G. Bruce Mann

Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: The C-100-21 study group

PURPOSE To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physicians choice. PATIENTS AND METHODS Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physicians choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival. RESULTS Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients. CONCLUSION These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.

Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.

The lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: A human cadaver study

BackgroundCurrent understanding of the lymphatic system of the breast is derived mainly from the work of the anatomist Sappey in the 1850s, with many observations made during the development and introduction of breast lymphatic mapping and sentinel node biopsy contributing to our knowledge.MethodsTwenty four breasts in 14 fresh human cadavers (5 male, 9 female) were studied. Lymph vessels were identified with hydrogen peroxide and injected with a lead oxide mixture and radiographed. The specimens were cross sectioned and radiographed to provide three dimensional images. Lymph (collecting) vessels were traced from the periphery to the first-tier lymph node.ResultsLymph collecting vessels were found evenly spaced at the periphery of the anterior upper torso draining radially into the axillary lymph nodes. As they reached the breast some passed over and some through the breast parenchyma, as revealed in the cross-section studies. The pathways showed no significant difference between male and female specimens. We found also perforating lymph vessels that coursed beside the branches of the internal mammary vessels, draining into the ipsilateral internal mammary lymphatics. In some studies one sentinel node in the axilla drained almost the entire breast. In most more than one sentinel node was represented.ConclusionThese anatomical findings are discordant with our current knowledge based on previous studies and demand closer examination by clinicians. These anatomical studies may help explain the percentage of false-negative sentinel node biopsy studies and suggest the peritumoral injection site for accurate sentinel lymph node detection.

Adjuvant Therapy in Gastric Cancer

Gastric cancer has a poor prognosis. The majority of patients will relapse after definitive surgery, and 5-year survival after surgery remains poor. The role of adjuvant therapy in gastric cancer has been controversial given the lack of significant survival benefit in many randomized studies so far. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which has led to the regimen being adopted as a new standard of care. However, controversies still remain regarding surgical technique, the place of more effective and less toxic chemotherapy regimens, and the use of more modern radiation planning techniques to improve treatment delivery and outcome in the adjuvant and neoadjuvant setting. This article reviews the current status of the adjuvant treatment for gastric cancer including discussion on the research directions aimed at optimizing treatment efficacy. Issues such as the identification of patients who are more likely to benefit from adjuvant therapy are also addressed. Further clinical trials are needed to move towards better consensus and standardization of care.

Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes correlates with traditional predictors of prognosis: An interim analysis of a prospective multi-institutional cohort study

Objective:We sought to establish the clinical relevance of micrometastatic disease detected by reverse transcription polymerase chain reaction (RT-PCR) in axillary lymph nodes (ALN) of breast cancer patients. Background:The presence of ALN metastases remains one of the most valuable prognostic indicators in women with breast cancer. However, the clinical relevance of molecular detection of micrometastatic breast cancer in sentinel lymph nodes (SLN) and nonsentinel ALN has not been established. Methods:Four hundred eighty-nine patients with T1–T3 primary breast cancers were analyzed in a prospective, multi-institutional cohort study. ALN were analyzed by standard histopathology (H&E staining) and by multimarker, real-time RT-PCR analysis (mam, mamB, muc1, CEA, PSE, CK19, and PIP) designed to detect breast cancer micrometastases. Results:A positive marker signal was observed in 126 (87%) of 145 subjects with pathology-positive ALN, and in 112 (33%) of 344 subjects with pathology-negative ALN. In subjects with pathology-negative ALN, a positive marker signal was significantly associated with traditional indicators of prognosis, such as histologic grade (P = 0.0255) and St. Gallen risk category (P = 0.022). Mammaglobin was the most informative marker in the panel. Conclusion:This is the first report to show that overexpression of breast cancer–associated genes in breast cancer subjects with pathology-negative ALN correlates with traditional indicators of disease prognosis. These interim results provide strong evidence that molecular markers could serve as valid surrogates for the detection of occult micrometastases in ALN. Correlation of real-time RT-PCR analyses with disease-free survival in this patient cohort will help to define the clinical relevance of micrometastatic disease in this patient population.

