bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of multidrug-resistance gene (MDR1) expression levels and outcome to adjuvant cisplatin/MTX based chemotherapy in patients enrolled in the AUO-AB 05/95 phase III trial
Authors: Hoffman A. C. , Wild P. , Gauler T. , Leicht C. , Bertz S. , Danenberg K. D. , Danenberg P. V. , Stöhr R. , Stöckle M. , Lehmann J. , Hartmann A.
Published: August 2020

5026

Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 221 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer enrolled for adjuvant therapy in the AUO-AB 05/95 phase III trial (Lehmann et al, J Clin Oncol. 2005;23:4963–4974) were analyzed (110 pts treated with cisplatin/MTX, 101 pts treated with MTX, vinblastine, epirubicin, and cisplatin, M-VEC).FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 and ERCC1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to progression free and overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p = 0.0001 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 2.8. Regarding survival MDR1 was strongly associated to ERCC1 expression in patients with M-VEC treatment. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer enrolled in AUO-AB 05/95. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/MTX based chemotherapy. Further studies are warranted to study this association.

[Table: see text]
Investigation of human mammary stem and progenitor subpopulations from BRCA1 mutation carriers and noncarriers
Authors: Lim E. , Vaillant F. , Wu D. , Forrest N. , Pal B. , Gyorki D. , Smyth G. K. , Visvader J. , Lindeman G.
Published: August 2020

504

Background: We have previously isolated discrete populations of mouse mammary epithelial cells (MECs) and defined a population that expresses ‘basal’ markers and is highly enriched for mammary stem cells. This subset was ‘triple negative’ for ER, PR and ErbB2 expression and is reminiscent of the basal subtype of breast cancer, suggesting that the mammary stem cell may be the ‘cell of origin’ for this poor prognosis group. Since tumors arising in BRCA1 mutation carriers often exhibit a ‘basal’ phenotype, we hypothesized that the mammary stem cell pool is aberrant in these women. Our objective was to define the human MEC hierarchy and evaluate the functional characteristics of MECs from BRCA1± and normal breast tissue. Methods: Single cell suspensions prepared from fresh human BRCA1± and normal breast tissue were sorted by flow cytometry. Hematopoietic (CD45+, CD235a+) and endothelial (CD31+) cells were removed, and the remaining viable ‘lineage minus’ (Lin-) MECs fractionated based on cell surface markers. These subpopulations were evaluated by immunostaining, RNA profiling, in vitro culture in Matrigel and in vivo xenotransplantation into ‘humanised’ mammary fat pads of immunocompromised mice. Results: Lin- cells fractionated with α6-integrin (CD49f) and epithelial cell adhesion molecule (EpCAM) revealed three discrete MEC subpopulations. A stem/progenitor population that preferentially yields breast outgrowths in vivo has been identified. These subpopulations gave rise in vitro to colonies that were either large and heterogenous or small and homogenous. Only the latter differentiated into milk-producing cells when exposed to lactogenic stimuli. Immunostaining confirmed their origins from myoepithelial and luminal progenitor cells respectively. Intriguingly, BRCA1± MECs exhibited perturbed in vitro growth properties when compared to normal controls. Conclusions: Our studies provide evidence for a human MEC hierarchy, a model to interrogate the perturbation noted in pre-neoplastic tissue derived from BRCA1 mutation carriers and the identification of the cell of transformation in BRCA1 associated breast cancer. These findings may have implications on developing prevention strategies for hereditary breast cancer.

No significant financial relationships to disclose.
Association of tumor burden characteristics with outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib
Authors: Golshayan A. R. , Elson P. , Wood L. S. , Garcia J. A. , Dreicer R. , Rini B. I.
Published: August 2020

5043

Background: An important goal of non-curative therapy for mRCC is tumor burden (TB) control. However, the impact of tumor burden characteristics on clinical outcome has not been studied in mRCC pts treated with VEGF-targeted therapy. Methods: Pts with clear-cell mRCC treated with sunitinib from June 1, 2004, to October 5, 2007, were retrospectively identified. CT scan images were re-reviewed from baseline, at the time of maximal tumor burden shrinkage (TS), at time of disease progression and at time of last assessment prior to death. TB and percent TS were measured per RECIST criteria. Results: Sixty-nine pts were identified. The majority (54%) were favorable risk based on CCF TKI risk group classification. All pts underwent prior nephrectomy and 77% had received prior systemic therapy. Sites of metastases included: lung (87%), mediastinal lymph nodes (52%), retroperitoneal lymph nodes (36%), adrenal (29%), bone (38%), liver (22%), pancreas (14%), kidney (7%), and brain (6%). There were a median of 8 metastatic deposits across all organs (range, 1–20). Median TB at start of therapy was 14.0 cm (range, 3.0–42.2 cm). Overall response rate was 52% and 87% had some degree of TS. Median progression-free survival (PFS) and overall survival (OS) were 13.5 months and 30.9 months, respectively. In multivariable analysis, disease confined to above the diaphragm (p = 0.03) and total TB <13cm (p = 0.09) prior to sunitinib were independent positive predictors of PFS. Total number of metastases <10 (p < 0.001) and tumor volume above the diaphragm <6.5 cm (p = 0.05) were independent positive predictors of OS. Increased TS while on sunitinib was also prognostic for OS (p < 0.001). Fifty-nine pts (86%) have progressed. At time of disease progression (PD), tumor location and pattern of progression were not associated with OS. However, total TB (p = 0.003) and total number of metastatic deposits (≤12 vs. >12, p < 0.001) were significant predictors of OS from PD. At the time of last assessment prior to death, median TB was 23.9 cm, significantly higher (p < 0.001) than in pts still alive (median TB 14.4 cm). Conclusions: Tumor burden shrinkage and tumor burden at time of disease progression are associated with overall survival in pts with mRCC treated with sunitinib.

[Table: see text]
Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)
Authors: Araujo J. , Armstrong A. J. , Braud E. L. , Posadas E. , Lonberg M. , Gallick G. E. , Trudel G. C. , Paliwal P. , Agrawal S. , Logothetis C. J.
Published: August 2020

5061

Background: Dasatinib, a potent inhibitor of SRC family kinases, inhibits in vitro prostate cancer cell proliferation and migration. Consistent with those findings are the clinical observations that osteoclast activity and bone turnover are downregulated in patients treated with dasatinib. We report promising preliminary results of dasatinib in combination with docetaxel (D) for treatment of metastatic castration-resistant prostate cancer (CRPC). Methods: Male pts with progressive CRPC and castrate levels of testosterone (≤50 ng/dL) requiring chemotherapy were enrolled. Escalating doses of dasatinib (50–120 mg QD) and D (60–75 mg/m2 Q 21 days) were evaluated (n = 16) followed by enrollment of 30 pts at the phase 2-selected dose (100 mg dasatinib QD + D at 75 mg/m2 Q 21 days). Continuation of bisphosphonates was permitted; anti-androgens were discontinued. Primary endpoint (Ph. 2) was to determine drug-drug interactions. Secondary endpoints were: changes in PSA, bone scans and tumor size, bone metabolism [urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP)] and PK. Results: 46 pts were treated with 28 pts still on therapy. Median treatment duration (n = 18, pts off study) was 4.2 months (0.13–9.63). Preliminary analysis showed no interaction between dasatinib and D. PSA response was seen in 13/32 (41%) pts, clinical benefit (PR + SD) for RECIST-evaluable pts was 21/21, [7 PR, 5 uPR and 4 SD (at ≥21 wks) and 5 SD at ≥6 wk)]. Of 31 pts with bone scans, 30 patients had a best response of either improved (32%) or stable (65%) at ≥6 weeks. For pts with measurable bone markers levels, 12/26 (46%) had a ≥35% decrease in uNTX and 17/24 (71%) had a decrease in BAP from baseline. 6 of 42 pts experienced ≥ grade 3 adverse events (AEs), including fatigue, myelosuppression and pleural effusion (n = 1). Most common grade 1/2 AEs were fatigue, dysgeusia, GI, and skin disorders. Conclusions: Dasatinib and D at doses up to 120 mg QD and 75 mg/m2 are safe with manageable toxicities and no drug-drug interactions. These data confirm the antitumor and antiosteoclast activity of dasatinib in combination with D and serve as the basis for the ongoing phase III study of this combination.

[Table: see text]
A single institution experience with induction and maintenance intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to BCG therapy
Authors: Benson M. C. , Barlow L. , McKiernan J.
Published: August 2020

5080

Background: Our initial phase I trial showed docetaxel to be a safe agent for intravesical therapy with no systemic absorption and minimal toxicity after 6 weekly instillations. In that trial, docetaxel appeared to show a 56% complete response (CR) but the durability was only 22% (no additional therapy) to 39% (CR with additional TURBT). Owing to this excellent initial response rate, a second group of patients were treated with a 6 week induction and then given monthly maintenance therapy with intravesical docetaxel for BCG refractory high-grade, non-muscle invasive bladder cancer (NMIBC). Methods: 13 patients with recurrent Ta (n=1), T1 (n=6), and Tis (n=6) TCC who failed at least one prior BCG treatment were treated. Induction therapy was administered to all 13 patients as 6 weekly instillations of 75mg intravesical docetaxel followed by single-dose monthly maintenance therapy for 9 additional instillations in 9 of the patients who experienced complete initial response. Initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy and urine cytology. Follow-up consisted of quarterly cystoscopy with biopsy and cytology and periodic CT scans. Results: The median follow-up was 14.4 months for the entire cohort. Median duration of maintenance treatment was 9 months. 10/13 patients (77%) from the entire cohort had a complete initial response after induction, and 6/13 patients (46%) have remained disease-free in follow-up. Of those who failed, 6 patients underwent TURBT and one underwent cystectomy. 9/10 initial responders completed at least 3 doses of maintenance therapy to date, of whom 6/9 (67%) have remained recurrence-free. Conclusions: Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a select group of patients with BCG refractory high risk NMIBC and may decrease overall risk of recurrence in NMIBC.

