Robert G. Mennel

American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer

PURPOSE To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast cancer. METHODS For the 2007 update, an Update Committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The Update Committees literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. In general, significant health outcomes (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations. Recommendations and CONCLUSIONS Thirteen categories of breast tumor markers were considered, six of which were new for the guideline. The following categories showed evidence of clinical utility and were recommended for use in practice: CA 15-3, CA 27.29, carcinoembryonic antigen, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, urokinase plasminogen activator, plasminogen activator inhibitor 1, and certain multiparameter gene expression assays. Not all applications for these markers were supported, however. The following categories demonstrated insufficient evidence to support routine use in clinical practice: DNA/ploidy by flow cytometry, p53, cathepsin D, cyclin E, proteomics, certain multiparameter assays, detection of bone marrow micrometastases, and circulating tumor cells.

2000 Update of Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology*

OBJECTIVE To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials. OPTIONS Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer. OUTCOMES In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used. EVIDENCE A computerized literature search from 1994 to March 1999 was performed. VALUES The same values for use, utility, and levels of evidence were used by the committee. BENEFITS, HARMS, AND COSTS The same benefit, harms, and costs were used. RECOMMENDATION Changes were recommended (see Appendix). VALIDATION The updated recommendations were validated by external review by the American Society of Clinical Oncologys (ASCOs) Health Services Research Committee and by ASCOs Board of Directors. SPONSOR American Society of Clinical Oncology.

Exemestane Is Superior to Megestrol Acetate After Tamoxifen Failure in Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Randomized Double-Blind Trial

PURPOSE This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

Phase III Trial Comparing Doxorubicin Plus Cyclophosphamide With Docetaxel Plus Cyclophosphamide As Adjuvant Therapy for Operable Breast Cancer

PURPOSE The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS). PATIENTS AND METHODS Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy. RESULTS Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure. CONCLUSION At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. METHODS A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. RECOMMENDATIONS In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.

Randomized Phase III Trial of Pegylated Liposomal Doxorubicin Versus Vinorelbine or Mitomycin C Plus Vinblastine in Women With Taxane-Refractory Advanced Breast Cancer

PURPOSE To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer. PATIENTS AND METHODS Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m(2) every 28 days); or comparator-vinorelbine (30 mg/m(2) weekly) or mitomycin C (10 mg/m(2) day 1 and every 28 days) plus vinblastine (5 mg/m(2) day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only. RESULTS Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P =.11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P =.71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P =.01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%). CONCLUSION PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.

Neoadjuvant chemotherapy and liver transplantation for hepatocellular carcinoma: A pilot study in 20 patients

BACKGROUND Liver transplantation for unresectable hepatocellular carcinoma yields disappointing results. Most cases recur within 2 years, often in the transplanted liver. METHODS A combination of neoadjuvant doxorubicin and orthotopic liver transplantation was used in 20 patients with unresectable hepatocellular carcinoma confined to the liver. Seventeen patients had tumors > 5 cm in greatest diameter, and 11 cases were stage IVA by the TNM classification. Doxorubicin was administered preoperatively, intraoperatively, and postoperatively at a dose of 10 mg/m2 weekly, totaling 200 mg/m2. RESULTS Chemotherapy was well tolerated although leukopenia was observed in 70% of patients. Eight patients died, five of recurrent tumor and three of hepatitis B. Three others remain alive 8-22 months after tumor recurrence. One patient had initial tumor recurrence in the allograft. Actuarial survival is 59% and tumor-free survival is 54% at 3 years. For the 17 patients with tumors > 5 cm, overall survival is 63% and tumor-free survival is 49% at 3 years. CONCLUSION The results of this pilot study suggest that neoadjuvant doxorubicin chemotherapy favorably alters the post-transplant survival of patients with hepatocellular carcinoma.

Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. METHODS A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective-retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. RESULTS The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective-retrospective studies that evaluated the clinical utility of biomarkers. RECOMMENDATIONS In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patients goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer

PURPOSEThe purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine. METHODSThis was a dose escalation trial in which gemcitabine (1000 mg/m2) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1–21 at escalating doses of 2, 4, 6, and 8 mg/m2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment. RESULTSTwenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limiting toxicity occurred atthe8-mg/m2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable. CONCLUSIONSThe 6-mg/m2 dose of CI-994 (p.o. × 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update

Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor-positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor-positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations. Additional information can be found at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki .