Aroop Mangalik

Anastrozole Is Superior to Tamoxifen as First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial

PURPOSE The efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as first-line therapy for advanced breast cancer in 353 postmenopausal women. PATIENTS AND METHODS The randomized, double-blind, multicenter study was designed to evaluate anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with hormone receptor-positive tumors or tumors of unknown receptor status who were eligible for endocrine therapy. Primary end points were objective response (OR), defined as complete (CR) or partial (PR) response, time to progression (TTP), and tolerability. RESULTS Anastrozole was as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively), with clinical benefit (CR + PR + stabilization > or = 24 weeks) observed in 59% of patients on anastrozole and 46% on tamoxifen (two-sided P =.0098, retrospective analysis). Anastrozole had a significant advantage over tamoxifen in terms of TTP (median TTP of 11.1 and 5.6 months for anastrozole and tamoxifen, respectively; two-sided P =.005). The tamoxifen:anastrozole hazards ratio was 1.44 (lower one-sided 95% confidence limit, 1.16). Both treatments were well tolerated. However, thromboembolic events and vaginal bleeding were reported in fewer patients who received anastrozole compared with those who received tamoxifen (4.1% v 8.2% [thromboembolic events] and 1.2% v 3.8% [vaginal bleeding], respectively). CONCLUSION Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in TTP and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.

Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer

Purpose: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor–positive metastatic breast cancer (MBC). Experimental Design: Postmenopausal women with hormone receptor–positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective. Results: Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed. Conclusion: This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor–positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted. Clin Cancer Res; 16(6); 1904–14

Telomere content correlates with stage and prognosis in breast cancer

SummaryPurposeTo evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissue correlates with TNM staging and prognosis.Experimental designSlot blot assay was used to quantitate TC in 70 disease-free normal tissues from multiple organ sites, and two independent sets of breast tumors containing a total of 140 samples. Non-parametric Rank–Sums tests, logistic regression and Cox proportional hazards models were used to evaluate the relationships between TC and tumor size, nodal involvement, TNM stage, 5-year survival and disease-free interval.ResultsTC in 95% of normal tissues was 75–143% of that in the placental DNA standard, whereas only 50% of tumors had TC values in this range. TC was associated with tumor size (p=0.02), nodal involvement (p<0.0001), TNM stage (p=0.004), 5-year overall survival (p=0.0001) and 5-year disease-free survival (p=0.0004). A multivariable Cox model was developed using age at diagnosis, TNM stage and TC as independent predictors of breast cancer-free survival. Relative to the high TC group (>123% of standard), low TC (<101% of standard) conferred an adjusted relative hazard of 4.43 (95% CI 1.4–13.6, p=0.009). Receiver operating characteristic curves using thresholds defined by the TC distribution in normal tissues predicted 5-year breast cancer-free survival with 50% sensitivity and 95% specificity, and predicted death due to breast cancer with 75% sensitivity and 70% specificity.ConclusionsTC in breast cancer tissue is an independent predictor of clinical outcome and survival interval, and may discriminate by stage.

Epithelioid hemangioendothelioma of bone.

Abstract Neoplasms of bone can arise from any of the cellular elements that constitute osseous tissues. Although tumors of vascular origin are not uncommon, the vast majority are benign. A rare malignant vascular tumor – epithelioid hemangioendothelioma of bone – classifically affects young males and produces osteolytic lesions involving the cortex and cancellous bone of the lower extremities. We present a case with these findings, as well as such unusual findings as cervical spine instability and lesions affecting no fewer than 45 different bones. We conclude that epithelioid hemangioendo-thelioma should be investigated by skeletal survey because (1) osteolytic lesions involving more that 50% of the cortex present a serious risk for pathologic fracture and (2) the natural history of multicentric epithelioid hemangioendothelioma is more indolent than its solitary counterparts

Pilot trial of infusional 5-fluorouracil, interleukin-2, and subcutaneous interferon-α for advanced renal cell carcinoma

