Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Comprehensive genomic studies: emerging regulatory, strategic, and quality assurance challenges for biorepositories.

As part of the molecular revolution sweeping medicine, comprehensive genomic studies are adding powerful dimensions to medical research. However, their power exposes new regulatory, strategic, and quality assurance challenges for biorepositories. A key issue is that unlike other research techniques commonly applied to banked specimens, nucleic acid sequencing, if sufficiently extensive, yields data that could identify a patient. This evolving paradigm renders the concepts of anonymized and anonymous specimens increasingly outdated. The challenges for biorepositories in this new era include refined consent processes and wording, selection and use of legacy specimens, quality assurance procedures, institutional documentation, data sharing, and interaction with institutional review boards. Given current trends, biorepositories should consider these issues now, even if they are not currently experiencing sample requests for genomic analysis. We summarize our current experiences and best practices at Washington University Medical School, St Louis, MO, our perceptions of emerging trends, and recommendations.

Microscopically positive margins for primary gastrointestinal stromal tumors: analysis of risk factors and tumor recurrence.

BACKGROUND: Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. STUDY DESIGN: We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. RESULTS: Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥ 10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio [HR] 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. CONCLUSIONS: Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years.

American College of Surgeons Oncology Group and the community surgeon.

The American College of Surgeons Oncology Group (ACOSOG) conducts cancer trials that are relevant to surgeons who treat patients with breast, thoracic, and gastrointestinal cancers. ACOSOG is funded by the National Cancer Institute and is charged with conducting prospective clinical trials that address important questions in academic and community practice settings. Examples include role of axillary dissection for microscopic nodal disease, neoadjuvant therapy for organ-conserving surgery, laparoscopic rectal cancer resection, mediastinal nodal staging, and sublobar resection for early-stage non-small cell lung cancer. Such trials are relevant to most practicing surgeons.

Features associated with successful recruitment of diverse patients onto cancer clinical trials: report from the American College of Surgeons Oncology Group.

BACKGROUND: The clinical trials mechanism of standardized treatment and follow-up for cancer patients with similar stages and patterns of disease is the most powerful approach available for evaluating the efficacy of novel therapies, and clinical trial participation should protect against delivery of care variations associated with racial/ethnic identity and/or socioeconomic status. Unfortunately, disparities in clinical trial accrual persist, with African Americans (AA) and Hispanic/Latino Americans (HA) underrepresented in most studies. STUDY DESIGN: We evaluated the accrual patterns for 10 clinical trials conducted by the American College of Surgeons Oncology Group (ACOSOG) 1999-2009, and analyzed results by race/ethnicity as well as by study design. RESULTS: Eight of 10 protocols were successful in recruiting AA and/or HA participants; three of four randomized trials were successful. Features that were present among all of the successfully recruiting protocols were: (1) studies designed to recruit patients with regional or advanced-stage disease (2 of 2 protocols); and (2) studies that involved some investigational systemic therapy (3 of 3 protocols). DISCUSSION: AA and HA cancer patients can be successfully accrued onto randomized clinical trials, but study design affects recruitment patterns. Increased socioeconomic disadvantages observed within minority-ethnicity communities results in barriers to screening and more advanced cancer stage distribution. Improving cancer early detection is critical in the effort to eliminate outcome disparities but existing differences in disease burden results in diminished eligibility for early-stage cancer clinical trials among minority-ethnicity patients.

Improved surgeon performance in clinical trials: an analysis of quality assurance audits from the American College of Surgeons Oncology Group.