No significant financial relationships to disclose.
Malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Outcome analysis with retroperitoneal lymph node dissection and PNET specific chemotherapy
Authors: Foster R. , Ehrlich Y. , Ulbright T. M. , Cheng L. , Bihrle R. , Beck S. D. , Andreoiu M. , Brames M. J. , Einhorn L. H.
Published: August 2020

5081

Background: Malignant transformation of teratoma to PNET is a rare entity. Surgical resection has been the mainstay of therapy because these tumors are not curable with cisplatin based chemotherapy. We report long-term survival and potential cure with retroperitoneal lymph node dissection (RPLND) and PNET specific chemotherapy. Methods: Retrospective review of 75 patients (pts) with PNET in the testis or at distant metastasis treated from Jan 1988 to Dec 2007. 74 had RPLND as part of initial treatment or at relapse. PNET specific chemotherapy consisted of cyclophosphamide, doxorubicin, vincristine alternating with ifosfamide and etoposide. Available PNET specimens were tested for the Ewing's sarcoma (EWS) translocation using a FISH-based method. Results: The median follow-up was 40 months (range 2 to 235). 27 pts presented with clinical stage I disease. 18 underwent primary RPLND with PNET in the retroperitoneum in 5. 4 are dead of disease (DOD). 9 elected surveillance or adjuvant chemotherapy. 8 relapsed with PNET. 4 are DOD. 48 pts presented with metastatic disease. 20 are DOD, 24 have no evidence of disease (NED) and 4 are alive with disease. 50 of 75 pts had PNET documented metastasis with an estimated 5 years disease specific survival of 47%. 10 of these were treated with PNET specific chemotherapy for unresectable disease. 8 of the 10 achieved objective response with the duration of response ranging from 4 to 73 months. 2 pts are NED. 2 additional pts were treated with PNET specific chemotherapy as adjuvant to RPLND. Both are continuously NED. Specimens from 14 pts were tested for the EWS translocation, 2 were positive. Conclusions: Malignant transformation of teratoma to PNET carries an adverse prognosis. RPLND is an integral part of the therapeutic strategy. PNET specific chemotherapy, adjuvant to RPLND or for treatment of unresectable disease followed by surgery, may result in long-term survival and potential cure.

No significant financial relationships to disclose.
Sunitinib in patients (pts) with unresectable primary renal cell carcinoma (RCC)
Authors: Wood L. , Garcia J. A. , Elson P. , Salas R. N. , Lane B. R. , Klein E. , Stephenson A. , Dreicer R. , Campbell S. C. , Rini B. I.
Published: August 2020

5096

Background: Sunitinib inhibits VEGF and related receptors, with high tumor shrinkage rates in metastatic (met) RCC. Shrinkage of primary tumors has been observed, although prospective investigation is lacking. The ability of sunitinib to convert primary RCC tumors from unresectable to resectable is of high clinical interest. Methods: Pts with histologically-confirmed RCC with an unresectable primary tumor with or without met disease were enrolled on a single-arm phase II trial. Primary tumors were unresectable due to ≥ 1 of the following: large tumor size, bulky lymphadenopathy, encasement of renal vessels, IVC thrombosis or proximity to vital structures. Pts received 50 mg sunitinib continuous dosing in repeated 6-week cycles. Staging by CT scans or MRI was done at baseline and every 2 cycles. A Simon 2-stage design was employed to test the alternative hypothesis of a conversion to resectability rate of 20% versus the null hypothesis of 5%; β = 0.8, α = 0.05 (n = 31). Results: 18 pts have been enrolled; 1 excluded due to a non-RCC diagnosis. Pts were unresectable due to bulky lymphadenopathy (6), IVC thrombosis (4), proximity to vital structures (4) or tumor size (3), although most pts had multiple factors. Median age among 14 evaluable pts was 61 years (range, 37–80), 59% male, 76% ECOG PS 0; 79% had distant met disease. The 14 evaluable pts have received a median of 3 cycles of therapy (range, 1–10+). Three pts (21%) have undergone primary tumor resection; viable RCC was identified in all specimens with no unexpected surgical morbidity. Nine pts (53%) had primary tumor reduction (median 19%; range, -64% to -1%). Overall, median best % change in tumor burden was 4.9% reduction for primary tumors (range, -43.1% to +8.5%) and 10.7% reduction for met sites (range, -89.5% to +28.6%). Median PFS is 4.9 months. Eleven pts (79%) discontinued therapy; 8 for PD, 1 for adverse events and 2 following surgery which removed all visible disease. Eight pts (57%) experienced grade 3 toxicity including thrombocytopenia, fatigue, hypertension, anemia, hemoptysis, and hand-foot syndrome; 1 pt had grade 4 neutropenia. Conclusions: Sunitinib has activity in unresectable primary RCC tumors, permitting resection in some pts. Continued prospective investigation is required to optimize patient selection and timing of surgery.

[Table: see text]
An open-label extension study to evaluate safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC)
Authors: Hawkins R. E. , Hong S. J. , Ulys A. , Rolski J. , Hong B. , Sternberg C.
Published: August 2020

5110

Background: The efficacy and safety of pazopanib (paz), a multikinase angiogenesis inhibitor, was evaluated in a randomized, double-blind placebo-controlled phase III study (VEG105192), in treatment-naïve and cytokine-pretreated patients (pts) with advanced RCC. Pts with progressive disease (PD) on placebo had the option to receive paz 800 mg QD via an extension study (VEG107769). Methods: Pts with ECOG PS ≤ 2, adequate organ function and no other systemic anticancer treatment since PD on VEG105192 were eligible. The primary endpoint was safety. Secondary endpoints included response rate (RR) per RECIST and progression-free survival (PFS). RR was described along with 95% confidence intervals (CIs). PFS was summarized descriptively using Kaplan-Meier estimates for the median, quartiles and PFS rates at 6, 12, and 18 mo along with approximate 95% CIs. Results: 70 placebo pts were enrolled (+ 1 paz pt as an exemption due to symptom improvement). 34 pts (48%) were treatment-naïve and 37 (52%) were cytokine pretreated (at baseline in VEG105192). Median age was 59 y (25–80); baseline ECOG PS 0 (32%), 1 (52%), and 2 (14%). Median time from randomization to placebo in VEG105192 to start of paz treatment on VEG107769 was 6.4 mo (1–18 mo). At VEG107769 clinical cut-off (May 08), 21 (30%) pts had died, 40 (56%) pts had discontinued paz, and 31 (44%) pts were still on paz. Median exposure to paz was 5.7 mo. Most pts died or discontinued paz due to PD. The majority of adverse events (AEs) were Gr 1/2. Gr 3/4 AEs were experienced by 21%/7% of pts. The most common AEs were hypertension (46%; 4% Gr 3/4), hair color changes (39%; 0% Gr 3/4), diarrhea (38%; 1% Gr 3/4), anorexia (24%; 1% Gr 3/4), and nausea (24%; 0% Gr 3/4). Two pts had fatal AEs: sudden death and gastrointestinal hemorrhage. The most common Gr 3 chemistry laboratory abnormalities were hyponatremia (7%) and elevated ALT (7%) and AST (6%); no Gr 4. RR was 32.4% (95% CI: 21.5, 43.3); median PFS was 8.3 mo (95% CI: 6.1, 11.4 mo). Conclusions: Patients with advanced RCC who developed PD on placebo in a phase III study subsequently achieved clinical benefit from paz treatment in this extension study. These findings support the continued evaluation of paz in advanced RCC.

[Table: see text]
Phase I dose escalation trial of tremelimumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Gordon M. S. , Stein M. , Shannon P. , Eddy S. , Tyler A. , Catlett L. , Hsyu P. , Huang B. , Healey D. , Rini B. I.
Published: August 2020

5115

Background: Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor that has antitumor activity in mRCC. Recent data show sunitinib reduces levels of myeloid-derived suppressor cells and prevents T-cell suppression in pts with mRCC. CTLA4 blockade with tremelimumab is an immunotherapy that enhances T-cell activation and proliferation, and is associated with durable objective responses in metastatic melanoma. It was hypothesized that combination therapy could safely be administered. Methods: The primary endpoint was to assess maximum tolerated dose (MTD) of tremelimumab Q12W in combination with 2 schedules of SU (50 mg/day for 4 weeks followed by 2 weeks off or 37.5 mg QD continuous) in pts with ≤1 prior treatment. Tremelimumab doses were 6, 10, and 15 mg/kg. Secondary objectives included best overall response (RECIST), duration of response, safety, and pharmacokinetics. Results: Twenty-one pts were enrolled. Two of 5 pts in the SU 50 mg (4/2 schedule) plus tremelimumab 6 mg/kg cohort experienced dose-limiting toxicities (DLTs): 1) G5 ruptured diverticula; 2) prolonged G3 mucositis and fatigue. Further exploration of this schedule for SU was excluded. In the SU 37.5 mg QD continuous cohorts, no DLTs were observed at 6 mg/kg tremelimumab (n = 3), 1 of 6 pts treated with 10 mg/kg tremelimumab in the protocol-defined cohort suffered sudden death, and 3 of 6 pts treated with 15 mg/kg tremelimumab + SU experienced DLTs, including: 1 pt with G3 acute renal failure and G3 lymphopenia, 1 pt with G3 elevated creatinine, and 1 pt with worsening G3 dyspnea. Therefore, SU 37.5 QD + tremelimumab 10 mg/kg Q12W was considered the MTD. Five pts achieved partial response: 1 at SU 50 (4/2) + tremelimumab 6 mg/kg; 3 at SU 37.5 + tremelimumab 10 mg/kg; and 1 at SU 37.5 QD + tremelimumab 15 mg/kg. Six pts stayed on study ≥11 mo. An expansion cohort is enrolling another 12 patients at the MTD to further define toxicity and clinical activity. Conclusions: Tremelimumab 10 mg/kg Q12W + SU 37.5 mg QD was tolerable and associated with antitumor activity in pts with mRCC. Further exploration of this combination is warranted.

[Table: see text]
Impact of ultrahigh baseline PSA levels on biochemical and clinical outcomes in two Radiation Therapy Oncology Group (RTOG) prostate clinical trials
Authors: Rodrigues G. , Bae K. , Roach M. , Lawton C. , Donnelly B. , Grignon D. , Hanks G. , Porter A. , Lepor H. , Sandler H.
Published: August 2020

5123

Background: Controversy exists regarding the outcomes of prostate cancer patients (PCP) presenting with ultra-high (UH; defined as PSA ≥ 50 ng/ml) PSA levels. The objectives of this study were to assess the outcome of this patient population compared to other high-risk patients and to identify predictors associated with biochemical/clinical outcomes. Methods: PCP from two phase III RTOG PC clinical trials (9202 and 9413) were divided into two groups; high-risk patients with and without UH baseline PSA level. Predictive variables included age, Gleason score, T stage, KPS, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF) by Phoenix definition. A Cox proportional hazards regression model was used for OS, and Fine and Gray's regression model was used for DM and BF to test the hypotheses that a difference in each outcome exists between the two groups. Results: There are 401 PCP in the UH PSA and 1792 in the non-UH PSA cohort. Median age was 70 years and PCP were evenly distributed across the Gleason groups (2–6, 7, 8–10) for the non-UH (median PSA 22.4 ng/ml) and the UH PSA (median PSA 72.8ng/ml) cohort. The UH PSA cohort had a larger proportion of T1-T2 disease (p = 0.01) and a smaller proportion of Gleason 8 disease (p = 0.04) than the non-UH group. PCP with UH PSA was found to have inferior OS (HR 1.19, 95% CI 1.02–1.39), DM rate (HR 1.51, 95% CI 1.19–1.92), and BF rate (HR 1.50, 95% CI 1.29–1.73) when compared to other high-risk PCP in multivariable modeling. In the UH cohort, PSA level was found to model risk of DM (HR 1.01, 95% CI 1.001–1.02) but not OS and BF. Gleason grade 8–10 was found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41 to 2.36) in both the overall and UH cohort multivariable analyses. Conclusions: UH PSA levels at diagnosis are related with detrimental changes in OS, DM, and BF. All three outcomes assessed in this investigation can be modeled by various combinations all predictive variables tested. Supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