The authors developed an outpatient, three-drug combination regimen for advanced renal cell carcinoma. Treatment was administered for 5 days each week for 4 weeks, followed by 2-week rests. Each weekly treatment consisted of 5-fluorouracil 1,750 mg/m2 continuous intravenous infusion for 24 hours followed by interleukin-2 6 mIU/m2 per day continuous intravenous infusion for 4 days, and interferon-alpha2b 6 mU/m2 subcutaneously on days 1, 2, and 5. This trial was undertaken to assess tolerability to this regimen and obtain a preliminary assessment of its effectiveness. Most patients required some dose adjustments (especially of cytokines), treatment interruptions, or both. Toxicities were as would be expected from individual drug profiles with only mild to moderate hematologic toxicities. Among 16 patients with renal cell carcinoma treated, four had major (clinical partial response) responses, one of which was demonstrated to be a pathologic clinical response after surgical resection of a residual mass. Estimated median survival time of all patients was 93 weeks. Response and survival were correlated with known clinical risk factors. Responding patients were noted to be significantly older in age (X = 61.75 years) than nonresponders (X = 48.92 years). There was no correlation between age and other clinical risk factors, treatment tolerance, or survival. The authors conclude that this three-drug regimen is a practical, tolerable, and promising regimen for further study in renal cell carcinoma.

Paraneoplastic Neurological Syndrome in Transitional Cell Carcinoma of the Bladder

Paraneoplastic neurological syndromes are well known sequelae of some malignancies but they have never been reported in transitional cell carcinoma of the bladder. A paraneoplastic neurological syndrome characterized by visual changes, glossal spasm and dysphagia associated with an invasive high grade transitional cell carcinoma of the bladder is reported. Neurological symptoms resolved after extirpation confirming a paraneoplastic condition. Recurrent disease was associated with recurrent neurological symptoms and resolved after a complete response to combination chemotherapy.

Molecular marker correlates of clinical outcome in a phase II study of gefitinib or placebo in combination with anastrozole in postmenopausal women with hormone receptor-positive metastatic breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3131 Background: Preclinical data suggest that crosstalk between growth factor receptor pathways and estrogen receptor (ER) is involved in the development of endocrine resistance. Therefore, inhibition of epidermal growth factor receptor (EGFR) is a potential target in this setting. This phase II randomized, double-blind, multicenter study evaluated the efficacy and tolerability of gefitinib (Iressa) or placebo in combination with anastrozole (Arimidex) in postmenopausal women with newly diagnosed hormone receptor-positive (HR+) metastatic breast cancer (MBC). Methods: Patients were randomized (1:1) to anastrozole 1 mg/day and either gefitinib 250 mg/day or placebo. The primary objective was progression-free survival (PFS); and secondary objectives included clinical benefit rate (CBR; defined as objective response plus stable disease ≥24 weeks), objective response rate (ORR) by RECIST, overall survival, safety and correlative biological markers. Biomarkers in tumor tissue (ErbB family receptors including EGFR, or other downstream related effectors and other markers of proliferation and apoptosis) by immunohistochemistry were assessed to explore potential correlations with outcome. Enrollment closed early due to slow recruitment and formal statistical testing was not performed. Results: 94 women were randomized to gefitinib plus anastrozole, and 43 to placebo plus anastrozole, 50 from 30 centers in 4 countries. PFS was significantly longer for gefitinib plus anastrozole over placebo plus anastrozole (HR [gefitinib:placebo] 0.55, 95% CI 0.32-0.94; median PFS 14.5 vs 8.2 months). A numerical advantage in CBR was seen for gefitinib plus anastrozole over placebo plus anastrozole (49% [21/43; 95% CI 35-65] vs 34% [17/50; 95% CI 21-49]). ORR was 2% (1/43) with gefitinib plus anastrozole and 12% (6/50) with placebo plus anastrozole. Too few patients died before data cut-off to allow conclusions on overall survival to be drawn. Safety and tolerability profiles showed no unexpected findings. Correlative biological markers data will be available later in the year after which the abstract will be updated and resubmitted. Discussion: This clinical trial demonstrated that EGFR inhibition and estrogen deprivation with gefitinib in combination with anastrozole was associated with a marked advantage in PFS and CBR vs placebo plus anastrozole in ER+ MBC. These data suggest that EGFR inhibition in combination with anastrozole warrants further investigation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3131.

