tbuckley/cabot-search huggingface dataset:
Changes in survival from metastatic breast cancer during the last twenty-years: A population based study in Northern Italy
Authors: L. Cortesi, C. Cirilli, I. Rashid, E. Artioli, M. Federico
Journal: Journal of Clinical Oncology (2009)

1125 Background: A significant improvement in overall survival was observed in the last two decades in patients with breast cancer due to early diagnosis and more effective therapies. However, a significant improvement in metastatic setting has been questioned. Our population based study was aimed to investigate the outcome of metastatic breast cancer from 1988 to 2005. Methods: Women with stage IV de novo or relapsed breast cancer diagnosed between 1988 and 2005 were identified by the Modena Cancer Registry (MCR). For all patients overall survival (OS) was measured from the date of first distant metastases to the date of death from any cause or last follow-up and compared across groups for four periods of similar duration time: 1988–1993 (A), 1994–1997(B), 1998–2001(C), 2002–2005(D). Results: Among 8,654 patients with breast cancer identified by the MCR, 409 had an initial metastatic disease (4.8%) and 693 (8.4%) had a distant recurrence. Median age at onset was 66 versus 59 years in de novo vs relapsed disease (p = 0.001). Significant differences for postmenopausal age (80% vs 71%) and for positive estrogen receptors (72% vs 63%) were registered in de novo and relapsed disease, respectively (p = 0.001). After a 27 months median follow-up for initial metastatic disease, the five-year OS was 12%, 14%, 9%, and 13% in the A, B, C, and D periods, respectively, (p = 0.5). Conversely, in relapsed breast cancer, after a 29 months median follow-up, a significant survival improvement was observed between the first and the other three periods, being the 5 year-survival rate after recurrence 10%, 22%, 30%, and 25%, respectively (p = 0.001). A survival improvement was seen in the last ten years for relapsed breast cancer using aromatase inhibitors (p &lt; 0.0001) while for initial metastatic disease the same treatment provided a better outcome only in the last 4 years (p &lt; 0.0001). Conclusions: Data from our study show that the outcome of initial metastatic breast cancer is still discouraging, despite the availability of several new drugs in recent years. A limited improvement was observed in relapsed breast cancer with the aromatase inhibitors introduction. In any case, the finish line is still far away, and robust investments in basic and translational research are still absolutely necessary. No significant financial relationships to disclose.
Interstitial pneumonitis type reactions in patients treated with gemcitabine in Japan and the rest of the world (ROW)
Authors: A. Czarnecki, K. Liming
Journal: Journal of Clinical Oncology (2005)

8240 Background: Specific adverse drug reactions (ADRs) classified as Interstitial Pneumonitis (IP) have been identified as occurring with gemcitabine and several other oncolytic agents. These reactions are of concern for licence holders, prescribers, patients and regulatory authorities. Even though IP type reactions are rare they cause substantial concern and in recent years it appeared that in Japan there were more IP type reactions reported than elsewhere. Methods: MedDRA terms matching IP type reactions on the spontaneous databases were searched for gemcitabine. IP reports were reviewed individually and as aggregate data. Subsequently a comparison was made between IP type reaction reported in ROW and Japan. This was accompanied by extensive personal contacts with Japanese physicians, and literature searches. Results: IP type reactions have been reported rarely in association with gemcitabine treatment. The frequency of reporting was consistent with the information provided on the gemcitabine label. Overall review found discrepancies between types of reported reactions in different countries. On the basis of numbers only, the reporting rate in Japan was higher than in the ROW. When all factors were considered the actual incidence can be assessed as very similar. The discrepancies were found to be due to specific differences in types of reactions reported, coding, types of cancers treated, age and sex of patients, health care system and medical services for patients. Also the majority of reports in Japan come from intensive post-marketing surveillance (early marketing), which is very dissimilar to spontaneous reporting (known for under-reporting) in ROW. The extensive review of literature excluded other factors (genetic, metabolic or other) that would support any potential difference between compared regions. It appears therefore that the true reporting rate/incidence of IP can be estimated from our large clinical trial database and spontaneous reporting to be between 0.41% and 0.047%, while calculated reporting rate from intensive surveillance in Japan was 0.44%. Conclusions: Taking into account all factors the full review does not support the higher notion of IP reactions in Japan. No significant financial relationships to disclose.
Phase I study of gefitinib in combination with capecitabine and irinotecan for 2nd- and/or 3rd-line treatment in patients with metastatic colorectal cancer
Authors: D. Arnold, C. Constantin, T. Seufferlein, C. G. Gahlemann, H.-J. Schmoll, A. Kretzschmar
Journal: Journal of Clinical Oncology (2005)

