tbuckley/cabot-search huggingface dataset:
Association of <i>PIK3CA</i> H1047R and <i>STK11</i> F354L mutations with response to neoadjuvant chemoradiotherapy and survival in esophageal cancer.
Authors: Po Kuei Hsu, Teh-Ying Chou
Journal: Journal of Clinical Oncology (2017)

55 Background: Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal cancer. However, its efficacy is limited in non-responders and there is no reliable clinical parameter in predicting treatment response. We aim to identify chemoradiation-resistant cancers and avoid unnecessary treatments in non-responders with mutation analysis. Methods: Genomic DNA was extracted from diagnostic biopsy specimens of 20 patients (10 with good and 10 with poor response) with esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy and esophagectomy. Using next-generation sequencing, we screened mutation hotspots in 46 cancer-related genes (Ion AmpliSeq Cancer Panel). Potential predictive genetic variations were validated in another cohort of patients. Chemoradiotherapy response was based on pathological evaluation of surgically resected specimens. The prognostic significance of genetic variations was evaluated with Cox regression survival analysis. Results: In the first cohort, we discovered PIK3CA H1047R and STK11 F354L as potential targets to predict chemoradiation resistance. Next, we investigate these genetic variations in another 54 patients. Altogether, 18.9% (14/74) and 6.8% (5/74) of patients had PIK3CA H1047R and STK11 F354L, respectively. In patients with poor response to chemoradiotherapy, 45.8% (11/24) had either PIK3CA H1047R or STK11 F354L; compared to 12.0% (6/50) in patients with good response ( p = 0.001). In other words, 64.7% of patients with either one genetic variation responded poorly to chemoradiotherapy. In survival analysis, the 5-yr survival rates were 7.7% and 43.7% in patients with either one genetic variation and those without, respectively ( p = 0.003). In multivariable analysis, the presence of either one genetic variation was a significant prognostic factor for overall survival (Hazard ratio: 2.43, 95% confidence interval: 1.195-4.944, p= 0.014). Conclusions: PIK3CA H1047R and STK11 F354L mutations are associated with poor response to neoadjuvant chemoradiotherapy and worse prognosis in esophageal cancer. It may potentially be biomarkers to guide treatment decisions.
In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-including chemotherapy
Authors: G. Metro, Z. Zheng, A. Fabi, M. Mottolese, A. N. Monteiro, P. Vici, D. Boulware, S. Lara Rivera, F. Cognetti, G. Bepler
Journal: Journal of Clinical Oncology (2009)

1129 Background: Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small cell lung cancer (NSCLC) and pancreatic cancer. We investigated the tumoral levels of RRM1 in a population of metastatic breast cancer (MBC) patients treated with gemcitabine-based regimens. The protein levels of the excision repair cross-complementation group 1 (ERCC1) and breast and ovarian cancer susceptibility gene 1 (BRCA1) were also measured. Methods: Fifty-five patients were treated and followed prospectively from September 2004 to December 2007. Treatment consisted of gemcitabine plus a taxane in 46 patients and gemcitabine plus pegylated liposomal doxorubicin in 9 patients. RRM1, ERCC1, and BRCA1 were determined by automated in situ protein quantification (AQUA v1.6) on a tissue microarray containing triplicate tumor specimens. Results: The average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6–2, 774.1, 74.0–410.3, and 54.4–1, 833.1, respectively. A statistically significant correlation between the levels of expression of all three markers (Spearman's rho &gt; .36; P &lt; 0.007) was observed. There was no significant association between RRM1, ERCC1, or BRCA1 levels and disease response, progression free survival, or overall survival. Conclusions: In tumor specimens from patients with MBC, RRM1, and BRCA1 had a range of expression and pattern of distribution that makes these markers potentially suitable for clinical decision making. In contrast, the relatively narrow range of ERCC1 expression might signify that ERCC1 protein levels are not useful predictors of platinum efficacy in MBC. Consistent with what has been shown in NSCLC, RRM1, ERCC1, and BRCA1 levels were significantly correlated, suggesting that the coexpression of such DNA repair proteins may be universal to epithelial malignancies. The lack of correlation between marker levels and clinical outcome may be explained by the specific chemotherapy combinations used. No significant financial relationships to disclose.
Joint pain and physical activity among breast cancer survivors on aromatase inhibitor therapy.
Authors: Kirsten A Nyrop, Hyman Muss, Betsy Hackney, Rebecca Clevalend, Leigh F. Callahan
Journal: Journal of Clinical Oncology (2014)

e11564 Background: Adjuvant endocrine treatment that includes an aromatase inhibitor (AI) is standard care for post-menopausal women with a diagnosis of hormone-receptor positive breast cancer (BC). Joint symptoms (pain, stiffness, achiness) are common side-effects of AIs, with an estimated prevalence of 33% to 74%. Joint pain is a barrier to engaging in national guidelines recommended levels of physical activity (PA) of 150 minutes/week; yet, engagement in PA is evidence-based for relieving joint symptoms among adults with arthritis. This study investigates eligibility for a PA intervention study among BC survivors who are reported to be taking an AI and are being seen in an oncology clinic. Methods: Review of 183 consecutive patients whose medical record reported being on AI therapy. Patients were queried to determine eligibility for a PA trial that required: (1) currently taking an AI, (2) experiencing joint symptoms, and (3) < 150 minutes/week of PA. Results: 8% percent (N=15) were excluded for not currently taking an AI and 19% (N=34) for medical or personal reasons (oncologist determined). Of the remaining 134, 23% (N=31) reported no joint discomfort, 14% (N=19) reported engaging in recommended levels of PA, and an additional 14% (N=19) reported both no joint discomfort and engaging in recommended levels of PA. This resulted in 65 survivors (35.5% of 183) being eligible for the study because they reported both joint discomfort and not being engaged in recommended levels of PA. Conclusions: Joint discomfort and PA below recommended levels are prevalent among BC survivors on AI therapy. There is a need to investigate the potential benefits of moderate PA both prior to starting an AI (protective) and during AI therapy (therapeutic). Clinical trial information: NCT01900418.
Disparities in quality-of-life outcomes in immigrant cancer patients.
Authors: David Goldstein, Ming Sze, Melanie Bell, Madeleine King, Michael Jefford, Maurice Eisenbruch, Afaf Girgis, Lisa Vaccaro, Phyllis Noemi Butow
Journal: Journal of Clinical Oncology (2012)

e16507 Background: Immigration is increasing world-wide. We explored disparities in quality of life outcomes for immigrant (IM) versus Anglo-Australian (AA) cancer patients having anti-cancer treatment. Methods: In a cross-sectional design, cancer patients were recruited through outpatient Oncology clinics in New South Wales, Victoria, and the Northern Territory in Australia. IM participants, their parents and grand parents were born in a country where Chinese, Greek, or Arabic is spoken and spoke one of those languages. AAs were born in Australia and spoke English. All were diagnosed with cancer &lt; 1 year previously. Questionnaires (completed in preferred language) included the Hospital Anxiety and Depression Scale (anxiety/depression), FACT-G (quality of life) and the Supportive Care Needs Survey (unmet needs). Adjusted regression models comparing AA and IM groups included age, gender, socio-economic status, education, marital status, religion, time since diagnosis, and cancer type (colorectal, breast, lung, other). Results: There were 910 participants (response rate 57%). IM were similar to AA, except that IM were more likely to be married (76 vs 67 %, p = 0.01) and in the low and the highly educated groups (p &lt; 0.0001). In adjusted analyses, IMs had clinically significant higher anxiety, greater unmet information and physical needs and lower quality of life than AAs (see table). The possible ranges are 0-21 for anxiety and depression, and 0-100 otherwise. Conclusions: In this hospital-based study with a high rate of advanced disease, immigrants with cancer experienced poorer quality of life outcomes, even after adjusting for socio-economic, demographic, and disease variables. Interventions are required to improve their experience of cancer care. Results highlight areas of unmet need that might be better addressed by the health system (particularly with regards to provision of information and meeting support and physical needs). [Table: see text]
Phase I study of HER3 targeted antibody patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).
