherapy response patterns. Eligible pts may continue pembrolizumab beyond initial RECIST-defined progression. Pts in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 9 wk. PFS per RECIST v1.1 is the primary end point; OS and ORR are key secondary end points. Other end points include duration of response and health-related quality of life. Planned enrollment in KEYNOTE-177 is 270 pts.
LPS activated dendritic cell vaccine in combination with immunomodulatory dose of cyclophosphamide in patients with stage IV melanoma: Preliminary report from the phase I/IIa clinical trial
Authors: A. K. Palucka, E. Akagawa, H. Ueno, J. Fay, J. Banchereau
Journal: Journal of Clinical Oncology (2008)

3049 Background: Our studies demonstrate that only a fraction of patients with stage IV melanoma who undergo DC vaccination mount an immune response to tumor antigens presented on the vaccines. Two immune parameters appear linked to clinical outcome of the patients: 1) objective clinical response is associated with induction of melanoma-specific effector cells; and 2) all patients display melanoma- specific Tregs that may counteract effector cells. Thus, we need to identify the next generation DC vaccines able to tilt the balance towards strong effector cells that can overcome Tregs control. Methods: We have initiated a phase I/II clinical trial (IRB #006–025; BB-IND #12919) enrolling patients with stage IV melanoma. Patients receive 7 injections of an autologous DC vaccine generated from monocytes by culturing with GM-CSF and Type I interferon, loaded with killed allogeneic melanoma cells and activated with lipopolysaccharide (LPS). Patients receive cyclophosphamide 300mg/m2 intravenously 3 days prior to DC vaccinations # 1, 3, 5, 6 and 7. The trial is based on an initial toxicity evaluation in the first 10 patients on top of a 2-stage response rule - 1/19 to continue and 5/30 to accept. The primary end-points are the rate of objective clinical response and the safety/feasibility of the vaccination preparation. Results: Our pre-clinical results demonstrate that LPS (TLR4 ligand) is superior to poly I:C (TLR3) and/or a mixture of inflammatory cytokines in priming IFN-DCs to secrete IL12p70. LPS-activated IFN-DCs loaded with killed allogeneic melanoma cells are better in priming of autologous CD8+ T cells. Thus, such vaccine is expected to induce stronger immune responses in patients, thereby leading to better clinical outcomes. To date 3 patients were enrolled and begun vaccinations. Vaccinations were safe and tolerable. One of two patients eligible for week 10 staging demonstrated a partial regression of multiple metastatic lesions by RECIST criteria. Conclusions: LPS activation improves in vitro cross-priming capacity of DC vaccines. Preliminary results in vivo show safety and feasibility of LPS-activated DC vaccine in patients with stage IV melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ODC Therapy, Inc
Evaluation of overexpression of HER2/neu in primary uterine, ovarian, and peritoneal papillary serous carcinoma.
Authors: M. Hatami, G. Goldberg, K. Whitney
Journal: Journal of Clinical Oncology (2010)

e15512 Background: Primary uterine papillary serous carcinoma (UPSC), ovarian papillary serous carcinoma (OPSC), and peritoneal papillary serous carcinoma (PPSC) share histologic features and are biologically more aggressive than other mullerian tumors. HER2/neu (c-erbB-2) is a proto-oncogene identified on chromosome 17 at q21which is responsible for unregulated cell growth, differentiation, and prolonged survival. The purpose of this study was to compare differences in HER2/neu overexpression in patients with primary UPSC, OPSC, and PPSC. Methods: After IRB approval was obtained, H&E stained slides and formalin-fixed paraffin-embedded blocks of the tumors were obtained from the Department of Pathology. HER2/neu overexpression in the tumor was evaluated by immunohistochemistry utilizing FDA approved IHC using the Hercep Test with appropriate controls. Scores of 0 to 1+ were considered negative and scores of 2+ to 3+ considered positive (weakly and strongly positive, respectively). Clinical data including age at diagnosis, FIGO stage and tumor grade was abstracted from the medical records; statistical methods included t-test, Chi-Square, attributable risk and relative risk determinations. Results: A total of 55 cases were analyzed, and included UPSC (26), OPSC (25), and PPSC (4). The patients with positive compared with negative HER2/neu expression were significantly older (69 ± 10.6 vs. 59.4 ± 5.9 years, p < 0.02). HER2/neu overexpression was observed more frequently in UPSC (13, 50%) than in OPSC (4, 16%, p < 0.05). The relative risk for HER2/neu overexpression in UPSC was found to be 3.1- fold higher than that for OPSC, and the attributable risk was 34%. No significant correlation was found by FIGO stage or tumor grade (p < 0.5). Of note, none of the PPSC tumors exhibited HER2/neu overexpression. Conclusions: HER2/neu overexpression is linked to older patients and to UPSC histology. Further investigation of HER2/neu overexpression in primary UPSC and as a potential marker to distinguish UPSC from similar tumors is warranted. Utilizing FISH is the necessary next step, in order to confirm gene amplification in these tumors if anti-HER2 antibody therapy would be a possible treatment option in these tumors. No significant financial relationships to disclose.
Feasibility of a physician-extender approach to increase advance care planning uptake.
Authors: Scott D Siegel, Cynthia Fanning
Journal: Journal of Clinical Oncology (2016)

