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.
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.
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.
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.
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 .
To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer.
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.
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.
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 patient's 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.
We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast ...cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were > or = 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity.
Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m(2); n = 510), or TC (75/600 mg/m(2); n = 506), administered by intravenous infusion every 3 weeks.
The median age in women younger than 65, was 50 years (range, 27 to 64) and for women > or = 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio HR, 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC.
With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.
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.
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.
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.
A computerized literature search from 1994 to March 1999 was performed.
The same values for use, utility, and levels of evidence were used by the committee.
The same benefit, harms, and costs were used.
Changes were recommended (see Appendix).
The updated recommendations were validated by external review by the American Society of Clinical Oncology's (ASCO's) Health Services Research Committee and by ASCO's Board of Directors.
American Society of Clinical Oncology.
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 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.
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.
At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.
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.
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.
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%).
PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.
Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 ...bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5′ RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action.
Treatment of advanced melanoma has significantly improved with the advent of checkpoint inhibitor therapy. With the widespread use of these agents, side effects are being increasingly recognized, ...including immune-related adverse events. We report the onset of adrenal insufficiency in a patient with advanced melanoma who was exposed to two checkpoint inhibitors: ipilimumab and nivolumab. His symptoms initially resolved with steroid replacement but he was unable to be weaned off hormone replacement and required long-term oral hydrocortisone treatment.
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