No significant financial relationships to disclose.
A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (MAb), against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastastic, asymptomatic castration-resistant prostate cancer (CRPC)
Authors: Higano C. , Alumkal J. , Ryan C. J. , Yu E. Y. , Beer T. M. , Chandrawansa K. , Katz T. , Youssoufian H. , Schwartz J. ,   Prostate Cancer Clinical Trials Consortium
Published: August 2020

5142

Background: IGF-IR-mediated signaling contributes to prostate cancer carcinogenesis and pathogenesis and may be associated with hormone resistance. IMC-A12 is a fully human IgG1 MAb that specifically targets the IGF-IR and inhibits ligand binding and signaling. In xenografts, IMC-A12 inhibits growth of both androgen-dependent and -independent prostate cancer. This phase 2, multicenter study was designed to assess the safety and antitumor activity of IMC-A12 in asymptomatic pts with metastatic CRPC who were chemotherapy-naive. Methods: Pts received IMC-A12 10 mg/kg IV every 2 wks; until evidence of progressive disease (PD), intolerable toxicity, or other withdrawal criteria were met. Radiologic evaluation was performed every 8 wks. PD by bone scan required at least 2 new lesions with confirmation at subsequent imaging per PCWG2. Results: 19 of 31 pts treated have discontinued IMC-A12, 12 due to PD. 9 of 31 pts experienced disease stabilization for ≥6 mos (range: 7.4–12.5 mos), 5 pts (3 with PSA reduction) continue on IMC-A12. The most common AEs possibly or probably related to IMC-A12, were fatigue (25.8%) and hyperglycemia (19.4%). In 4 pts cases of Grade 3 hyperglycemia was treatment related none requiring discontinuation of IMC-A12; 1 pt required insulin but continued on study. Approximately 70% of pts experienced at least transient elevation of nonfasting glucose to above normal range. Other AEs grade ≥3 at least possibly related to IMC-A12 were one case each of thrombocytopenia (requiring IMC-A12 discontinuation), hyperkalemia, fatigue, pneumonia (resulting in death), and Grade 4 pharmacokinetic and pharmacodynamic analayses are pending leukoencephalopathy (probably related; requiring IMC-A12 discontinuation). Pharmakinetic and pharmacodynamic analyses are pending. Conclusions: IMC-A12 monotherapy appears well tolerated in pts with metastatic asymptomatic CRPC. As in phase I, hyperglycemia was largely asymptomatic and manageable. Disease stabilization for > 6 months in 9 of 31 pts suggests that IMC- A12 may have modest antitumor activity. Additional studies of IMC-A12 in CRPC are planned.

[Table: see text]
Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Mohebtash M. , Madan R. A. , Arlen P. M. , Rauckhorst M. , Tsang K. Y. , Cereda V. , Vergati M. , Poole D. J. , Dahut W. L. , Schlom J. , Gulley J. L.
Published: August 2020

5144

Background: There are few treatment options for mCRPC pts. Immunotherapy + adjuvant immunomodulators is a promising modality. PSA-TRICOM V is composed of poxviral vectors encoding PSA and 3 costimulatory molecules (ICAM-I, LFA-3, and B7.1) and has clinical activity in mCRPC. Ipi blocks CTLA-4, a T-cell downregulatory receptor, has clinical activity in mCRPC as monotherapy and has also been shown to enhance anti-tumor responses in combination with V in preclinical studies. Methods: Pts received V and GM-CSF q 4 weeks in 4 sequential cohorts of escalating doses of ipi at 1, 3, 5, and 10 mg/kg (DL1–4 respectively). After 6 courses of ipi, pts could receive a maintenance dose q 3 months (mo) until progression. Results: Study accrual is complete with 30 pts. There was no DLT and no > G2 adverse event (AE) attributed to V. There were 20 ≥ G2 immune-related AE (irAE): 0/3, 2/6, 5/6 and 13/15 pts on DL1–4, respectively. There was no evidence of clinical benefit in the 6 pts who had prior chemo on DL1 and 2, so subsequently we excluded pts with prior chemo. Median TTP for 9 chemo-naïve pts treated on DL2 and 3 was 6.1 mo (2.9–11.6 mo). Median PSA doubling time (DT) ↑ from 2.2 mo at baseline to 3.7 on study (p = 0.17). 5 of 9 had ≥ 50% ↓ in PSA from peak during study and 1 had a sustained ↓ PSA > 95% from baseline. 4 of these pts had stable disease (SD) for ≥ 6 mo and 2 had unconfirmed partial responses by RECIST. Of the 15 pts on DL4, to date 9 have had SD for ≥ 6 mo (2 ≥ 12 mo); 4 remain on trial. 1 had a sustained ↓ in PSA > 99% from baseline and is still on study after 12 mo. Median PSA DT ↑ > 3-fold from 2.6 mo at baseline to 8.2 on study (p = 0.01) in DL4. The 24 chemo-naïve pts had PSA DT ↑ from 2.5 to 6 mo (p = 0.003). 14 of 30 pts had a PSA ↓ from baseline or peak PSA on study. 2 of 14 had no irAE, 12 showed ≥ G2 irAE temporally associated with PSA ↓. 5 of 9 pts had > 2–5 fold ↑ in T-cell responses by ELISPOT assay and 4 of 13 had significant ↓ in their IL-6 levels. Immune responses appeared to correlate with clinical activity. Conclusions: This combination has clinical activity in pts with chemo-naïve mCRPC and seems to correlate with immune responses. It is associated with manageable side effects; however, further studies are required to see if the combination is more effective than either agent alone.

