tbuckley/cabot-search huggingface dataset:
PX-171–004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update
Authors: R. Vij, M. Wang, R. Orlowski, A. K. Stewart, S. Jagannath, V. Kukreti, M. H. Le, L. Kunkel, D. Siegel
Journal: Journal of Clinical Oncology (2009)

8537 Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m 2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had &gt; 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range &gt;1.9 to &gt;9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (&gt;8.5 mos) (range &gt;1 d to &gt;8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM. [Table: see text] [Table: see text]
A meta-analysis of receptor status discordance between primary breast cancer and metastases.
Authors: Gaetano Aurilio, Davide Disalvatore, Vincenzo Bagnardi, Elisabetta Munzone, Laura Adamoli, Giuseppe Curigliano, Giancarlo Pruneri, Angela Sciandivasci, Fernando De Vita, Aron Goldhirsch, Franco Nole
Journal: Journal of Clinical Oncology (2012)

546 Background: There is an increasing awareness that biology of breast cancer may evolve over time. The discordance in estrogen (ER), progesterone (PgR) and HER2 receptor status between primary breast cancer and metastases is being intensively investigated and a large amount of data has been produced. However, results from different studies seem to be conflicting and heterogeneous. To highlight this issue, a meta-analysis of published data was performed. Methods: A literature search was performed with Medline. All studies published from 1983 to 2011 comparing changes inER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumors were included. We used random-effects models to estimate pooled discordance proportions. Results: We selected 42 articles, mostly reporting retrospective studies. Twenty-eight, 20 and 27 articles were focused on ER, PgR and HER2 changes, respectively. A total of 2806 tumors were evaluated for ER discordance, 1809 for PgR discordance and 2801 for HER2 discordance. The heterogeneity between study-specific discordance proportions was high (I 2 &gt;75%, p&lt;0.0001) for ER, PgR and HER2. Pooled discordance proportions were 20% (95% CI: 16-25%) for ER, 33% (95% CI: 28-38%) for PgR and 9% (95% CI: 6-12%) for HER2. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 24% and 12% for ER (p=0.0115), respectively. The same figures were 44% and 15% for PgR (p&lt;0.0001), and 14% and 6% for HER2 (p=0.04). Conclusions: To our knowledge, this is the first meta-analysis addressing this topic. The findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer and therefore clinical implications with possible impact on treatment choice cannot be excluded. However, the high heterogeneity observed in our analysis may explain the disagreement among oncologists on performing a reassessment of the biological features. In our opinion, only high-powered prospective and randomized trials could clarify the controversies in this field.
Breast cancer subtype variation by ethnicity in a population-based cohort in British Columbia.
Authors: Dante Wan, Diego Villa, Ryan Woods, Rinat Yerushalmi, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2013)

1585 Background: Reports suggest breast cancer subtypes (BCS) are different in developing countries, often attributed to ethnicity. We assessed BCS in our multiethnic population with access to screening mammography and universal health care. Methods: The Breast Cancer Outcomes Unit database was used to identify women diagnosed with invasive breast cancer in 2006 and referred to the BCCA. Ethnicity was abstracted by chart review from a patient questionnaire completed by all new referrals. Ethnicities were grouped into: Caucasian (CA), East Asian (EA), Aboriginal (A), South Asian (SA), South-East Asian (SEA) and Other (O). BCS were grouped as: ER/PR+ HER2-, ER/PR+ HER2+, ER/PR- HER2+, ER/PR- HER2-. Rates of ER and HER2 positivity and BCS were compared by ethnicity using the Chi-square test; age at diagnosis was compared by ethnicity using the Kruskal-Wallis test. Results: 2,222 women were eligible with 2072 having completed questionnaires. Median age was 59 years. The distribution of ethnicities: 73% CA, 8% EA, 4% A, 3% SA, 3% SEA and 9% O. T stage was T1 57%, T2 34%, T3 8% and Tx 1%. N stage was N0 55%, N1 25%, N2 9%, N3 3% and NX 9%. 4.5% were Stage IV at diagnosis. HER2 positivity was significant by ethnicity; 14% CA, 18% EA, 25% A, 29% SA, 26 % SEA, 17% O (p = 0.0008). Age varied significantly (p&lt;0.0001); mean age in SEA was 53 compared to 60 years in CA. Conclusions: Although the subsets are small there appear to be differences in the rates of ER and HER2 positivity by ethnicities. ER negative disease was more frequent in Aboriginal and South Asians. These groups and SE Asians had more HER2 + disease. Validation on larger populations is pending. Genomics analysis may provide epidemiologic information. Differences in BCS may impact screening and prevention strategies. [Table: see text]
Rectal versus left-sided colon cancers: Clinicopathological differences observed in a pooled analysis of 4,182 patients enrolled to 8 clinical trials from the ARCAD database.
Authors: Mohamed E. Salem, Jun Yin, Lindsay A. Renfro, Benjamin Adam Weinberg, Tim Maughan, Richard Adams, Eric Van Cutsem, Alfredo Falcone, Niall C. Tebbutt, Matthew T. Seymour, Eduardo Diaz-Rubio, Enrique Aranda, Carsten Bokemeyer, Volker Heinemann, Aimery De Gramont, Axel Grothey, John Marshall, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2017)

675 Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p &lt; 0.001), have lung metastases (mets) (56% vs. 37%, p &lt; 0.001), and have 2 or more metastatic sites (64% vs. 60%, p &lt; 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p &lt; 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.
Patterns of local-regional relapse after complete response by definitive chemoradiotherapy for stage II/III (non–T4) esophageal squamous cell carcinoma.
Authors: Kazuki Sudo, Ken Kato, Hiroki Kuwabara, Yusuke Sasaki, Naoki Takahashi, Hirokazu Shoji, Satoru Iwasa, Yoshitaka Honma, Natsuko T. Okita, Atsuo Takashima, Tetsuya Hamaguchi, Yasuhide Yamada, Narikazu Boku
Journal: Journal of Clinical Oncology (2015)

4045 Background: Definitive chemoradiotherapy (dCRT) has been recognized as one of treatment options for esophageal squamous cell carcinoma (ESCC) patients who are not fit for surgery. Recent studies revealed that surveillance after dCRT was important in an adenocarcinoma dominant population. However, clinical utility of surveillance for ESCC is not clear. Methods: The subjects of this retrospective study were patients who underwent dCRT for stage II/III (excluding T4 disease) ESCC from 2000 to 2011 at National Cancer Center Hospital in Tokyo, Japan. We reviewed the patterns of relapse after clinical complete response (cCR). Each patient was generally surveyed with computed tomography (CT) and esophagogastroduodenoscopy (EGD) every 3-6 months. We also recorded new cancers (NC) diagnosed by EGD during surveillance after cCR. Local-regional relapse (LRR) without distant metastasis was classified into luminal-only relapse (LR) and other type of regional relapse (RR) with or without luminal relapse. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Among 351 patients treated with dCRT, 233 (66%) achieved cCR. The median follow-up time was 64.0 months. A total of 94 (40% of 233) patients had relapse after cCR: 45 (19%) with distant metastasis and 49 (21%) with LRR including 33 with LR and 16 with RR. Of the remaining 139 patients without relapse, 20 (14%) had NC: 17 with new esophageal cancer, 2 with hypopharynx cancer and 1 with esophagogastric junction cancer. Of 49 LRR, 31 (63%) were diagnosed within 1 year of dCRT and 46 (94%) within 3 years. Fifty-three of 69 patients (77%) with LRR or NC underwent local treatment (salvage surgery, endoscopic treatment or radiation). For these 53 patients with local treatment, the median OS from diagnosis of LRR or NC was 57.1 months (95% CI, 25.3-88.9). Conclusions: Our data suggest that 94% of LRR occurred within 3 years of dCRT. Of patients without relapse after cCR, 14% were diagnosed with NC by EGD. Outcome of local treatment for LRR or NC was excellent.
Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients
Authors: P. Lorigan, P. Corrie, D. Chao, P. Nathan, T. Ahmad, R. Marais, K. Burk, F. Erlandsson, M. Gore, T. Eisen
Journal: Journal of Clinical Oncology (2006)

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m 2 . Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in &lt;5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]
Survival post-progression (SPP) in phase III trials of chemotherapy in advanced NSCLC: Its potentially different impact on OS in the first-line and salvage settings.
Authors: Katsuyuki Hotta, Nagio Takigawa, Yoshiro Fujiwara, Akiko Hisamoto, Eiki Ichihara, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2012)

e18027 Background: We previously demonstrated that in advanced NSCLC, survival after progression to first-line chemotherapy (SPP-1) has significantly improved and has become more closely associated with OS after the initiation of first-line chemotherapy (OS-1), potentially because of the recent development of active agents even in salvage settings (Plos One 2011). We conducted a literature survey to examine time trend in survival after progression to second- or third-line chemotherapy (SPP-2/3) and its potential correlation with OS after the initiation of second- or third-line chemotherapy (OS-2/3). Methods: SPP-2/3 was pragmatically defined in each second- or third-line chemotherapy trial as the interval of MST (OS-2/3) minus median PFS time (PFS-2/3) (OS-2/3 = PFS-2/3 + SPP-2/3). The relationship between PFS-2/3 and OS-2/3 or SPP-2/3 and OS-2/3 was assessed in the regression analysis using the coefficient of determination (r 2 ); higher r 2 means a higher correlation. Results: Twenty trials of the second- or third-line chemotherapy initiated between 2001 and 2009, were defined (14,951 patients, 37 chemotherapy arms). Contrary to our previous findings regarding SPP-1, SPP-2/3 has not been significantly prolonged over the years (8.0-day increase per year; p = 0.161) despite a steady increase in OS-2/3 (17.2-dayincrease per year; p = 0.003) and PFS-2/3 (9.8-day increase per year; p = 0.005). Overall, a moderate association was observed between OS-2/3 and SPP-2/3 (r 2 = 0.6755), suggesting SPP-2/3 could predict 68% of the variation in OS-2/3. Interestingly, the association between OS-2/3 and SPP-2/3 became less close over the years (r 2 = 0.9849, 0.8280, and 0.5667 in 2001–2003, 2004–2006, and 2007–2009, respectively). Conclusions: During the period SPP-2/3 seemed stable, and the association between SPP-2/3 and OS-2/3 has become unclear probably because of recent survival improvement in PFS-2/3 rather than SPP-2/3. This seems in contrast with our previous report that SPP-1 has become more tightly associated with OS-1 over the year, potentially due to the establishment of active post-study treatments just in second- or third-line setting.
A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer
Authors: Alexis A. Kurmis, Fei Yang, Timothy R. Welch, Nicholas G. Nickols, Peter B. Dervan
Journal: Cancer Research (2017)

Abstract The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein–DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer. Cancer Res; 77(9); 2207–12. ©2017 AACR.
Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma.
Authors: Grant A. McArthur, Richard J. Young, Karen E Sheppard, Victoria Mar, Kelly Waldeck, Stephen B. Fox, Fergal C Kelleher, Wendy Liu, Alexander Dobrovic, Richard Pearson, John Kelly, James G. Christensen, Sophia Randolph
Journal: Journal of Clinical Oncology (2012)

8520 Background: Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to transformation of melanocytes indicating that CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a viable target for the treatment of human melanoma we have analyzed the frequency and clinico-pathological associations of genomic alterations of the CDK4 pathway in primary human melanoma and examined the genomic predictors of sensitivity to the highly selective CDK4/6 inhibitor PD 0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167 primary melanomas with clinical, molecular and pathological annotation, including median follow up of 6.6 years, were analyzed for copy number variation (CNV)- gain of CDK4 or CCND1 (average gene copy &gt;2.4) or loss of CDKN2A (average gene copy &lt;1.4), by fluorescence in situ hybridization. A panel of 39 cell lines were treated with 991 in vitro and GI50s calculated. The mean GI50 of the melanoma cell lines was used to define sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were used to identify predictors of sensitivity. Results: 75% of primary melanomas had at least one CNV (75%, 70% and 82% for BRAF, NRAS or wild-type BRAF/NRAS mutation status respectively). 55% showed loss of CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two or more CNVs involving CCND1 had worse overall survival (HR 5.56, p=0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive compared to only 2/6 wild type lines (p&lt;0.006). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991. Conclusions: Genomic alterations in the CDK4 pathway are frequent in melanoma and are associated with worse survival, particularly when melanomas harbor two or more CNVs involving CCND1. Mutation, loss or low expression of CDKN2A in melanoma cell lines predicted sensitivity to the CDK4 inhibitor 991. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic predictor of sensitivity to these agents.
Weekly cisplatin and radiotherapy for low-risk human papillomavirus positive oropharyngeal squamous cell carcinoma (HPVOPC).
Authors: Damien Urban, June Corry, Benjamin J. Solomon, Annette May Ling Lim, Tsien Fua, Andrew Coleman, Ieta D'Costa, Albert Tiong, Chen-Shin Liu, Danny Rischin
Journal: Journal of Clinical Oncology (2014)

e17017 Background: There is considerable interest in de-intensification strategies for good prognosis HPVOPC. Weekly cisplatin concurrent with radiotherapy is believed to be associated with less toxicity than high dose cisplatin, and may have similar efficacy in good prognosis HPVOPC. We reviewed our experience with weekly cisplatin which has been routinely used in our institution for low risk HPVOPC since 2010. Methods: Data from patients with low risk HPVOPC treated with concurrent weekly cisplatin (40mg/m2) and radiotherapy (70 Gy in 7 weeks) was collected from a prospective database and retrospective review of patient charts. Low risk was based on the prospective TROG 12.01 trial definition and included p16 positive OPC with stage III-IV disease excluding T1-2N1, T4 or N3 disease, or N2b-c disease in patients with greater than 10 pack year smoking history. Results: Of 32 patients identified, the median age was 56 (range 41-69) with 24 (75%) male and 22 (69%) tonsillar primary. The majority (91%) had stage 4 disease with 5 (16%), 16 (50%) and 11 (34%) patients staged T1, T2 and T3, respectively and 2 (6%), 1 (3%) and 29 (91%) patients staged N0, N1 and N2, respectively. All patients underwent staging and post-treatment assessment with positron emission computed tomography (PET CT). All patients completed the prescribed radiotherapy within 50 days and 84% completed at least 5 cycles of weekly cisplatin. Grade (Gr) 3 or 4 toxicities: Gr 3 mucositis - 28 (88%), Gr 3 nausea - 5 (16%), Gr 3 febrile neutropenia - 7 (22%), Gr 3 reversible acute kidney injury - 1 (3%) and Gr 4 thrombocytopenia - 1 (3%) . No patients required enteral feeding at 12 months. One patient experienced pharyngeal stenosis requiring intervention. The median follow up was 23 months (range 9-51) with no recurrences or deaths. Thirty-one patients achieved a complete metabolic response on PET CT, with 1 patient having minimal residual uptake in the primary site but biopsy was negative. Conclusions: Concurrent weekly cisplatin is well tolerated and associated with excellent disease control in low risk HPVOPC. Longer term follow-up is required but our data supports the validity of the weekly cisplatin arm in the TROG12.01 phase 3 trial.