3691 Background: Gefitinib (IRESSA), an orally active epidermal growth factor receptor tyrosine kinase inhibitor (TKI), can potentiate the effect of cytotoxic agents in colorectal cancer cells in vivo (Ciardiello et al, Proc Am Assoc Cancer Res 2000). Capecitabine (C) and irinotecan (I) have been used to treat metastatic CRC (mCRC), with adverse events (AEs) including neutropenia and diarrhea. This dose-finding Phase I study investigated the tolerability of gefitinib combined with increasing doses of C and I in patients (pts) with mCRC who had previously received oxaliplatin and 5-FU/FA. Methods: Each 3-week cycle consisted of gefitinib (250 mg/day) in combination with a sequential combined 4-level (L) dose escalation of oral C (mg/m2, twice daily on days 1–4) and iv I (mg/m2 on days 1 and 22), respectively: L1, 800 and 200; L2, 800 and 225; L3, 800 and 250; L4, 1000 and 250. Predefined dose-limiting toxicities (DLTs) were determined in pts who had completed 2 full cycles of combination therapy. Tumor assessment (RECIST) was performed every 3rd cycle; therapy continued until disease progression. AEs were recorded and graded using NCI-CTC. Results: 13 pts were enrolled: median age 62 years (range 32–77); male/female 6/7. The most common toxicities during the 1st 2 cycles are shown in the table. DLT at L1 was diarrhea (G3, n=1). Dose escalation was halted at L2 (as per protocol) due to DLTs of diarrhea (G3, n=3), neutropenia (G3, n=2), and severe epistaxis (G3, n=1). The study was terminated without further investigation into L1. Efficacy data will be presented later. Conclusion: The combination’s safety profile was similar to that of C/I alone with the addition of skin and GI events and epistaxis. Similar to other studies of TKIs combined with I, the combination regimen of gefitinib with C/I does not have a favorable safety profile in mCRC pts. IRESSA is a trademark of the AstraZeneca group of companies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Roche AstraZeneca, Roche
Risk factors for brain metastases in patients with a metastatic relapse of breast cancer
Authors: K. Slimane, S. Delaloge, F. André, A. Dunant, A. Perez, J. Grenier, M. Spielmann, C. Hill
Journal: Journal of Clinical Oncology (2004)

837 Background: Brain metastases are a more and more frequent, difficult clinical problem in advanced breast cancer (BC) patients (pts). We searched for risk factors of brain metastasis (BM) among pts diagnosed with a metastatic relapse of BC. Methods: A total of 557 premenopausal BC pts receiving systematic adjuvant chemotherapy were accrued at Institut Gustave-Roussy in a randomized trial of ovarian suppression [Arriagada et al, ASCO 03]. After a median follow-up of 9.5 years, 215 developed a first metastasis at a site other than brain alone. Of these 215 metastatic patients, 31 developed BM. The risk of BM in these 215 patients was analyzed as a function of patient, tumor and treatment characteristics by Cox models. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic relapse registered at Institut Gustave-Roussy in two randomized adjuvant chemotherapy trials (691 postmenopausal node-positive pts [Arriagada et al, Ann Oncol 2002] and 247 premenopausal node-negative pts [Arriagada et al, submitted]). Of these 199 pts, 19 developed BM. Results: In the first series, risk factors for BM in univariate analyses were lung metastasis as first site (yes/no): 2-year incidence rates of BM 24% vs 7% (p<0.001), negative hormone receptor (HR- vs HR+): 2-year BM rates 34% vs 5% (p<0.001) and short interval between BC and metastatic relapse (≤ vs >24 months): 18% vs 6% (p<0.008). In the multivariate analysis, only lung metastases remained prognostic (RR 5.3, 95% confidence interval (95%CI): 2.6–11, p<0.001). This was confirmed in the second series where the 2-year rates of BM were respectively 44% [95% CI: 26%–64%] and 3% [95%CI: 1–7%] in pts with or without lung metastases (RR 10 [95%CI: 3.8–27], p< 0.0001). Conclusions: This study shows that lung metastasis is a strong risk factor for the occurrence of brain metastases among BC patients. The occurrence of brain and lung metastases could be due to a common, albeit unknown, biological determinant. We suggest that prophylaxis of brain metastases may be evaluated in BC patients with lung metastases. No significant financial relationships to disclose.
Risk for subsequent breast cancer after lobular carcinoma in situ: Do clinical factors matter?
Authors: S. Muhsen, M. Morrogh, A. P. Andrade, R. Sakr, W. Paik, M. Morrow, T. A. King
Journal: Journal of Clinical Oncology (2010)

