Whole-genome sequencing and cancer therapy: is too much ever enough?

Summary: This issue of Cancer Discovery features an article that describes the use of whole-genome sequencing to discover an actionable genetic alteration that was not detected using a lower resolution diagnostic approach. This finding highlights the growing debate surrounding the optimal deployment of powerful new genomics technologies in the clinical oncology arena. Cancer Discov; 2(9); 766-8. ?2012 AACR.     

Breast-conserving surgery: how much is enough?

Breast-conserving operations for the treatment of small, apparently localized invasive breast cancer are now accepted by most surgeons. Still controversial are (1) the size of the primary tumor selected for breast conservation treatment, (2) how much breast tissue must be removed to provide an "adequate" margin to achieve local control, and (3) whether the entire breast needs to be treated by radiation therapy in all patients after adequate partial mastectomy. The results of breast-conserving operations at the Cleveland Clinic are presented and the case for selected, individualized therapy utilizing partial mastectomy without radiation therapy for selected patients with small invasive cancers is made.     

Bone health in postmenopausal women with early breast cancer: How protective is tamoxifen?

Breast cancer is a leading threat to women's health. Tamoxifen, the most successful selective estrogen receptor modulator, has been used in hormonal therapy for three decades. Along with its therapeutic effect on breast cancer, tamoxifen also demonstrates potential benefits for bone health. However, the extent and quality of such benefits have not been systematically evaluated. We conducted a comprehensive literature search and identified 27 peer-reviewed articles investigating the relationship between tamoxifen and bone health in postmenopausal women with early stage breast cancer. The majority of studies reported that tamoxifen therapy alone protected against the loss of spinal bone mineral density. The bones in the hip also benefited from tamoxifen treatment while there was no evidence demonstrating tamoxifen's protection against bone loss in arms. When tamoxifen was combined with chemotherapy, it was found to partially prevent or reverse the bone loss resulting from chemotherapy. Patients with a history of hormone replacement therapy experienced bone loss while patients without the history had increased bone mineral density during tamoxifen therapy. Despite an apparent impact of tamoxifen on bone mineral density, the few available studies of tamoxifen and bone fractures appear to suggest no protective effect but an increase in fracture incidence. More investigation is necessary to clarify the discrepancy between bone mineral density and fracture in postmenopausal breast cancer patients treated with tamoxifen.     

Sentinel lymph node biopsy for breast cancer: How many nodes are enough?

INTRODUCTION: Sentinel lymph node (SLN) biopsy using blue dye and radioisotope often results in the removal of multiple SLNs. We sought to determine whether there is a point where the surgeon can terminate the procedure without sacrificing accuracy. METHODS: One thousand one hundred ninety-seven patients from University of Michigan and the Mayo Clinic undergoing SLN biopsy formed the study population. Surgeons removed all SLNs until counts within the axilla were less than 10% of the highest node ex vivo and recorded the order in which they were removed. RESULTS: The mean number of SLNs removed per patient was 2.5 (range 1-9). Approximately 42% of patients had three or more lymph nodes removed, while 19% had four or more lymph nodes removed. Eighteen percent of patients (132/725) at University of Michigan and 22% (103/472) at Mayo Clinic had a positive SLN. Ninety-eight percent (231/235) of patients with lymph node metastases were identified by the 3rd SLN while 100% were identified by the 4th SLN. CONCLUSION: Among patients undergoing SLN biopsy for breast cancer, the only positive SLN is rarely identified in the 4th or higher node. Terminating the procedure at the 4th node may lower the cost of the procedure and reduce morbidity.     

Targeting metabolism in breast cancer: How far we can go?

Adjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer.     

HER2 in well differentiated breast cancer: is testing necessary?

Background In addition to providing a timely and accurate diagnosis, pathologists routinely provide prognostic and predictive information to assist in the treatment of patients with invasive breast cancer. As our understanding of breast cancer at the molecular and genetic level improves, sophisticated new treatment options have become available to patients. The demonstrated improvements in disease-free and overall survival with the use of trastuzumab (Herceptin) has made HER2 testing a standard of care in the evaluation of patients with breast cancer. Specialized breast centers have accumulated sufficient experience to recognize that HER2 positive tumors tend to be of higher grade and to be estrogen receptor negative, whereas well-differentiated breast cancers rarely are HER2 positive. Methods To determine whether HER2 testing is necessary in well-differentiated breast cancer, we analyzed the frequency of HER2 positivity among 1,162 cases from 7 major breast centers or commercial laboratories in the United States and Europe. Results Well-differentiated breast cancers, defined by either nuclear grading or the Scarff-Bloom-Richardson system, rarely are HER2 positive (mean 1.6%, range 0–2.8%). Conclusions Given the low rate of well differentiated HER2 positive tumors, falling within the range reported for false negative IHC tests for HER2, and the absence of published data demonstrating a beneficial effect of trastuzumab therapy in this subset of patients, HER2 testing should not be considered a standard of care for all patients with well-differentiated breast cancer.     

Cytology-based treatment decision in primary lung cancer: is it accurate enough?

Accurate distinction of lung cancer types has become increasingly important as recent trials have shown differential response to chemotherapy among non-small cell lung carcinoma (NSCLC) subtypes. Cytological procedures are frequently used but their diagnostic accuracy has been previously questioned. However, new endoscopic and cytological techniques might have improved cytological accuracy in comparison with prior findings. The aim of this study was to reassess cytological accuracy for diagnosis of lung cancer subtypes. A retrospective chart review of subjects who underwent fiberoptic bronchoscopy (FOB) for suspicion of lung cancer in 2007-2008, was undertaken. Reports of bronchoscopically derived cytological specimens were compared to those of histological material. Endoscopic findings and specific investigational techniques were taken into account. A total of 467 FOB with both cytological and histological diagnostic techniques were performed in 449 subjects. Patients consisted of 345 men and 104 women (median age, 65 yrs). Cytology proved malignancy in 157 patients. Cytologically diagnosed carcinomas were classified into squamous cell carcinoma (SqCC) in 56, adenocarcinoma (ADC) in 6, small cell lung carcinoma (SCLC) in 12, non-small cell lung carcinoma not otherwise specified (NSCLC-NOS) in 71, and unclassified carcinoma in 12. Cytology correlated fairly with biopsy specimens, as agreement was observed in 83% of SCLC, 100% of ADC, 74% of SqCC and 8% of NSCLC-NOS. Interestingly, 61% of cytologically identified NSCLC-NOS were classified as ADC by histology. Cytological accuracy improved in case of an endobronchial lesion, mainly for SqCC. These results indicate that cytological accuracy remains fair with regard to diagnosis of squamous and non-squamous lung cancer subtypes. Improvement of cytological accuracy is expected however with novel diagnostic strategies.