Risk Factors for Invasive Breast Cancer When Core Needle Biopsy Shows Ductal Carcinoma In Situ

HYPOTHESIS A core needle biopsy (CNB) diagnosis of ductal carcinoma in situ (DCIS) may be associated with a final diagnosis of invasive cancer. Preoperative radiologic, clinical, and pathological features may identify patients at high risk of diagnostic upstaging, who may be appropriate candidates for sentinel node biopsy at initial surgery. DESIGN Review of prospectively collected database. SETTING Tertiary teaching referral hospital and a population-based breast screening center. PATIENTS Consecutive patients from January 1, 1994, to December 31, 2006, whose CNB findings showed DCIS or DCIS with microinvasion. MAIN OUTCOME MEASURES Upstaging to invasive cancer. RESULTS Eleven of 15 cases of DCIS with microinvasion (73.3%) and 65 of 375 cases of DCIS (17.3%) were upstaged to invasive cancer. Ten of 21 palpable lesions (47.6%) were found to have microinvasion. For impalpable DCIS, multivariate analysis showed that noncalcific mammographic features (mass, architectural distortion, or nonspecific density) (odds ratio [95% confidence interval], 2.00 [1.02-3.94]), mammographic size of 20 mm or greater (2.80 [1.46-5.38]), and prolonged screening interval of 3 years or longer (4.41 [1.60-12.13]) were associated with upstaging. The DCIS grade on CNB was significant on univariate analysis (P = .04). The rate of upstaging increased with the number of significant factors present in a patient: 8.3% in patients with no risk factors, 20.8% in those with 1 risk factor, 39.6% in those with 2 risk factors, and 57.1% in those with 3 risk factors. CONCLUSIONS The risk of upstaging can be estimated by using preoperative features in patients with DCIS on CNB. We propose a management algorithm that includes sentinel node biopsy for patients with DCIS who have microinvasion on CNB, palpable DCIS, 2 or more predictive factors, and planned total mastectomy.

The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer

Objectives: To assess how the recurrence score of the Oncotype DX breast cancer assay influences adjuvant systemic treatment decisions in the multidisciplinary meeting (MDM) for patients with early breast cancer (EBC) in Australia.

Screening for depression and anxiety in women with breast and gynaecologic cancer: course and prevalence of morbidity over 12 months

This study aims to investigate the course and prevalence of anxiety and depression symptoms over 56 weeks in women with newly diagnosed breast and gynaecologic cancer and determine the acceptability and efficiency of incorporating routine screening into practice.

Which sentinel lymph-node (SLN) positive breast cancer patient needs an axillary lymph-node dissection (ALND) – ACOSOG Z0011 results and beyond

Axillary management has evolved from routine axillary lymph node dissection (ALND) for most patients to a selective approach based on the assessment of the sentinel node (SN). Validation of this approach for staging the axilla is based on observational studies and multiple randomized trials with near general consensus that in case of negative SN completion ALND is not required and if the SN contained metastatic disease, a completion ALND is recommended. Multiple observations have challenged the need for routine completion ALND and growing evidence from institutional series have indicated that selective omission of ALND in patients with positive SN was safe. Unfortunately, the main randomized study addressing the question of the need for a completion axillary dissection closed early having failed to meet its accrual targets. The presentation and publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 study has provoked controversy around the world regarding the extent to which this is a practice-changing study. The aim of this review was to critically re-appraise Z0011 results and assess available evidence which should be used to support the decision of which SN positive breast cancer patient needs an ALND.

Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group.

PURPOSE The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery. METHODS AND MATERIALS Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques. RESULTS A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%. CONCLUSIONS This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute-sponsored, randomized Phase III trial.