1593 Background: Increased breast cancer risk conferred by lobular carcinoma in situ (LCIS) is poorly understood. Molecular studies suggest a subset of LCIS may behave as precursors to invasive disease, yet criteria for risk stratification in the clinical management of women with LCIS are lacking. We reviewed our experience with LCIS over 25 yrs to identify clinical factors associated with a subsequent cancer diagnosis. Methods: Patients participating in surveillance following a diagnosis of LCIS were identified from institutional databases and clinical practice records (1984-2009). Those taking tamoxifen were excluded. Comparisons were made between patients who developed cancer (cases) and those without evidence of cancer after ≥ 96 months of followup (controls). Cases were further analyzed by time to cancer diagnosis, < 12 months vs. ≥ 12 months from LCIS. Results: 675 pts with LCIS w/out concurrent cancer at presentation were identified; 31 (5%) had bilateral LCIS. Average age at LCIS dx was 52 yrs (range 24-83). At a median of 58 months from LCIS dx (0-344mos), 78 pts (12%) developed 89 breast cancers (11 bilateral). Of 597 pts remaining cancer free, 152 (25%) have been followed ≥ 96 mos (controls); median followup for this gp 131 mos (96-344 mos). There was no difference in age at LCIS, FH breast cancer, finding of concurrent atypia, or number/site of biopsies after LCIS dx between cancer cases and controls. Cases were more likely to have had ≥ 1 MRI after LCIS dx compared to controls (73% vs. 46%, p < 0.001). Among cases, median time to cancer after LCIS dx was 39 mos, without a dominant histology (DCIS 35%, IDC 31%, ILC 25%, IDC w/ lobular fts 4.5%, and rare subtypes 4.5%). Comparing those dx with cancer < 12 mos (n = 15) vs. ≥ 12 mos (n = 63) after LCIS, there was no difference in histology, tumor size, stage, clinical risk factors or use of ≥ 1 MRI. Conclusions: In this large cohort of patients undergoing surveillance for LCIS, we observed a 2% annual incidence of breast cancer, yet we were unable to identify additional clinical risk factors associated with the development of cancer. Greater use of MRI among those diagnosed with cancer suggests a role for enhanced imaging in this cohort, however this finding requires confirmation in prospective studies. No significant financial relationships to disclose.
Outcomes of crossover treatments with paclitaxel- or gemcitabine-based combination chemotherapy for non-small cell lung cancer (NSCLC)
Authors: T. Y. Kim, S. I. Kim, S. R. Park, J. Y. Paek, I. S. Choi, D. W. Kim, T. Y. Kim, D. S. Heo, Y. J. Bang, N. K. Kim
Journal: Journal of Clinical Oncology (2004)

