tbuckley/cabot-search huggingface dataset:
PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer.
Authors: Melinda L. Telli, Kristin C. Jensen, Allison W. Kurian, Shaveta Vinayak, Jafi A. Lipson, Elizabeth A. Schackmann, Irene Wapnir, Robert W. Carlson, Joseph A. Sparano, Bobbie Head, Lori J. Goldstein, Barbara B. Haley, Shaker R. Dakhil, Judith Manola, James M. Ford
Journal: Journal of Clinical Oncology (2013)

1003 Background: TN and BRCA1-deficient breast cancer (BC) cell lines exhibit enhanced sensitivity to DNA damaging agents. This study was designed to assess efficacy, safety and predictors of response to iniparib in combination with GC in early-stage TN and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled pts with clinical stage I-IIIA (T ≥ 1cm by MRI) ER-negative (≤ 5%), PR-negative (≤ 5%), and HER2-negative or BRCA1/2 mutation-associated BC. Neoadjuvant G (1000 mg/m 2 ; IV; D1, 8), C (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles, with enrollment of 80 pts at multiple PrECOG institutions. The primary endpoint is pathologic complete response (pCR), defined as no invasive carcinoma in the breast and axilla. Pathologic response was centrally assessed by the residual cancer burden (RCB) index. Assuming 76/80 eligible and treated pts, the regimen would be deemed effective if the lower bound of a 90% exact binomial CI on the pCR rate exceeded 25%. Secondary endpoints are safety, MRI response, and breast conservation. Results: Among 80 eligible pts treated with 6 cycles, median age is 48 years, 19 pts have germline BRCA1/2 mutations (90% tested to date) and clinical stage is I (13%), IIA (36%), IIB (36%), IIIA (15%). Pathologic response data (ITT population) are detailed below. 69 pts completed treatment per protocol: 5 progressed, 5 discontinued due to an AE and 1 mutation carrier was lost to follow-up. Most common G3/4 adverse events are neutropenia (49%), elevated ALT/AST (14%), and anemia (10%). Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage TN and BRCA1/2 mutation-associated BC. Clinical trial information: NCT00813956. [Table: see text]
The importance of continued surveillance of high risk cancer families as illustrated in a family with Gardner’s syndrome
Authors: R. D. Legare, J. Scalia-Wilbur, J. Kent
Journal: Journal of Clinical Oncology (2007)

1551 Background: The scientific community continues to rapidly discover cancer predisposition genes allowing high risk families to identify underlying genetic abnormalities providing more individualized medical management. Therefore, continued follow-up becomes critical and is exemplified by Family A, a case that had been lost to follow-up for almost 40 years. Family A was first reported in the literature in 1955 by Weiner and Cooper presenting with a dominant inheritance pattern of osteomatosis, multiple soft tissue tumors and colorectal adenomatosis polyposis consistent with several families previously reported by Gardner et al. between 1950–1953. The clinical diagnosis of Gardner syndrome was established. In 1969 Coli et al. further described the phenotypic manifestations of Family A’s second and third generations after which the family was largely lost to follow-up until two second generation members presented to our high-risk clinic. Methods: An updated family history was collected and compared to that previously reported in the literature. Results: An updated pedigree revealed new cases of breast, ovarian and primary peritioneal cancers in the second and third generations. A 39 year old woman diagnosed with a glioblastoma was also discovered. No family members had undergone genetic testing, however, analyses of the APC and BRCA genes are underway. Conclusions: The presence of multiple newly reported cases of breast and ovarian cancers within Family A raises concern for two independent cancer predisposition syndromes, Hereditary Breast and Ovarian Cancer Susceptibility syndrome (HBOCS) as well as Familial Adenomatous Polyposis (FAP). Though rarely gynecological tumors have been reported in FAP, this case emphasizes the need for practitioners to be aware of the potential presence of multiple hereditary cancer syndromes in one family. The dynamic changes in the pedigree of Family A underscore the importance of continued follow up for cancer families in which the underlying etiology is unknown. Such families should be followed in cancer genetics clinics to update family histories, ensure that appropriate screening regimens are followed, and to offer genetic testing if the appropriate analysis becomes available. No significant financial relationships to disclose.
Response to second-line taxane-based therapy after first-line epothilone B analogue BMS-247550 (BMS) therapy in hormone refractory prostate cancer (HRPC)
Authors: J. E. Rosenberg, M. D. Galsky, V. Weinberg, W. K. Kelly, E. J. Small
Journal: Journal of Clinical Oncology (2004)

