Larry Norton

Arterial Thrombosis Associated with Adjuvant Chemotherapy for Breast Carcinoma: A Cancer and Leukemia Group B Study

PURPOSE Multiagent chemotherapy and chemohormonal therapy for breast cancer are associated with an increased risk for venous thromboembolic complications. We observed instances of arterial thrombosis in two studies of breast cancer involving multiagent chemotherapy for stages II and III disease. Our purpose in this study was to determine the incidence of this complication and whether it appeared to be related to the chemotherapy or was a random event. PATIENTS AND METHODS Episodes of arterial thrombotic events were identified from record reviews of 1,014 assessable patients with breast cancer entered on two Cancer and Leukemia Group B protocols. Details of the kind of arterial event, when it occurred, the outcome, and the occurrence of metastases were analyzed. RESULTS Thirteen (1.3%) patients had an arterial thrombosis: six (5.3%) of 113 patients with stage III disease and seven (0.8%) of 901 patients with stage II disease. Four of these patients had a peripheral arterial thrombosis and nine had strokes (four were fatal). All these events occurred while the patients were receiving adjuvant chemotherapy. Only one additional arterial event (a stroke approximately four years later) has occurred in this patient group after chemotherapy was completed. CONCLUSION Arterial thrombosis is also associated with multiagent chemotherapy in patients with breast cancer. The mechanism is unknown.

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance)

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha=0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio=1.20; 95% confidence interval=0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P=0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P=0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Clinical cardiotoxicity of esorubicin (4′-deoxydoxorubicin,DxDx): Prospective studies with serial gated heart scans and reports of selected cases - A Cancer and Leukemia Group B report

SummaryEsorubicin (4′-deoxydoxorubicin, DxDx) has undergone extensive Phase II investigation for the treatment of cancer. Based on in vitro and animal data, esorubicin may possess less myocardial toxicity when compared to doxorubicin. One hundred thirty-six patients with histologically or cytologically documented non-small cell lung cancer or advanced breast cancer were enrolled in two concurrent CALGB clinical trials using esorubicin at a dose of 30 mg/m2 administered intravenously every 21 days. No patient had previously received an anthracycline agent or had evidence of severe cardiovascular disease. Cardiotoxicity was observed in eleven patients. Four patients developed symptoms of congestive heart failure and three asymptomatic patients had a significant fall in left ventricular ejection fraction (LVEF) as measured by gated pool heart scan. Four patients had cardiac signs or symptoms of indeterminate relationship to esorubicin therapy. Of 44 patients receiving more than four cycles of therapy, 36 patients (82%) had serial gated pool heart scans permitting assessment of subclinical myocardial toxicity. A 5% drop in LVEF was observed following approximately 240 mg/m2 esorubicin; a 10% drop was observed after approximately 480 mg/m2. If further clinical studies are undertaken with esorubicin, investigators are advised to monitor cardiac function frequently once the cumulative esorubicin dose exceeds 240 mg/m2. If congestive failure appears during therapy, prompt cessation of esorubicin and institution of inotropic agents may provide effective palliation. Normal myocardial function may be restored within several months.

Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review

Capecitabine is widely used in the management of metastatic breast cancer; however, drug delivery is limited by gastrointestinal and other toxicity. We employed mathematical modeling to rationally design an optimized dose and schedule for capecitabine of 2,000 mg twice daily, flat dosing, 7 days on, 7 days off. Preclinical data suggested increased efficacy and tolerability with this novel dosing, and three early-phase clinical trials have suggested a favorable toxicity profile. To further define the tolerability of this regimen, we conducted a systematic review of the gastrointestinal adverse events of patients on these studies. This review demonstrated a favorable gastrointestinal toxicity profile with capecitabine in this novel schedule when given as single agent or in combination therapy with either bevacizumab or lapatinib. No patients discontinued therapy for gastrointestinal toxicity, and there were no grade 4 or 5 gastrointestinal toxicities reported. Grade 3 or greater diarrhea occurred in two (2%); grade 2 or greater mucositis, constipation, and vomiting were reported in three (4%) patients. We conclude that capecitabine administered on a 7 days on, 7 days off schedule has limited gastrointestinal toxicity. Our methodology was based on an analysis of individual patient toxicity data from one phase I single-agent capecitabine and two phase II capecitabine combination studies (with bevacizumab and lapatinib, respectively), focusing specifically on gastrointestinal toxicity.

Implications of growth kinetic concepts for cancer chemoprevention.

AbstractOur consideration of the possibility of using pharmacological agents to prevent the development of clinical breast cancer is properly rooted in cell biology. Whatever the interrelationships of host factors, including the immune and endocrine environments, with intrinsic neoplastic factors, such as paracrine and autocrine growth influences, the fundamental unit of cancer is the cancer cell, without which there would be no malignant disease. Unlike some other polycytomas-which cause disease primarily by the secretion of hormone-like substances or other bioactive chemicals-breast cancers usually disrupt their host by inappropriately occupying space. In this way breast cancers exemplify the cardinal features of growth, metastasis, and invasiveness. If cancer therapy is aimed at reversing this process, usually by removing, killing, or otherwise inactivating cancer cells, chemoprevention must prohibit the primary expression of these malignant characteristics.