7304 Background: The aim of this study was to compare the treatment outcomes of crossover treatments with paclitaxel- or gemcitabine-based combination chemotherapy for non-small-cell lung cancer (NSCLC). Methods: A retrospective analysis was performed on newly diagnosed patients with stage IIIB or IV NSCLC who had received either paclitaxel (P)- followed by gemcitabine (G)-based chemotherapy (P→G; group A) or gemcitabine- followed by paclitaxel-based chemotherapy (G→P; group B). A total of 157 patients were evaluated. All the patients received combination chemotherapy with platinum compounds in the first-line treatment but either vinorelbine or platinum was added to the second-line chemotherapy. Results: There patient characteristics of group A (n=115) and group B (n=42) were similar. The response rates of the first-line treatment were 46% for group A, 33% for group B (p=0.185), and response rates of the second-line treatment were 26% and 38%, respectively (p=0.143). The maximum cumulative response rates of the first- and second-line treatments were 61.7% for group A, 57.1% for group B (p=0.602). The time to progression of the first-line chemotherapy was 4.1 months for group A, 4.4 months for group B (p=0.9736), and for the second-line chemotherapy, it was 3.4 months and 3.9 months (p=0.7100). The median overall survival times were 18.9 months and 15.0 months, respectively (p=0.1420). Conclusions: There was no difference in terms of the response rates, the maximum cumulative response rates, the time to progression, and the overall median survival time as to whether the NSCLC patients received paclitaxel- followed by gemcitabine-based chemotherapy or gemcitabine- followed by paclitaxel-based chemotherapy. No significant financial relationships to disclose.
Retargeting nanoparticle albumin-paclitaxel to radiation-inducible receptors.
Authors: D. Hallahan
Journal: Journal of Clinical Oncology (2010)

e13560 Background: Ionizing radiation induces physiologic changes in cancer that uniquely alters cell surface molecules. Phage displayed peptide libraries were used to discover peptides that bind specifically to irradiated cancers. Methods: The amino acid sequence HVGGSSV achieved tumor-specific binding when conjugated to nanoparticles containing radiation sensitizing paclitaxel. Results: Near-infrared images showed binding in irradiated tumors treated with HVGGSSV-nab-paclitaxel, whereas tumors treated with SGVSGHV-nab-paclitaxel or nab-paclitaxel alone showed minimal radiance. Untreated (0 Gy) control tumors showed similar levels of radiance across all treatment groups. Irradiated tumors treated with HVGGSSV-nab-paclitaxel showed greater tumor specificity than SGVSGHV-nab-paclitaxel, or nab-paclitaxel (p<0.05). Radiation-guided delivery of nanoparticles improved both bioavailability of drug delivery and efficacy of radiotherapy in mouse models of lung cancer. Therapeutic efficacy of HVGGSSV guided nab-paclitaxel was studied in LLC and H460 lung carcinomas. On day 7 after tumor implantation, mice were injected with 10 mg/kg of either HVGGSSV-nab-paclitaxel, SGVSGHV-nab-paclitaxel, or nab-paclitaxel. Tumor volumes for each treatment group were measured until they reached a 4-fold increase in volume. Radiation alone achieved only a slight tumor growth delay (2 days) in LLC tumors, and 6 days in H460 tumors as compared to untreated controls. SGVSGHV-nab-paclitaxel controls showed no significant growth delay in LLC tumors and only 2 days delay in H460. After subsequent irradiation, this was improved to 2 days (LLC) and 6 days (H460). Treatment with nab-paclitaxel alone produced tumor growth delay of 2 days (LLC) and 6 days (H460), and upon additional irradiation increased to 6 days (LLC) and 11 days (H460). Both LLC and H460 lung carcinoma showed significant tumor growth delay for HVGGSSV-nab-paclitaxel as compared to nab-paclitaxel, SGVSGHV-nab-paclitaxel and saline controls. HVGGSSV-nab-paclitaxel treatment achieved a growth delay of 10 days (LLC) and 15 days (H460) over untreated controls. Conclusions: Thus, radiation can be used to guide nanoparticles to cancer. No significant financial relationships to disclose.
Comparison of genetic alterations from the bladder cancer genome atlas (TCGA) and a prospective set of high-grade urothelial carcinoma tumors using a CLIA laboratory next generation sequencing assay.
Authors: Gopa Iyer, Aditya Bagrodia, Eugene K. Cha, Mariel Elena Boyd, Ahmet Zehir, Donavan T Cheng, David Michael Hyman, Richard Martin Bambury, Maria E. Arcila, Marc Ladanyi, Agnes Viale, Hikmat Al-Ahmadie, Michael F. Berger, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, David B. Solit
Journal: Journal of Clinical Oncology (2015)