No significant financial relationships to disclose.
First-line sunitinib in type I and II papillary renal cell carcinoma (PRCC): SUPAP, a phase II study of the French Genito-Urinary Group (GETUG) and the Group of Early Phase trials (GEP)
Authors: Ravaud A. , Oudard S. , Gravis-Mescam G. , Sevin E. , Zanetta S. , Théodore C. , de Fromont M. , Mahier-Aït Oukhatar C. , Chêne G. , Escudier B.
Published: August 2020

5146

Background: Sunitinib (Su) has been approved in metastatic clear cell carcinoma due to high objective response rates (ORR) and a prolonged progression-free survival (PFS). Subgroups analysis of previous studies hypothesized that Su may be active in PRCC. Type I and II papillary RCC pts have a poor prognosis, with limited effective agents. Methods: SUPAP is a single-arm prospective study using a 2-stage design including 21 patients (pts) to achieve a 20% ORR and if ≥ 2 pts have an OR, 20 additional pts will be included. SUPAP is exploring type I and II PRCC separately with an identical design. Main eligibility criteria included type I or II PRCC confirmed by central pathological review, PS 0–1, measurable disease, first line of treatment. Sunitinib was given at 50 mg/d, 4/6 weeks. Primary endpoint was ORR, while safety and time to progression were secondary endpoints. Results: From 10/07 to 11/08, 5 pts with type I and 23 pts with II PRCC were included. The median age was 65 years old. 25 (89%) pts had a nephrectomy. PS was 0 in 14 (56%) pts and 1 in 11 (44%) pts. Using the MSKCC scoring system : 5, 14 and 4 pts were in the favorable, intermediate or poor risk group, 4 undetermined. With a median follow-up of 5 months (0.7–12), 22/28 pts were evaluable for response rate and toxicity. In type II PRCC, 1/23 pts had a partial response (PR), 13/23 pts had a stable disease (SD) with 4 pts with a SD ≥ 12 weeks, 5/23 pts were progressive, 3/23 pts were too early for evaluation and 1/23 was not evaluable. In type I PRCC, none had a partial response (PR), 3/5 pts had stable disease (SD) and 2/5 pts were too early for evaluation. A cardiac infarction occurred during treatment and was considered as related to Su. Toxicity of sunitinib was similar as reported in pivotal phase III with Su in metastatic RCC. 12 pts required a dose reduction at any time mainly for non-hematologic toxicities. Conclusions: Although some activity has been observed, response rate was lower than in clear cell tumors. Updated data will be presented at the meeting.

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Dose finding and safety analysis of inecalcitol in combination with a docetaxel-prednisone regimen in hormone-refractory prostate cancer (HRPC) patients
Authors: Medioni J. , Deplanque G. , Maurina T. , Ferrero J. M. , Rodier J. M. , Raymond E. , Allyon J. , Kalla S. , Dufour-Lamartinie J. F. , Oudard S.
Published: August 2020

5151

Background: Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive HRPC patients (pts). Safety and efficacy were evaluated in groups of 3–6 patients receiving oral inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Five dose levels: 40, 80, 160, 300, 600 μg have been evaluated in 34 pts; 9 pts are still being treated at 600 μg; 25 pts have completed 6 cycles (13 bone metastases; 3 extrasqueletic metastasis, 8 bone and extrasqueletic metastases; 1 PSA-only disease). Median age was 72 years (range, 53–87), median Gleason score (Gs) 7 (36% Gs 10–8, 64% Gs 7–6) and median PSA 41.5 ng/mL (range, 0.9–962.4). No increased calcemia was reported. Most adverse events (AE) were G1–2, asthenia (19pts), constipation (14pts), diarrhea (13pts). G3–4 AEs were neutropenia (11pts) lymphopenia (9pts), asthenia (3pts), arrhythmia (2 pts), general health deterioration (2pts) and diarrhea (1pt). None of these AEs was considered related to inecalcitol. Of the 23 evaluable pts for PSA response, 20 (87%) had ≥30% PSA decline. Conclusions: Results from this ongoing study show the safe profile of inecalcitol when given daily in in HRPC pts. PSA responses with this combination are encouraging. As DLT was not reached, a higher dose of inecalcitol (1000 μg/day) will be further tested.

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Treatment of node-negative infra-centimetric HER2+ invasive breast carcinomas: A joint AERIO/REMAGUS study
Authors: Rodrigues M. J. , Wassermann J. , Albiges-Sauvin L. , Stevens D. , Brain E. , Delaloge S. , Mathieu M. , Guillot E. , Vincent-Salomon A. , Cottu P. H.
Published: August 2020

517

Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or supra-centrimetric HER-2+ breast carcinomas. There are limited data concerning infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). These tumors are being recognized as a high-risk group among all T1a/b tumors. Methods: Retrospective multicenter series from 2000 to 2008 of infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). Tumors with ≥80% of ductal carcinoma in situ, multifocal and metastatic tumors were excluded. Results: 96 cases have been evaluated, 75 were node negative (N- InfraHER-2). All patients had surgery. 57% (n = 43) had a sentinel lymph node procedure. 73% (n = 55) had a local irradiation and 36 a tumor bed boost. Nodal irradiation of internal mammar and infra/supraclavicular regions was done in 20% and 17% respectively. 44% (n = 33) had chemotherapy (CT), almost all (31) were associated to TZM. Anthracycline-based (A), taxane-based (T) and A/T combinations were chosen for 54%, 4% and 42% respectively. One patient developed myocardial infarction after A resulting in heart failure; 2 had a transient left ventricular ejection fraction decrease below 50% after TZM. Decision of adjuvant CT was associated (all p < 0.05) with hormonal receptors (HR) negative status, Elston-Ellis grade (EE) 2/3 and high mitotic index (MI) while patients with HR+/low MI tumors were rarely treated (p < 0.001). 32/39 HR+ patients received hormonotherapy (80%); 21 received aromatase inhibitors, 6 tamoxifen and 5 LHRH agonists. With a 25 months median follow-up, there was no invasive recurrence in TZM treated patients. 3 of the 44 patients treated without TZM nor CT (7%) had local or metastatic recurrence including one fatal; they had initially HR- EE 2/3 T1b tumors. Conclusions: In our practice, decision of TZM-based therapy for InfraHER-2 N- tumors is associated with high-risk profile. Indeed, N- InfraHER-2 tumors may have a significant risk of recurrence which could be avoided by adjuvant TZM. Patients with N- InfraHER-2 tumors should be included in HER-2-targeted adjuvant trials.

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Baseline and recurrence levels of soluble HER2 (sHER2) in early-stage HER2-neu positive breast cancer (HER2+BC) from the NCCTG adjuvant Intergroup trial N9831
Authors: Moreno-Aspitia A. , Hillman D. W. , Dueck A. C. , Carney W. P. , Lingle W. L. , Tenner K. S. , Lafky J. M. , Reinholz M. M. , Kutteh L. A. , Perez E. A.
Published: August 2020

539

Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels <50, 24% (15/63) of Arm A patients had very high recurrence sHER-2 levels (≥50) as compared to 9% (2/23) on Arm C (p=0.10). Patients with recurrence sHER-2 levels ≥15 had shorter survival time following recurrence with 3 year overall survival of 51% compared to 76% for the <15 sHER-2 group (HR = 2.77; 95% CI: 1.20–6.43, p = 0.02). Conclusions: Based on serial specimens during treatment, the concurrent trastuzumab arm (C) had constant sHER-2 levels, whereas the standard chemotherapy arm (A) had increasing sHER-2 levels. In arm A, recurrence sHER-2 levels increased significantly from baseline while recurrence sHER-2 levels did not change in arm C. Additionally, pts with high sHER-2 levels at recurrence had shorter overall survival following recurrence. Partial support: CA25224, CA114740 , Genentech, Siemens, and the BCRF.

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Clinicopathological features and sites of recurrence according to breast cancer subtype in the National Comprehensive Cancer Network (NCCN)
Authors: Lin N. U. , Vanderplas A. , Hughes M. E. , Theriault R. L. , Edge S. B. , Wong Y. , Blayney D. W. , Niland J. C. , Winer E. P. , Weeks J. C.
Published: August 2020

543

Background: Gene expression profiling has defined multiple breast cancer subtypes which can approximated using standard immunohistochemical markers. Methods: We assessed clinicopathological features and sites of recurrence for patients (pts) presenting to NCCN sites with stage I-III breast cancer from Jan 2000 to Dec 2006 where estrogen receptor (ER), progesterone receptor (PR), and HER2 status were known. Tumors were grouped as luminal A (ER+ and/or PR+, and HER2-), HER2+ (any ER or PR, and HER2+), or triple-negative (ER-, PR-, and HER2-). Chi-square compared proportions across tumors; univariate logistic regression estimated risk of first site of recurrence. Results: 12,858 pts met inclusion criteria. Median follow-up from NCCN presentation was 3.2 years. Subtype distribution was: triple-negative (TN) 17%; HER2+ 18%; luminal A 66%. Compared to pts with luminal A and HER2+ tumors, TN were younger (p<0.0001), more likely African-American (p<0.0001) and overweight (p=0.0006). TN and HER2+ tumors were less often detected by screening mammography (TN, 28.9%; HER2+, 33.6%; luminal A, 48.4%) and less likely to present as T1 (TN, 46.5%; HER2+, 50.5%; luminal A, 67.0%) or diagnosed as stage I (TN, 32.6%; HER2+ 33.2%; luminal A, 49.4%) than luminal A (all p<0.0001). Rate of node positivity was lowest in TN (TN, 37.1%; HER2+, 44.9%; luminal A, 38.1%; p<0.0001). 83% of TN tumors were high grade; 93% were invasive ductal histology. Extensive intraductal component and lymphovascular invasion were more often associated with HER2+, compared to TN or luminal A (p<0.0001). Recurrences were recorded for 1,235 pts. Relative to luminal A, TN and HER2+ were more likely to experience lung (TN, odds ratio [OR] 2.27, 95% confidence interval [CI] 1.50, 3.43; p=0.0001; HER2+, OR 1.65, 95% CI 1.05, 2.60; p=0.03) and brain (TN, OR 5.32, 95% CI 2.85, 9.91; p<0.0001; HER2+, OR 5.53, 95% CI 2.93, 10.43; p<0.0001) as first site of recurrence; bone was less likely (TN, OR 0.23, 95% CI 0.16, 0.33; p<0.0001; HER2+, OR 0.38, 95% CI 0.28, 0.53; p<0.0001). Conclusions: Clinicopathological features and patterns of recurrence differed significantly by subtype and may inform the design of future clinical trials.

No significant financial relationships to disclose.
Use of molecular classification combined with p53 and topoisomerase IIa expression to identify tumors highly responsive to FEC regimen: A tissue microarray
Authors: Berrada N. , Conforti R. , Delaloge S. , Spielmann M. , Andre F.
Published: August 2020

546

Background: Identification of highly responsive tumors to specific regimen is needed in order to better tailor post-operative chemotherapy regimen. We previously reported using a tissue microarrays that basal-like and HER2-overexpressing tumors derive higher benefit from adjuvant chemotherapy than luminal-like tumors. Previous studies have reported that p53+/basal-like tumors, and HER2+/topoisomerase IIa + tumors were highly sensitive to alkylating agents and anthracyclines respectively. In the present study, we have evaluated whether p53+/basal-like and HER2+TopIIa+ tumors derive high benefit from an alkylating/anthracyclines based chemotherapy. Methods: A tissue microarrays was built with tumor samples from 823 patients randomized between FEC/FAC regimen and no chemotherapy. Basal-like breast cancers were defined as HER2-/ER-/EGFR+ and/or CK5/6+ tumors. HER2-overexpressing were defined using HER2 expression by IHC (3+ score). P53 and topoisomerase IIa expression were assessed by IHC. Treatment effect was assessed by Cox model that included prognostic parameters and stratification variables. Predictive value for treatment effect were assessed by interaction test and test for heterogeneity. Results: 823 patients were included. 12.5% and 12.9% patients presented a basal-like and HER2-overexpressing breast cancer respectively. P53 and topoisomerase IIa were expressed in 20% and 35% patients. Hazard ratio for relapse associated with FEC/FAC regimen was 0.79 (95%CI: 0.62–1). Hazard ratio associated with FEC/FAC were 0.31 (0.1–0.97 ) and 1.19 (0.38–3.7 ) in patients with p53+/basal-like and p53- basal-like breast cancer. A p53/basal-based classification was associated with a trend for heterogeneity (p = 0.15). Hazard ratio associated with FEC/FAC were 0.34 (0.11–1.0 ) and 1.27(0.32–4.9) in patients with topIIa+/HER2+ and topIIa-/HER2+ breast cancer. A HER2/TopIIa classification was associated with a trend for heterogeneity (p = 0.07). Conclusions: The present study suggest that p53+/basal-like cancer and TopIIA+/HER2 cancers derive high benefit from adjuvant FEC/FAC regimen. This finding requires further validation given multihypothesis testing and subgroup analysis.

No significant financial relationships to disclose.
Triple-negative receptor status and the 2007 St. Gallen consensus guidelines for early breast cancer
Authors: Caggiano V. , Bauer K. R. , Parise C. A.
Published: August 2020

547

Background: The 2007 St Gallen consensus statement describes three risk categories and provides guidelines for treatment. We previously described the distribution of ER/PR/HER2 in breast cancer and analyzed the triple-negative subtype. We now examine the 2007 St Gallen consensus-risk categories with respect to the ER/PR/HER2 subtypes. Methods: Using the population-based California Cancer Registry from 2000 through 2006, we identified 63,925 cases of stages I-III first primary invasive female breast cancer with known status of ER, PR, and HER2. We retrospectively assigned cases to risk categories using pathologic tumor size and grade, age, and status of ER, PR, HER2, and lymph nodes. Extensive peritumoral vascular invasion was not readily available and could not be utilized. We determined the ER/PR/HER2 subtypes for each risk category and performed five-year relative survival. Results: Five year relative survival was 95% or greater for the low risk (LR), node-negative intermediate risk (NNIR), and node positive (1–3) intermediate risk (NPIR) categories. The 5-year relative survival for the node positive (1–3) high-risk (NPHR) category was 85% and 74% for the node positive (> 3) high-risk (NPHR4) category; both had significantly worse survival than the low- and intermediate-risk categories. Classification of the risk categories by ER/PR/HER2 subtype showed no differences between the subtypes in the low risk category and clear differences in all other risk categories. All ER-negative subtypes had the worst survival within the NNIR, NPHR, and NPHR4 categories. The triple negative subtype had the worst survival in all of these risk categories. The greatest differences in 5-year relative survival were noted in the NPHR4 category with survival ranging from 85% in the ER+/PR+/HER2- subtype to 50% in the triple negative subtype. Conclusions: The St Gallen risk model clearly separates early breast cancer into three risk categories and helps with treatment decisions. Use of the ER/PR/HER2 subtypes within these categories clearly illustrates the heterogeneity of the intermediate and high risk categories and may prove to be important in this era of tailored therapy.

No significant financial relationships to disclose.