4564 Background: Epothilone analogues and taxanes exert anti-cancer activity by interfering with microtubule function. BMS is an epothilone analogue that has activity in taxane-resistant cell lines and as first-line therapy in HRPC patients (pts). Clinical cross resistance of BMS with taxanes is not known. The utility of second-line taxane therapy was evaluated in a cohort of HRPC pts previously treated with BMS. Methods: Records from HRPC pts treated on a randomized phase II trial of BMS with or without estramustine (E) and who received taxane-based second-line therapy were evaluated. PSA response and time to PSA progression (TTPP) were defined by Consensus Criteria. Results: 29 pts received BMS with (18) or without (11) E and subsequent second-line taxane therapy. Second-line therapy consisted of E/docetaxel (D) (19), single agent D (3), E/paclitaxel (P)/carboplatin (3), E/P (2), D/calcitriol (1), or D/cyclophosphamide (1). The overall PSA response to second-line therapy was 59% (95% CI= 39–77%). Median TTPP for pts treated with a second-line taxane was 4.9 months. No difference in response to second-line taxane therapy was seen in pts based on whether or not they received first-line E therapy. The PSA response proportion to second-line taxane therapy in pts who had obtained a PSA response to front-line BMS was 68% (95% CI= 43–87%), compared with 40% (95% CI= 12–74%) for pts who did not have a PSA response to BMS (p= 0.23). The median TTPP on second-line taxane therapy in pts who had obtained a PSA response to front-line BMS was 5.7 months, compared with 1.4 months for pts who did not have a PSA response to BMS (p= 0.19). Conclusions: Second-line taxane therapy following BMS results in a PSA response proportion of 59%. Response to second-line taxane therapy does not appear conditional on response to first-line BMS therapy. Second-line PSA responses are independent of prior E treatment, suggesting that these response frequencies are not simply due to treatment of E-naïve pts with E. A trial of second-line BMS following progression on taxane-based first-line therapy is underway. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Critical analysis of care and payment within a DRG reimbursement system for primary breast cancer.
Authors: M. Warm, N. Harbeck, C. Moers, R. Wuerstlein, P. Mallmann, V. R. Jacobs
Journal: Journal of Clinical Oncology (2010)

e16513 Background: German DRGs are an entity-individual flat rate reimbursement system covering everything, hospital and physician costs, for inpatient diagnostic and treatment. Introduced in 2004 and after transition period it is now active. DRGs are calculated as representative mean provider costs in Germany and serve for providers as target costs. For transparency of this cost containment solution for the international health care market the German experience with DRG reimbursement is analyzed for a selected DRG. Methods: DRG analyzed is J06Z: Mastectomy with prosthesis implant and plastic procedure in malignant disease. Database used for detailed cost calculation is DRG-Report-Browser V2007/2009 issued by InEK and valid for all hospitals in Germany 2009 with data of cost calculations from 2007. A comparison of clinic's own costs with DRG is performed. Breast Centre is university-based and certified according to highest standards. Patient care follows strictly German S3-Guidelines for diagnostic and treatment of primary breast cancer. Results: Overall DRG payment is including preop diagnostics. Detailed analysis shows that costs for a) implants with 69.65 € at actual costs of up to 1165 €, b) intraoperative preimplant antibiotic rinsing of implants with 6.51 € at actual costs of 50 €, c) breast ultrasound, d) MRI and e) wire marking are not adequately calculated. Costs for certification and quality measures are also not calculated. The development of DRG payments shows for J06Z a value of 4,747.34 € in 2004 compared to only 4,144.24 € in 2009 (- 12.7%). The costs for implant were calculated with 53.35 € (+30.6%) then. Conclusions: DRGs are a highly effective method for cost containment. At increasing quality of care DRG reimbursement is decreased without even inflation compensation. Providers are forced to subsidize each case with ∼1.300 € with reduced investments and cross financing from research budgets. Care provided below own costs is economically price dumping. From international view high quality of care at prices below costs is highly interesting for selective contracts for insurances and patients looking for remarkable cheaper care than e.g. in the United States at highest and exactly defined quality level of care. No significant financial relationships to disclose.
Molecular genetics of familial cutaneous melanoma.
Authors: F G Haluska, F S Hodi
Journal: Journal of Clinical Oncology (1998)

PURPOSE A family history of melanoma is a significant risk factor for the disease, and recently several loci that determine susceptibility to the development of melanoma have been identified. The most important of these is p16/CDKN2A. We attempted to determine the degree to which the p16/CDKN2A gene has been implicated in the development of melanoma, and to identify other genetic factors that play a role as well. METHODS We reviewed the literature published since the isolation of p16/CDKN2A and identified 13 studies that report the status of the gene in melanoma samples and 12 reports that examine p16/CDKN2A in melanoma kindreds. We also reviewed associated studies on CDK4 and RB1 involvement in melanoma, and examined the role of p16/CDKN2A in other inherited cancers. RESULTS The evidence strongly implicates p16/CDKN2A in determining predisposition to malignant melanoma. Overall, approximately 20% of families that have been studied show mutations in the gene. However, because of clustering of sporadic cases in families, and potentially because of technical factors, this is likely an underestimate of the proportion of the genetic predisposition for melanoma that is due to p16/CDKN2A mutation. Rare families carry a mutated CDK4 gene that is also responsible for inherited melanoma. CONCLUSION The gene p16/CDKN2A is an important determinant of melanoma risk. A commercial test is presently available to assess the status of this locus. However, because of uncertainties regarding the interpretation of the results of p16/CDKN2A genetic testing, we do not recommend routine clinical use of this test at this time.
Relevance of serum HER2 extracellular domain (sECD) in EGF30008, a study of letrozole ± lapatinib in patients (pts) with hormone-receptor positive (HR+) metastatic breast cancer (MBC)
Authors: G. T. Platek, M. Koehler, R. Gagnon, L. O'Rourke, J. D. Maltzman, M. Press, S. Johnston, M. Pegram
Journal: Journal of Clinical Oncology (2009)

1019 Background: Elevated baseline sECD (BsECD) correlates weakly with HER2 overexpression (HER2+). HR+ MBC. Lapatinib benefit was reported in pts with HER2+ tumors irrespective of BsECD status; BsECD status did not predict benefit for HER2- negative (HER2-ve) tumors. sECD levels and their predictive and prognostic value for progression-free survival (PFS) were further examined in a randomized, phase III trial of letrozole ± lapatinib. Methods: Pts (n=1286) with HR+ MBC were randomized to letrozole with placebo (P) or lapatinib (L). HER2 status was evaluated by FISH or IHC in archived tissue. sECD was measured by ELISA at baseline (n=1102 available samples), and every 4 wk. Pts were considered sECD+ if serum sECD was &gt;15 ng/ml. Results: BsECD was positive in 14% (125/894) and 42% (87/208) of pts with HER2-ve and HER2+ tumors, respectively. Correlation between BsECD and FISH was weak but significant in HER2+ pts (R=0.35, p&lt;0.0001) but not in HER2-ve pts (R=0.03, p=0.362). Unlike for HER2+ tumors, BsECD+ did not predict benefit in PFS from L in pts with HER2-ve tumors. HR: Hazard Ratio In pts with HER2- ve tumors, median ECD levels were stable in the P arm but increased slightly (4 ng/mL) in the L arm. In the HER2+ group, median levels in the P arm declined (3.5 ng/mL) but increased at 4 wk in L arm (3.4 ng/mL) and were stable thereafter. Conversion from sECD-ve to sECD+ was observed in both arms but did not correlate with outcome or provide predictive value. Data related to ECD status conversion will be reported. Conclusions: BsECD+ status correlates with HER2+ tumor status and may predict L benefit but BsECD+ status did not predict benefit in pts with HER2-ve tumors. On therapy changes in median sECD were small. Conversion from BsECD-ve to sECD+ did not predict L benefit and we could not confirm that evaluation of on treatment ECD status may help treatment decision. [Table: see text] [Table: see text]
Phase I/II study of BIBW 2992 with or without daily temozolomide in the treatment of patients with recurrent malignant glioma.
Authors: D. A. Reardon, Y. Fu, H. C. Thurm
Journal: Journal of Clinical Oncology (2010)

2590 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of epidermal growth factor receptor EGFR/HER1 and HER2 receptor tyrosine kinases, as well as the constitutively active EGFRvIII mutant, which has demonstrated a high level of in vitro resistance to reversible EGFR inhibitors. Protracted (metronomic) temozolomide (TMZ) regimens may overcome MGMT resistance. Methods: The primary objective of the phase I part of the trial (reported here) was to determine the maximum tolerated dose (MTD) of continuous, daily BIBW 2992 following dose escalation from 20 mg/dose to a maximum of 50 mg/dose in combination with daily 75 mg/m2 TMZ administered for 21 days, followed by 7 days off (TMZ 21/7) among patients with recurrent malignant glioma. A standard “3+3” dose-escalation design was employed. Patients were treated either until occurrence of dose-limiting adverse events (DLAEs) or disease progression. Results: In total, 32 patients were treated (20 mg/dose, n=6; 40 mg/dose, n=8; 50 mg/dose, n=18) and the BIBW 2992 MTD was 50 mg/dose. DLAEs reported in cycle 1 included a grade 4 intracranial hemorrhage in a patient on enoxaparin sodium injections (Levonox), as well as grade 3 hypokalemia (n=1) and grade 3 diarrhea (n=1). The percentage of patients with DLAEs, any adverse events, related adverse events, adverse events leading to discontinuation, CTCAE grade 3/4 events and serious adverse events was consistently higher in the 50 mg dose cohort (BIBW 2992) compared to the 40 mg and 20 mg dose cohorts. Across all dose cohorts, patients were treated for between 6 and 276 days. Most patients were treated for one or two cycles. Average treatment duration was longer in the 20 mg/dose and 40 mg/dose cohorts compared to the 50 mg/dose cohort. Conclusions: Although the MTD of BIBW 2992 in combination with daily TMZ was observed at 50 mg, the proposed recommended dose for phase II was 40 mg BIBW 2992 in combination with daily 75 mg/m2 TMZ administered for 21 days, followed by 7 days off. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim
Phase 1 clinical trial of anti-CTLA4 human monoclonal antibody CP-675,206 in patients (pts) with advanced solid malignancies
Authors: L. H. Camacho, A. Ribas, J. A. Glaspy, G. Lopez-Berestein, J. M. Reuben, C. Parker, E. Seja, B. Comin-Anduix, C. Bulanhagui, J. Gomez-Navarro
Journal: Journal of Clinical Oncology (2004)

2505 Background: Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4) is a T lymphocyte receptor responsible for negative regulation of cellular immune responses. CTLA4 blockade with CP-675,206 may break peripheral immunological tolerance and induce anti-tumor activity. Methods: We studied the safety, pharmacokinetics (PK), immune properties, and clinical activity of CP-675,206 in 39 pts with measurable disease (34) and no evidence of disease (5) (melanoma 34; renal cell 4; colon 1) after a single IV infusion at one of 7 dose levels: 0.01 (3 pts), 0.1 (3), 1.0 (3), 3.0 (8), 6.0 (5), 10.0 (11), and 15 mg/kg (6). Five pts at the lowest dose cohorts were re-enrolled at a higher dose level, for a total of 44 administered doses. Results: Therapy was delivered as planned. CP-675,206 proved safe and overall was well tolerated. Common adverse events included dermatitis (17, 39%), fatigue (17, 39%), pruritus (11, 25%), and diarrhea (11, 25%). DLTs were G3 diarrhea (1 at 6 mg/kg; 3 at 15 mg/kg) and G3 dermatitis (1 at 15mg/kg). The single dose MTD is 10 mg/kg. All observed autoimmunity except vitiligo (asthma, dermatitis, diarrhea, hypophysitis, and hyperthyroidism) was manageable and reversible. Plasma CP-675,206 concentrations were measured by ELISA. Peak concentrations and systemic exposure increase with dose. Concentrations remain >10 μg/mL (target efficacious concentration) for >4 weeks at doses ≥6 mg/kg; t½ is 25.6 days. Immune activation was assessed in a whole blood assay determining secreted IL-2 levels in response to Staphylococcal Enterotoxin A (SEA). CP-675,206 administration increased mean SEA reactivity 1-hr post-dose at all dose levels with a dose-response trend (P < 0.03). There were 2 CRs (18+, 8+ mo), 1 PR, and 6 SDs (3+ to 16 mo) among 34 pts with measurable disease. Conclusions: CTLA4 blockade can be induced with a single injection of CP-675,206. Related autoimmunity is reversible. Observed anti-tumor activity may be associated with breaking peripheral tolerance through this mechanism. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer Inc.
Are comorbidities present in non-Hodgkin's lymphoma (NHL) patients (pts) enrolled in recent clinical trials different from those observed in previous clinical trials?
Authors: S. J. Noga, M. Mo, L. Dreiling, H. Ozer
Journal: Journal of Clinical Oncology (2009)