8 Background: Advanced care planning (ACP) for people with life-limiting cancer has been associated with improved patient quality of life and care more consistent with patient wishes. Nevertheless, even though approximately 70% of patients with a life-limiting illness will require the substituted judgment of a proxy, fewer than 25% of patients have documented goals of care. This poor uptake has been attributed to limits in physician time and ACP training. The current study evaluated the feasibility of utilizing a physician-extender trained in ACP best practices to overcome these barriers and improve ACP uptake. Methods: Patients who met criteria for a life-limiting cancer diagnosis were identified by support staff in Medical Oncology offices and the Emergency Department (ED) in a large North East community health care system. Pending physician approval, a Licensed Clinical Social Worker (LCSW) with training and experience in ACP was available to provide support and assistance to patients, which included but was not limited to ACP. The LCSW initially met patients in clinic and subsequently in whatever way was most convenient for the patient (at future appointments, by phone, inpatient, or at the patient’s home). The program was approved by the Medical Oncology section and the Emergency Department. Results: ACP uptake, calculated as the percentage of eligible patients who participated in the program, was 14.6% in the Medical Oncology practices (60/140) and 44.6% (41/92) in the ED. The difference in uptake between the two sites was significant, χ 2 (1, N = 502) = 41.88, p &lt; .01, and was primarily the result of Medical Oncologists determining that ACP was not appropriate for a subset of eligible patients. Conclusions: The results of this feasibility evaluation suggest that limits in time and ACP training are not the primary barriers to ACP uptake in oncology. Instead, the type of physician and setting proved to be important correlates of uptake. We consider the implications of these findings and identify next steps to better understand the factors that influence physician participation in ACP.
An academic medical center's journey to a survivorship care plan.
Authors: Susan Korber
Journal: Journal of Clinical Oncology (2013)

210 Background: Cancer clinicians are challenged by the need to give patients an initial treatment plan and a summary of their care at the end of the treatment period. Both are essential elements in the care continuum and the summary is now a required standard for accreditation by the Commission on Cancer. By 2015, each patient’s Survivorship Care Plan should be a collaborative document shared with the patient, their primary care and/or referring provider. A well-written plan includes a road map for the patient and their PCP to use as the patient transitions from active care into surveillance. Our academic medical center, part of the Lifespan system, began exploration of the transition process in 2007. The goal of our multidisciplinary group was to develop a patient and PCP friendly record of the treatment experience and recommendations for follow up. Methods: Two oncology staff nurses at The Miriam Hospital developed an early home-grown tool in 2008, a simple one page document in layman’s terms. From 2009 to 2010 we participated in a national Breast Cancer Registry Pilot Program using ASCO templates and assessing patient and staff perspectives on the use of treatment plans and summaries. Lessons learned from both experiences was to "keep it simple." At the urging of the CoC we moved on to the Journey Forward website and tried to utilize plans for breast and colorectal patients. We have now formed a partnership with our state Department of Health and have developed a template for use by all cancer programs in our state. Results: Our state will be the first to offer to all cancer programs the ability to download a user friendly one page template for a Survivorship Care Plan. Clinicians enter demographics, the patients’ providers, simplified disease information, treatment given and surveillance suggestions. A list of community references is included on the second page. The Department of Health will have this available on their website for download into each cancer center’s electronic system. Conclusions: Development of a user friendly summary of patient treatment and future surveillance needs is possible with a collaborative effort between clinicians and engaged public health officials. Understanding the value of a simple, single page form available online has been essential.
HER2 amplification as a ‘molecular bait’ for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: The HERACLES-RESCUE trial.
Authors: Salvatore Siena, Alberto Bardelli, Andrea Sartore-Bianchi, Cosimo Martino, Giulia Siravegna, Alessandro Magri', Francesco Leone, Vittorina Zagonel, Sara Lonardi, Alessio Amatu, Federica Tosi, Patrizia Racca, Agostino Ponzetti, Fortunato Ciardiello, Silvia Marsoni
Journal: Journal of Clinical Oncology (2016)

TPS774 Background: We previously documented HER2 amplification in 5% of KRAS wild-type metastatic colorectal cancer (mCRC; Valtorta E. et al, Modern Pathology, 2015). Despite refractoriness to standard chemotherapy and to cetuximab, patients with HER2 amplified mCRC achieve 30% response rate (RR) and long lasting objective responses (median duration 8.5 mos.) when treated with lapatinib (L) and trastuzumab (T) [HERACLES trial - EudraCT 2012-002128-33; Siena et al. J Clin Oncol 33, 2015 (suppl; abs 3508)]. We sampled responding HERACLES patients at progression, and found persistent high levels of HER2 tested by IHC and FISH on tissue re-biopsies, or by droplet digital liquid biopsy in plasma ctDNA (LB). We reasoned that HER2 in these tumors could still be exploited as “molecular bait” for T-DM1, an antibody-drug conjugate of trastuzumab linked to the cytotoxic agent emtansine. We thus conducted a preclinical trial in a patient-derived xenograft (PDX) model generated from the viable biopsy of a acquired-resistant HERACLES patient. In a 2-arm trial against control (6 PDXs per arm), we compared T-DM1 to pertuzumab, and found that only T-DM1 treated animals achieved tumor responses. We therefore designed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after T+L treatment. Methods: HERACLES-RESCUE is an independent phase II trial assessing the efficacy of T-DM1 in HER2 amplified mCRC progressing after anti-HER2 (L+T) therapy within the HERACLES trial. Response rate is the primary endpoint. Using the A’Hern approach to retrofit the sample size from the constrained sample size of patients treated in HERACLES, and assuming α = 0.15, β = 0.85 and H 0 = 5%, if 2 responses will be observed in 13 patients we would be able to define a clinically relevant true response rate of 25% (H 1 ). Eligibility: progression/relapse within HERACLES L+T treatment, lack of KRAS mutations by LB, measurable disease (RECIST v1.1), ECOG PS ≤ 1, and adequate organ function. Treatment: T-DM1: 3,6 mg/kg q21d. A first patient was treated on August 2015. EudraCT number: 2015-003275-30; Funded by AIRC Grant # 9970. Clinical trial information: 2015-003275-30.
External validation of a prediction model of survival after cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC).
Authors: Axel Bex, Erik D. van Werkhoven, Allard Noe, Jose A. Karam, Surena F. Matin, Vitaly Margulis, Grant Stewart, Michael D. Staehler, Christopher G. Wood
Journal: Journal of Clinical Oncology (2016)

556 Background: In 2013 a model to predict cancer-specific survival (CSS) after CN was published (Eur Urol 63:947-52, 2013), consisting of a preoperative nomogram to predict 6-month (mo) probability of death (PoD) based on serum albumin and serum lactate dehydrogenase and a postoperative nomogram (12-mo PoD) to which were added pathologic primary tumour stage, nodal stage and intraoperative blood transfusion. We externally validated the model with a contemporary European dataset of patients treated in the VEGF-targeted therapy era. Methods: After having received the original calibration indices, data from 205 mRCC patients who underwent CN between 2006 and 2013 at 3 European centres in Amsterdam, Edinburgh and Munich were used for external validation. Next to the variables for the nomogram, age, MSKCC, IMDC, number and metastatic sites and subtype were collected. Both nomograms were used to obtain predictions for the subjects. Based on the quantiles of the distribution of predictions subjects were grouped into 4 categories and Kaplan-Meier estimates calculated as were calibration plots of observed versus predicted PoD. Since all subjects had follow-up for &gt; 1.25 years CSS at 6 and 12 mo as a dichotomous outcome and the ROC curves were plotted. Results: With a median follow-up of 29 mo and a median OS of 15 (95% CI 12-22) mo for the entire cohort, 32 and 82 patients died from RCC at 6 and 12 mo after CN respectively. For the pre- and postoperative nomogram the respective ROC curve had an AUC of 0.667 and 0.712. In the preoperative calibration plot the observed PoD at 6 mo was higher than the predicted, resulting in a lower discrimination when compared to the original validation (0.76 and 0.74 for pre- and postoperative nomograms respectively). Conclusions: In external validation the pre- and postoperative nomograms perform well in patients with primary mRCC. Their discrimination is in the reported range of MSKCC and IMDC risk scores, which were not developed to address the decision of CN (concordance index 0.657 and 0.71, Lancet Oncol 14:141-8, 2013). Although discrimination of the preoperative nomogram was lower in external validation, it retains ability to predict early death after CN.
Phase I study of anti-VEGF monoclonal antibody bevacizumab and HDAC inhibitor valproic acid in patients with advanced cancers.
Authors: J. J. Wheler, F. Janku, T. Jackson, S. Fu, M. Sun, H. Yang, A. Naing, S. L. Moulder, A. M. Tsimberidou, D. S. Hong, G. S. Falchook, S. A. Piha-Paul, G. Garcia-Manero, R. Kurzrock
Journal: Journal of Clinical Oncology (2011)

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