Abstract P3-12-01: Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide

Background NSABP B-36 compares 6 cycles of FEC-100 with 4 cycles of standard AC in pts with node-negative breast cancer. As reported separately, no significant differences between the two treatment arms were observed in the primary endpoint of disease-free survival or in the secondary endpoints of overall survival, recurrence-free, or distant recurrence-free intervals. Greater toxicity was reported in pts who received FEC compared to AC. We present here the results of the QOL and MH studies obtained prospectively in conjunction with the treatment study. We hypothesized that pts on FEC would experience greater treatment toxicity in the first 12 months of the study, and would have greater rates of amenorrhea at 18 months compared to pts on AC. Methods Among the 1,357 pts enrolled in the QOL study, 1,332 (675 AC, 657 FEC) submitted the baseline form and had QOL follow-up (fup) information. Pts completed: 1) the FACT-B instrument; 2) a symptom checklist; and 3) the SF-36 Vitality Scale, all at baseline, day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months after random assignment. FACT-B Trial Outcome Index (TOI), symptom severity, and vitality scores were compared between the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, type of surgery, and hormone receptor status, examining the first 12 months and the later time points separately. Menstrual status was collected at baseline for all enrolled pts, with subsequent assessments on day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months for pts with menstrual bleeding within 12 months prior to random assignment and not having had a hysterectomy and/or bilateral oophorectomy (1, 096 pts). Post-chemotherapy amenorrhea was defined as the lack of menstrual periods during the 12 months preceding the 18-month fup evaluation. Data from 921 pts (475 AC, 446 FEC) were available for analysis. Logistic regression, adjusted for type of surgery and hormone receptor status, was used to test for association of amenorrhea status and treatment. Results Both TOI and vitality scores were worse for pts on FEC compared to those on AC at 6 months (p Conclusions Women receiving FEC had diminished QOL at 6 months after random assignment, but no difference at 12 months or later. Premenopausal women receiving FEC experienced a higher rate of post-chemotherapy amenorrhea than women receiving AC. Support NCI grants U10-CA-12027, -37377, -69974, -69651 and -44066-26, and Pharmacia & Upjohn Company, a subsidiary of Pfizer, Inc. Citation Format: Patricia A Ganz, John W Wilson, Hanna Bandos, Andre Robidoux, Alexander HG Paterson, Johnathan Polikoff, Luis Baez-Diaz, Adam M Brufsky, Louis Fehrenbacher, Aroop Mangalik, Patrick J Ward, Louise Provencher, John T Hamm, Philip J Stella, Robert L Carolla, Richard G Margolese, Henry R Shibata, Edith A Perez, Norman Wolmark. Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-01.

A B-cell "chameleon": striking clinical, morphological, and immunophenotypic diversity of a single low-grade B cell clone.

A patient with an 18-year history of low-grade B-cell lymphoproliferative disorders is presented. Although the precise classification of these B-cell disorders was problematic, the blood, bone marrow, spleen, lymph node, and gastrointestinal lesions evaluated were compatible morphologically with such apparently disparate diagnoses as hairy cell leukemia, marginal zone lymphoma, mantle cell lymphoma, and gastrointestinal multiple lymphomatous polyposis. Although each low-grade disease that developed over an 18-year interval was clinically, morphologically, and immunophenotypically distinct, genotyping showed their derivation from a single B cell clone. This case emphasizes that a single B-cell clone may give rise to several distinct low-grade B-cell lymphoproliferative disorders with diverse clinical and pathological features.

Phase I dose finding study of carboplatin, paclitaxel, and temozolomide in advanced solid tumors.

This phase I study was carried out to evaluate the optimal dose of temozolomide in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Patients with advanced melanoma or small cell lung cancer that could benefit from the combination of carboplatin and paclitaxel were eligible. A standard 3+3 patient cohort dose escalation design was used. Paclitaxel and carboplatin were administered at fixed doses of 175 mg/m2 on day 1 and an area under the curve of 5, respectively. Temozolomide was administered at a dose of 75 mg/m2/day from days 2–6 and subsequent cohorts were dose escalated by 25 mg/m2 increments. Cycles were repeated every 28 days. The primary objective of this study was to determine the maximum tolerated dose of this combination. Fourteen patients were enrolled and 12 patients were evaluable for toxicity and response (six with melanoma and six with small cell lung cancer). The maximum tolerated dose of temozolomide was 125 mg/m2, with fixed doses of carboplatin and paclitaxel. There were no treatment delays nor dose reductions at this level. There were two partial responses and two patients with stable disease in the melanoma group. Four patients had a partial response, and one had stable disease in the small cell lung cancer group. There were sustained responses in three of the four patients with melanoma who achieved a clinical benefit. In conclusion, the combination of carboplatin, paclitaxel, and temozolomide is well tolerated and warrants further study.