Authors: Toshiaki Saeki, Hirofumi Mukai, Kenjiro Aogi, Takashi Shigekawa, Shigeto Ueda, Yoichi Naito, Nobuaki Matsubara, Seiki Takashima, Fumikata Hara, Tomonari Yamashita, Shoichi Ohwada, Yasutsuna Sasaki
Journal: Journal of Clinical Oncology (2015)

584 Background: It is considered that HER2-HER3 heterodimerization is mechanically important in HER2-overexpressing breast cancer. Patritumab is a fully human anti-HER3 monoclonal antibody, which inhibits ligand binding, receptor activation and induces HER3 down-regulation. This study aimed to assess recommended dose for subsequent studies as well as the safety, pharmacokinetics (PK), and preliminary efficacy of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing MBC. Methods: This study was an open-label, multicenter phase I study in patients with HER2-overexpressing MBC who had progressed after at least one prior chemotherapy regimen including trastuzumab. Patients received patritumab 9 mg/kg or 18 mg/kg i.v. Q3W, trastuzumab 8 mg/kg loading dose, followed by 6 mg/kg maintenance dose i.v. Q3W, and paclitaxel 175 mg/m2 i.v. Q3W or 80 mg/m2i.v. 2 weeks administration followed by 1 week rest (Q3W). Results: Eighteen patients were enrolled in total in this study. As of the October 10, 2014 cutoff, four patients were continuing treatment. All patients had received prior trastuzumab and 66.7% patients had received prior paclitaxel. No DLTs were observed. The most common ( ≥ 50.0%) adverse events (AEs) were diarrhea (88.9%), alopecia (72.2% ), leukopenia (72.2%), neutropenia (66.7%), and rash maculo-papular (50.0%). Some AEs including leukopenia and neutropenia were more frequent in patients received paclitaxel 175 mg/m2i.v. Q3W. These AEs were generally mild and manageable. As a serious adverse event (SAE), cataract was reported in one patient and it was not related to study drugs. All patients were negative for anti-patritumab antibodies. The target trough serum concentration of patritumab was achieved in all patients at a dose of 18 mg/kg. The response rate was 38.9% (2 CR and 5 PR). The median progression-free survival was 274 days. Conclusions: Patritumab in combination with trastuzumab and paclitaxel was well tolerated up to 18 mg/kg and the preliminary efficacy was encouraging in patients with HER2-overexpressing MBC. Clinical trial information: JapicCTI-121772.
STEAP1 as a predictive biomarker for antibody-drug conjugate (ADC) activity in metastatic castration resistant prostate cancer (mCRPC).
Authors: Daniel Costin Danila, Martin Fleisher, Jorge A. Carrasquillo, Houston Gilbert, Michael J. Morris, Lawrence P Bellomo, Petrus J Hendrikx, Edith Szafer-Glusman, Amrita Herkal, Chintan Patel, Nicole A. Schreiber, Kristen Rebecca Curtis, Daniel J. Maslyar, Vanessa Lemahieu, Bernard M. Fine, Michael J. Mamounas, Alexander Joachim Ungewickell, Mark R. Lackner, Howard I. Scher, Omar Kabbarah
Journal: Journal of Clinical Oncology (2015)

5029 Background: STEAP1 is overexpressed in mCRPC and is an ADC target. STEAP1 expression in tissue assayed by IHC, protein and mRNA expression levels in circulating tumor cells (CTC) and by 89Zr-labeled anti-STEAP1 antibody uptake by iPET. Methods: Patients (pts) with progressive mCRPC received doses of the ADC ranging from 0.3 to 2.8 mg/kg once every three weeks. Antitumor activity was assessed by PSA declines, time on study and changes in CTC number (CellSearch). STEAP1 expression in tumor tissue by a validated IHC assay was used as reference biomarker on a scale of 0 (not detected) to 3+ (highest expression). Protein and mRNA expression in CTCs was explored by FACS and RT-PCR, and standardized uptake values (SUV) of 89Zr-labeled anti-STEAP1 antibody by iPET. Results: At doses of ≥ 2 mg/kg, a ≥ 50% PSA decline was observed in 22% (10/45, 11-37%), and CTC conversions from unfavorable (> 5 cells) to favorable (4 or fewer/7.5 ml of blood) in 55% (11/20, 32-77%) of cases. CTC showed a readily detectable STEAP1 +ve signal in EpCAM +ve events by FACS in 48% (14/29, 30-67%), confirmed by RT-PCR, along with AR (androgen receptor) and KLK3 expression. STEAP1 +ve events were EpCAM +ve in a range from 0-74%. ADC activity by IHC and CTC is shown in Table. For STEAP1 iPET imaged pts, PSA decline by ≥ 50% was noted in 4/14 (29%, 8-58%) pts. Time on treatment correlated with bone metastasis SUVmax (r = 0.63). All 8 PET-guided biopsies were confirmed STEAP1 IHC 2+/3+. Conclusions: The best evidence for STEAP1 ADC activity by PSA declines, time on study, and CTC conversion was seen in high expression tumors. Pts with IHC 2+/3+ tumors are being prospectively selected in an expansion study where predictive biomarkers are studied as companion diagnostics. STEAP1 IHC score and treatment response. IHC Score Pts Observed/ Total (%, 95% CI) PSA decline by ≥ 50% > 6 months on treatment CTC conversion from U to F 1+ 5/45 (11%, 4-24%) 1/5 (20%, 1-72%) 0/5 (0%, 0-52%) 1/3 (33%, 1-91%) 2+ 27/45 (60%, 44-74%) 4/27 (15%, 4-34%) 6/27 (22%, 9-43%) 7/14 (50%, 23-77%) 3+ 13/45 (29%, 16-44%) 5/13 (39%, 14-68%) 6/13 (46%, 19-75%) 3/3 (100%, 29-100%)
Clinical versus radiographic progression and overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) from COU-AA-302.
Authors: Charles J. Ryan, Thian Kheoh, Howard I. Scher, Peter De Porre, Margaret K. Yu, Michael J. Morris
Journal: Journal of Clinical Oncology (2017)

193 Background: COU-AA-302 evaluated abiraterone acetate plus prednisone (AA) vs prednisone (P) in chemotherapy-naïve mCRPC pts, with overall survival (OS) and radiographic progression-free survival (rPFS) as co-primary end points. Per study criteria, pts with radiographic progression (RAD) only were allowed to continue treatment, while those with unequivocal clinical progression (UCP) only were not, and were censored for rPFS. We evaluated the clinical significance of survival outcomes for pts with UCP only vs RAD only from the prospective COU-AA-302 trial. Methods: UCP was defined per protocol as ≥ 1 of the following: initiation of chronic opiates, ECOG performance status (PS) decline to ≥ 3, or initiation of chemotherapy, palliative radiation therapy, or surgery. OS was evaluated for each type of progression using Cox proportional hazard models. Results: 500 (92%) pts in the AA arm and 540 (100%) in the P arm discontinued study treatment. Of the 736 pts who discontinued treatment for a protocol-defined reason, 280 (38%) discontinued for UCP only, 332 (45%) for RAD only, and 124 (17%) for both UCP and RAD. Clinical events cited as the reason for discontinuation for UCP (AA vs P arm) included pain requiring opiates (22% vs 25%), ECOG PS ≥ 3 (4% vs 5%), and initiation of chemotherapy (50% vs 53%), radiation therapy (36% vs 27%) and surgery (3% vs 5%). UCP only pts had shorter median OS compared with RAD only pts (Table). Conclusions: UCP is a criterion used as an indicator for a censored event, yet appears to confer inferior survival relative to RAD. The high frequency of UCP implies that it may be an important determinant of clinical outcome. The events that drive UCP should be defined as part of the development of more informative interim trial end points, in line with the PCWG3-proposed “no longer clinically benefitting” outcome measure, which captures pts with UCP. Clinical trial information: NCT00887198. [Table: see text]
Should de-escalation of bone-targeted agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis.