e19540 Introduction: Co-morbidities are often more prevalent in community practice than in clinical studies due to an increased mortality risk (Kuderer 2006; Noga 2007). As NHL treatments have changed and NHL rates in the US have increased 81% from 1973 to 1997 (Garber 2001), pt characteristics of NHL practice-changing studies may have changed to reflect the general NHL population. Here we summarize major co-morbid conditions present in pts from 4 key NHL trials published from 1976 to 2007. Methods: Intermediate/high-grade NHLs are sensitive to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; McKelvey 1974; Fisher 1993), especially when combined with rituximab (RCHOP; Coiffier 2002). Entry criteria and demographics were tabulated from 4 interventional NHL trials published from 1976 to 2007: McKelvey 1976, a randomized study of 420 pts comparing CHOP and HOP; Fisher 1993, a phase 3, randomized study of 899 pts comparing CHOP, m-BACOD, ProMACE-CytaBOM, and MACOP-B; Coiffier 2002, a randomized study of 399 pts comparing CHOP with RCHOP; Noga 2007, an open-label study that included 325 NHL pts in community practice. Results: More recent NHL trials enrolled older pts compared with earlier trials ( Table ). Further, in the community-practice study by Noga et al (2007), nearly 1/3 of treated pts had at least 1 major co-morbidity. Such co-morbidities may have been formally or informally excluded in earlier clinical trials. Conclusions: More recent clinical trials tend to enroll older pts compared with earlier trials and tend to include pts with the major co-morbidities often seen in the general NHL population. Physicians may be more aware that cancer pts often have a significant prevalence of co-morbid conditions and that supportive care may allow these pts to benefit from study treatment. Clinical practice may also be changing to allow more elderly pts with co-morbidities to receive aggressive chemotherapy. [Table: see text] [Table: see text]
A phase III protocol of androgen suppression (AS) and radiation therapy (RT) versus AS and RT followed by chemotherapy with paclitaxel, estramustine, and etoposide (TEE) for localized, high-risk, prostate cancer, RTOG 9902.
Authors: H. M. Sandler, D. Hunt, A. O. Sartor, L. G. Gomella, A. Hartford, K. L. Zeitzer, R. Rajan, K. Kerlin, J. M. Michalski, S. A. Rosenthal
Journal: Journal of Clinical Oncology (2010)

4632 Background: High-risk, localized prostate cancer (PCa) is generally treated with a combination of RT and long-term AS. It was our hypothesis that adjuvant CT would improve the survival rate of high-risk PCa when used in combination with RT and AS. Methods: Pts with PSA 20-100 and Gleason score (GS) ≥7 or clinical stage ≥T2 and GS ≥8 were randomized to RT and AS with or without four 21-day cycles of CT, starting 28 days after RT, with oral estramustine 280 mg tid × 14 days, oral VP-16 50 mg/m2 in divided doses bid × 14 days, and paclitaxel 135 mg/m2 iv on day 2. Warfarin was originally given at 1 mg/day during CT, but, after thromboembolic (TE) toxicity was observed, the dosage was increased to keep the INR between 1.5 and 2.5. RT consisted of 46.8 Gy to a small pelvic field followed by a prostate boost of 23.4 Gy for a total of 70.2 Gy. AS consisted of LHRH for 24 mos beginning 2 mos preRT plus oral antiandrogen before and during RT. Results: This study opened in Jan 2000 and closed in Oct 2004 with a total of 397 pts (of a planned 1,440) entered (380 eligible). We previously reported on the TE toxicities that led to early protocol closure (Rosenthal, et al. IJROBP 73:672, 2009), but pts have been followed for the primary endpoint, and we report now overall survival (OS) as well as biochemical failure (BF). Pts had high-risk features: 68% had GS ≥8, median PSA was 24.2, and 33% were cT3. Median FU is 6 yrs. 5-yr OS was 86% for both the RT+AS and RT+AS+CT arms (p=0.79). 5-yr BF rates were also similar: 43% for RT+AS and 48% for RT+AS+CT (p=0.26). Conclusions: RTOG 9902 failed to reach its accrual goal due to toxicity. With 5-yr data, there is no difference in OS observed with the addition of adjuvant CT. No difference in 5 yr BF rates was noted. Sample size reduction because of premature closure may have reduced the ability to detect a significant difference. A similarly designed trial, RTOG 0521, completed accrual in 2009, but CT was delivered with docetaxel/prednisone rather than TEE. Results of RTOG 0521 are pending and may help better define the role for adjuvant CT for high risk, localized PCa pts. Supported by NCI grants U10 CA21661 and U10 CA37422. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Bristol-Myers Squibb, Ferring Pharmaceuticals, Watson Pharmaceuticals Bristol-Myers Squibb