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) represents an organized effort by surgeons to participate in clinical trials research. To assess the quality of trial conduct by surgeons on a national level and the feasibility of improvement through education, this study examined the findings of the Quality Assurance Audit Program of the ACOSOG over time. STUDY DESIGN: Outcomes of 249 routine audits conducted from 2001 to 2004 were reviewed for major and minor deficiencies and overall performance (acceptable versus unacceptable) in compliance with regulatory requirements (REG) and patient case review (PCR). RESULTS: From 2001 to 2004, active trials have increased. Major deficiencies in REG fell from 31% to 20% for IRB documentation (p = 0.002) and from 31% to 9% for informed consent (p < 0.001). The major deficiency rates in PCR decreased from 21% to 6% (patient consent), 16% to 7% (eligibility), 13% to 7% (treatment), 34% to 6% (outcomes), 6% to 1% (toxicity), and 16% to 3% (data). During 2001 to 2004, the overall acceptable performance rates were 82%, 72%, 84%, and 92%, respectively, in REG (p = 0.093), and significantly improved in PCR (47%, 55%, 77%, 94%, respectively; p < 0.001). No difference was detected in acceptable rates between academic versus community sites, for either REG (86% versus 76%, respectively; odds ratio: 1.91; 95% CI: 0.87 to 4.19) or PCR (63% versus 68%, respectively; odds ratio: 0.81; 95% CI: 0.42 to 1.53). CONCLUSIONS: Despite initial deficiencies, surgical trials are now conducted with high standards nationwide. In response to educational programs, surgeon performance in clinical trials has measurably improved. Quality assurance audits have served both surveillance and educational roles.

Use of the National Cancer Data Base to develop clinical trials accrual targets that are appropriate for minority ethnicity patients: a report from the American College of Surgeons Oncology Group (ACOSOG) Special Population Committee.

BACKGROUND: Disparities in cancer outcome among different subsets of the American population related to ethnic background have been well documented. Clinical trials represent the most powerful strategy for improving cancer treatments, but racial and ethnic minority patients are frequently underrepresented among patients accrued to these protocols. Proof of comparable efficacy for a promising cancer therapy in different groups of patients requires diversity in the clinical trial populations so that study results will be generalizable. Appropriate targets for accrual of minority ethnicity patients have not previously been defined. METHODS: The National Cancer Database (NCDB) is maintained jointly by the American Cancer Society and the American College of Surgeons. Information submitted by tumor registries throughout the United States represents an estimated 70% of newly diagnosed cancer cases. The authors analyzed NCDB reports on ethnic distribution of patients with breast, prostate, nonsmall cell lung, and colorectal cancer, stratified by stage of disease at diagnosis. RESULTS: African Americans with cancer of the breast and prostate had the most notable patterns of disproportionate representation among populations with advanced-stage disease. The authors compiled a table of suggested accrual targets for selected solid-organ cancers based on NCDB stage-specific reports. CONCLUSIONS: Clinical trial results will be more meaningful if participating patients reflect the site- and stage-specific populations that are under study. The authors recommended that clinical trial investigators incorporate accrual targets for minority ethnicity populations into the study design.

Feasibility of breast duct lavage performed by a physician extender.

BACKGROUND: The safety and feasibility of ductal lavage (DL), a risk-assessment tool utilizing a minimally invasive technique that permits sampling of breast duct epithelium, performed primarily by a nurse practitioner (NP), was studied prospectively. METHODS: Women at high risk for breast cancer with a normal clinical breast exam and mammogram were enrolled. Nipple aspirate fluid (NAF)-yielding ducts were identified, cannulated, and lavaged primarily by an NP in collaboration with a breast surgeon. Samples with sufficient cellularity were categorized as benign, mild atypia, marked atypia, or malignant. Pain and adverse events were recorded. RESULTS: Thirty-seven women, with a mean age of 51.7 years, were enrolled. Thirty-one (83.8%) women yielded NAF and, of those, 28 (90.3%) had one or more ducts successfully cannulated. Of 65 lavaged ducts in these 28 women, cellularity was adequate for diagnosis in 44 (67.7%) samples. Cytologic findings were as follows: 24 benign, 15 mild atypia, 4 marked atypia, and 1 malignant. The procedure was well tolerated with a mean pain score of 3.2 (SD +/- 1.81). The most frequent adverse event was breast fullness, reported by 44.8% of the women. Two women with marked atypia were evaluated further and found to have intraductal papillomata. The woman with malignant cytology had ductal carcinoma in situ. CONCLUSION: DL is a safe, generally well-tolerated procedure that can be performed successfully by a trained NP.