Authors: Mohamed F.K. Ibrahim, Mark J. Clemons, Brian Hutton, John Frederick Hilton, Lisa Vandermeer, Sasha Mazzarello, Risa Shorr
Journal: Journal of Clinical Oncology (2015)

e17711 Should de-escalation of bone-targeted agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis Background: De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 3-4 weekly to less frequent dosing is increasingly being explored in patients with bone metastases from breast cancer. As of yet, it is unclear whether there is enough evidence to support de-escalation as a standard of care. Methods: A systematic review of randomised trials comparing de-escalated (q12-weekly) versus standard schedules (q3-4-weekly) of bone-targeted therapies was performed following PICOS criteria. Medline, Embase (ASCO, ESMO, SABCS), and Cochrane Register of Controlled Trials were searched up until November 2014 with no date restrictions. All citations were reviewed by a minimum of 2 individuals. Outcomes included; skeletal related event (SRE) rates. Random effects meta-analyses were pursued when studies were judged to be homogeneous. Results: After screening 935 abstracts, 8 relevant citations representing 7 different studies (n = 1521 patients) were identified. Of these 7 studies 5 had relevant reported outcome data for SRE rates. Sample sizes ranged from 38 to 425. Data was collected from peer-reviewed manuscripts (n = 4) and meeting abstracts (n = 1). Data was available comparing standard versus de-escalated therapy for; pamidronate (1 study, 38 pts), zoledronate (2 studies, 828 pts) and denosumab (2 studies, 284 pts). Meta-analysis of 5 trials for on-study SRE rates between standard (599 SREs) and de-escalated (551 SREs) arms produced a summary risk ratio of 0.99 (95% CI 0.76-1.28). Conclusions: Despite variability in outcome reporting between trials, de-escalated treatment appeared equally effective as the standard schedule for on study SREs. Meta-analysis of pain, adverse events and bone turnover data is ongoing. Differences between studies with respect to the choice of agent, period of prior 3-4-weekly dosing and duration of de-escalation means that more studies are likely needed for further validation of this approach.
Evaluation of the Decipher prostate cancer classifier to predict metastasis and disease-specific mortality from genomic analysis of diagnostic prostate needle biopsy specimens.
Authors: Paul L. Nguyen, Zaid Haddad, Lucia L.C. Lam, Kaye Ong, Christine Buerki, Samineh Deheshi, Kasra Yousefi, Elai Davicioni, Jeffrey J. Tosoian, Tamara L. Lotan, Felix Yi-Chung Feng, Bruce J. Trock, Ashley Ross, Eric A. Klein
Journal: Journal of Clinical Oncology (2017)

4 Background: Accurate risk stratification after diagnosis of prostate cancer (PCa) is key to optimal treatment decision-making. Decipher RP is an extensively validated genomic classifier used to determine biological potential for metastasis. Here, in a multi-institutional cohort, we aimed to evaluate its ability to predict metastasis and prostate cancer-specific mortality from analysis of PCa needle biopsy tumor tissue specimens. Methods: We identified 175 patients treated with either first-line RP or first-line radiation therapy (RT) + androgen deprivation therapy (ADT) with available genomic expression profiles generated from diagnostic biopsy specimens obtained from three tertiary referral centers: Cleveland Clinic, Brigham and Women’s Hospital and Johns Hopkins. The core with the highest grade was sampled and Decipher was calculated based on a locked random forest model. Cox univariable and multivariable (MVA) proportional hazards model and survival c-index were used to evaluate the performance of Decipher. Results: Overall, 85% of patients had NCCN intermediate and high-risk disease. Of the 175 patients, 43% and 57% were treated with first-line RP and RT+ADT, respectively. With a median follow-up of 6 years, 32 patients developed metastases and 11 of these patients died of PCa. For prediction of metastasis 5 years post biopsy, Decipher had a c-index of 0.74 (95% confidence interval [CI] 0.63-0.84) compared to 0.66 (95% CI 0.53-0.77) for CAPRA and 0.66 (95% CI 0.55-0.77) for NCCN risk group. On MVA, when modeled with CAPRA, Bx Decipher remained a significant predictor of metastasis (Decipher Bx hazard ratio [HR] 1.33 per 10% increase in score, 95% CI 1.06–1.69, P = 0.01). Decipher Bx was also a significant predictor of PCSM (Decipher Bx HR 1.57 per 10%, 95% CI 1.07–2.40, P = 0.02) Conclusions: Decipher Bx was able to predict metastasis and PCSM from diagnostic biopsy specimens in a cohort of primarily intermediate and high-risk men regardless of first line treatment. This additional genomic information provides important risk stratification to help guide therapy for men with intermediate- and high-risk disease.
A phase I/I b study of GSK1120212 (trametinib) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Takayasu Kurata, Junji Furuse, Isamu Okamoto, Akiyoshi Kasuga, Yasuhito Fujisaka, Hiroshi Kitamura, Toshio Shimizu, Atsuko Takasu, Wataru Okamoto, Daisuke Naruge, Fumio Nagashima, Koichi Katsura, Akihira Mukaiyama, Hideki Matsushita, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2013)

e20004 Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as monotherapy and in combination with various agents including gemcitabine in the studies with pancreatic cancer, melanoma and other types of cancer. According to these studies, the recommended dose (RD) and maximum tolerated dose (MTD) were determined as 2.0 mg QD and 3.0 mg QD respectively as monotherapy, and as 2.0 mg QD for both in combination with gemcitabine. The objectives of this study are to assess its tolerability and safety, and to evaluate the RD and the MTD in Japanese patients (pts). Methods: This open-label, dose-escalation study evaluated the tolerability/safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of trametinib alone (part 1) and in combination with gemcitabine (1000 mg/m 2 on Days 1, 8, and 15 of each 28-day cycle) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability and safety in part 1, part 2 was investigated. Results: (Part 1) Thirteen pts received trametinib at doses of 1.0 mg (n=4), 2.0 mg (n=6), and 3.0 mg (n=3). Various cancer types including melanoma were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in part 1 in a subject at the 2.0 mg dose. The most common AE was Grade 1/2 rash (n=12). One PR (salivary gland cancer) and 3 long SDs (appendix cancer (n=1) and melanoma (n=2)) were observed. Preliminary PK results showed no obvious ethnic difference. (Part 2) Five pts with pancreatic cancer received trametinib (2.0 mg QD) in combination with gemcitabine. Although there was no DLT in the first 28 days (DLT observation period), interstitial lung disease (ILD) was observed in 3 pts after DLT observation period. Best responses were 3 PRs and 2 SDs. Conclusions: The RD (2.0 mg QD) and the MTD (3 mg QD) of trametinib that were determined in Western countries were tolerated in Japanese patients as monotherapy. In combination with gemcitabine, although trametinib was tolerated in the short term and showed promising antitumor efficacy, it is required to closely monitor patients for ILD while the combination is administered to patients. Clinical trial information: NCT01324258.