298 Background: The type and frequency of recurrent, targetable alterations in muscle-invasive, treatment-naïve urothelial cancer (UC) have been well-catalogued through the bladder TCGA. We sought to validate these findings within a prospective cohort of patients (pts) with progressive UC treated at our institution. This cohort typifies the UC patient population managed by medical oncologists. Methods: Pts with a diagnosis of UC were enrolled onto an IRB-approved protocol between 1/14/14 and 7/29/14, which allowed for sequencing of all exons in 341 oncogenes and tumor suppressor genes using an exon capture next generation sequencing assay (NGS) platform (MSK-IMPACT) in a CLIA lab from tumor and matched germline DNA. Somatic point mutations, truncations, copy number alterations, and insertions/deletions were detected. Results: 49 UC pts were sequenced, 5 (10%) having upper tract disease. 33 (67%) tumors were pure UC histology with the remainder containing divergent differentiation. 17 samples (24%) were metastatic in origin, and 40 samples were analyzed from pts who had received prior chemotherapy. The most common alteration identified was point mutations within the TERT promoter (71%), a region not sequenced by TCGA. Additional alteration frequencies were similar between both sets. FGFR3 mutations overlapped with both PIK3CA and TSC1 alterations and co-alterations were observed between FGFR3 and CDKN2A as well as PIK3CA and CCND1. Conclusions: TERT promoter mutations were found at high frequency in the MSK-IMPACT tumor cohort. The frequency and type of alterations identified in the bladder TCGA are similar to the MSK-IMPACT cohort, suggesting that TCGA data can be used to guide clinical trials in the metastatic, pre-treated population. Overlap of alterations within and across core signaling pathways underscores the need for functional validation of alterations and for rational combinations of targeted therapies to effectively treat advanced UC. [Table: see text]
Dynamic evaluation of tumoral transcriptome for a blind study of mechanisms of chemoradiotherapy resistance in rectal cancer patients
Authors: E. Casado, P. Cejas, J. de Castro, P. Vaquez, B. Sanchez, J. Feliu Belda, B. Singh, B. Castelo Ja Fresno, N. Manceñido, R. Perona, M. Gonzalez Baron
Journal: Journal of Clinical Oncology (2005)

3604 Background: Distant metastases are the major obstacule for cure of locally advanced rectal cancer. The mechanisms of chemoradiation resistance (CR) are elusive since efforts to elucidate them have been hypothesis-orientated. Unravelling them will provide the opportunity to overcome treatment failure. In this context, dynamic high throughput gene profiling, comparing tumour samples before and after CR offers great promise. To this end serial analysis of gene expression (SAGE) is a truely blind and powerful tool, as it evaluates precisely the whole transcriptome, and can be performed from very small samples (microSAGE), a key hurdle in the colorectal cancer setting. Methods: A cohort of 52 patients with advanced adenocarcinoma of the rectum had been preoperatively treated with neoadjuvant oxaliplatin-raltitrexed and radiotherapy. With a medium follow up of 30 months, we selected the four most paradigmatic patients showing clear progression during CR, and four showing complete pathological responses. 12 frozen tumor samples were selected for SAGE: eight from “progressors” (four endoscopic preCR biopsies and four surgical specimens) and four from “responders”. MicroSAGE was performed in all selected samples. Transcriptomes have been compared before and after CR (intrapatient), and between (interpatient) patients. Statistical analysis was done with SAGE2000 vs 4.5, and Bitia (a specific software that we have helped to develop). Results: About 30.000 tags have been sequenced for each SAGE library. A profile of more than 100 genes changed significantly after CR. Striking differences have been found for certain transcripts (this has prompted plans for functional in vitro and clinical prospective evaluation). Also a differential profile has been observed between “responders” and progressors“. Conclusions: Certain genes have shown remarkable differences in their expression before and after CR. The intrapatient analysis notably reduces random variations. This is the first time that the whole transcriptome has been fully evaluated in tumour samples from rectal cancer patients. New and relevant mechanisms of CR resistance could be pinpointed from this study. This work has been supported by FIS PI021094. No significant financial relationships to disclose.