Intradermal radioisotope is superior to peritumoral blue dye or radioisotope in identifying breast cancer sentinel nodes.

BACKGROUND: Sentinel lymph node (SLN) mapping and biopsy have emerged as the technique of choice for axillary staging of breast cancer. Several methods have been developed to identify SLNs, including peritumoral or intradermal injection of isosulfan blue dye or technetium sulfur colloid (TSC). We hypothesize that intradermal TSC is the optimal mapping technique and can be used alone to identify SLNs. STUDY DESIGN: From March 1997 through January 2001, 180 women with T1 and T2 invasive breast cancer and clinically negative axilla underwent SLN mapping and biopsy. Peritumoral TSC was injected in 74 patients, 62 of whom also received peritumoral blue dye. Intradermal TSC (above tumor) was performed in 94 patients, 76 of whom also received peritumoral blue dye. Technetium-rich nodes were identified intraoperatively using a hand-held gamma probe and blue nodes were identified visually. Hematoxylin- and eosin-stained SLN sections were examined by light microscopy for breast cancer metastases. RESULTS: Overall, the SLN mapping procedures were successful in 91% of patients. Peritumoral and intradermal TSC were successful in identifying SLNs in 78% and 97% of patients, respectively. Peritumorally injected isosulfan blue was successful in identifying 83% of SLNs. Intradermal TSC was found to be superior to peritumoral TSC and peritumoral blue dye in identifying SLNs (p = 0.00094, chi-squared, and p = 0.020, ANOVA). CONCLUSIONS: SLN mapping by intradermal TSC has a significantly higher success rate than peritumoral TSC or blue dye. There was minimal benefit in identifying additional SLNs with addition of peritumoral blue dye to intradermal TSC. So, SLN mapping and biopsy using intradermal-injected TSC can be used alone to effectively stage the axilla for breast cancer.

A comparison of laparoscopically assisted and open colectomy for colon cancer.

BACKGROUND: Minimally invasive, laparoscopically assisted surgery was first considered in 1990 for patients undergoing colectomy for cancer. Concern that this approach would compromise survival by failing to achieve a proper oncologic resection or adequate staging or by altering patterns of recurrence (based on frequent reports of tumor recurrences within surgical wounds) prompted a controlled trial evaluation. METHODS: We conducted a noninferiority trial at 48 institutions and randomly assigned 872 patients with adenocarcinoma of the colon to undergo open or laparoscopically assisted colectomy performed by credentialed surgeons. The median follow-up was 4.4 years. The primary end point was the time to tumor recurrence. RESULTS: At three years, the rates of recurrence were similar in the two groups--16 percent among patients in the group that underwent laparoscopically assisted surgery and 18 percent among patients in the open-colectomy group (two-sided P=0.32; hazard ratio for recurrence, 0.86; 95 percent confidence interval, 0.63 to 1.17). Recurrence rates in surgical wounds were less than 1 percent in both groups (P=0.50). The overall survival rate at three years was also very similar in the two groups (86 percent in the laparoscopic-surgery group and 85 percent in the open-colectomy group; P=0.51; hazard ratio for death in the laparoscopic-surgery group, 0.91; 95 percent confidence interval, 0.68 to 1.21), with no significant difference between groups in the time to recurrence or overall survival for patients with any stage of cancer. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group, as reflected by a shorter median hospital stay (five days vs. six days, P<0.001) and briefer use of parenteral narcotics (three days vs. four days, P<0.001) and oral analgesics (one day vs. two days, P=0.02). The rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were very similar between groups. CONCLUSIONS: In this multi-institutional study, the rates of recurrent cancer were similar after laparoscopically assisted colectomy and open colectomy, suggesting that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer.