Cervical cancer control in Latin America: A call to action.

Cervical cancer (CC) is second most common cause of cancer in Latin America and is a leading cause of cancer mortality among women. In 2015, an estimated 74,488 women will be diagnosed with CC in Latin America and 31,303 will die of the disease. CC mortality is projected to increase by 45% by 2030 despite human papillomavirus (HPV) vaccination and screening efforts. In this setting, the goal was of the current study was to examine CC control efforts in Latin America and identify deficiencies in these efforts that could be addressed to reduce CC incidence and mortality. The authors found that HPV vaccination has been introduced in the majority of Latin American countries, and there is now a need to monitor the success (or shortcomings) of these programs and to ensure that these programs are sustainable. This topic was also reviewed in light of emerging data demonstrating that visual inspection with acetic acid and HPV DNA testing without Papanicolaou tests have efficacy from a screening perspective and are good alternatives to cytology-based screening programs. Overall, there is a need to build capacity for CC control in Latin America and the best strategy will depend on the country/region and must be tailored to meet the needs of the population as well as available resources.

Early-Stage Breast Cancer in the Octogenarian: Tumor Characteristics, Treatment Choices, and Clinical Outcomes.

BACKGROUND: Nodal staging with sentinel node biopsy (SLNB), post-lumpectomy radiotherapy (RT), and endocrine therapy (ET) for estrogen receptor-positive (ER+) tumors is valuable in the treatment of early-stage (stages 1 or 2) breast cancer but used less often for elderly women. METHODS: This retrospective study investigated women referred for surgical evaluation of biopsy-proven primary early-stage invasive breast cancer from January 2001 to December 2010. Clinicopathologic features, treatment course, and outcomes for women ages 80-89 years and 50-59 years were compared. RESULTS: The study identified 178 eligible women ages 80-89 years and 169 women ages 50-59 years. The elderly women more often had grade 1 or 2 disease (p = 0.003) and ER+ tumors (p = 0.007) and less frequently had undergone adjuvant therapies (all p ≤ 0.001). Lumpectomy was performed more commonly for the elderly (92 vs. 83 %, p = 0.02), and axillary surgery was less commonly performed (46 vs. 96 %; p < 0.001). Fewer elderly women had undergone post-lumpectomy RT (42 vs. 89 %; p < 0.001) and ET for ER+ tumors (72 vs. 95 %; p < 0.001). During the median follow-up period of 56 months for the 80- to 89-year old group and 98 months for the 50- to 59-year-old group, death from breast cancer was similar (4 vs. 5 %; p = 0.5). The two groups respectively experienced 7 versus 6 locoregional recurrences and 11 versus 13 distant recurrences. CONCLUSIONS: The octogenarians had disease survivorship similar to that of the younger women despite less frequent use of adjuvant therapies, likely reflecting lower-risk disease features. Whether increased use of axillary surgery, post-lumpectomy RT, and/or ET for ER+ tumors would further improve outcomes is an important area for further study, but treatment should not be deferred solely on the basis of age.

New targets for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) lacks the three most commonly targeted receptors in human breast cancer--the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu--and it is associated with an aggressive natural history. More recently, TNBC has been further dissected into smaller, distinct subsets with unique molecular alterations and response to therapy. Large-scale genomic projects have yielded new knowledge about the molecular characteristics of TNBC, including similarities with high-grade serous ovarian cancers, suggesting a possible coordinated treatment algorithm for these malignancies. Moreover, translation of preclinical findings has led to clinical trials testing a plethora of targets and pathways in TNBC, which will be reviewed here; these include epidermal growth factor receptor (EGFR), angiogenesis, DNA repair capacity, epigenetic regulation, androgen receptor (AR) and folate receptor (FR) signaling, cell-cycle control, and cell survival. Given the complexity of TNBC biology and the lack of "traditional" therapeutic targets, the advancement of care for women with TNBC will require a true partnership between clinicians, translational investigators, and basic scientists.

Reliable data on 5- and 10-year survival provide accurate estimates of 15-year survival in estrogen receptor-positive early-stage breast cancer.

There are few studies of model-based survival projections using early empirical results for estimating long-term survival. Utilizing Early Breast Cancer Trialists' Collaborative Group (EBCTCG) data, a Markov model was generated to compare empirical results with those modeled beyond the empirical result time horizon in estrogen receptor (ER)-positive early-stage breast cancer (ESBC). Modeling 15-year survival based on 5- and 10-year EBCTCG data resulted in an average error estimate in breast cancer mortality of 0.75% [range -0.83 to 2.19%]. Although modeling life expectancy differences ranged from an underestimate of -7.93% to an overestimate of 12.64%, over the span of 15 years this corresponded to a loss of 18 days or a gain of 40 days of life. Reliable early survival data may be used to generate models that accurately estimate 15-year survival in ER-positive ESBC. Whether early survival data can be employed over the lifetime horizon remains to be demonstrated.

Primary systemic therapy in breast cancer: past lessons and new approaches.

Primary systemic therapy (PST) is a common treatment strategy used to optimize surgical outcomes for women with locally advanced breast cancer. Several cooperative group trials have shown equivalent survival outcomes between neoadjuvant and adjuvant chemotherapy and have identified pathologic complete response (pCR) as a biologic marker for survival. Research efforts to optimize PST include the development of strategies to predict individual response and to guide the choice of chemotherapy. These emerging approaches are informed by our knowledge of subtypes of breast cancer, as well as genomic technologies, such as chemosensitivity signatures. Following definitive surgery, the management of residual disease is controversial.

Aromatase inhibitors for breast cancer: proven efficacy across the spectrum of disease.

For more than 100 years, hormonal therapy has been known to be effective in the treatment of breast cancer. Initially, this therapy was dominated by the selective estrogen receptor antagonists such as tamoxifen. Aromatase inhibitors (AIs) are a distinct drug class with demonstrated activity in the treatment of hormone-sensitive breast cancer. All 3 third-generation AIs, exemestane, anastrozole, and letrozole, have been studied in multiple lines of therapy in advanced breast cancer and have demonstrated equivalence or superiority compared with tamoxifen. While initially developed as a treatment option for advanced disease, the AIs have also shown efficacy in the treatment of curable disease, including the neoadjuvant and adjuvant settings. In addition, the AIs demonstrate a tolerable side effect profile in comparison with tamoxifen, and this has led to their early incorporation as standard of care therapy. Given the proven efficacy of AIs across the spectrum of breast cancer, the remaining questions include definitive sequencing strategy, timing, and duration of use. Ongoing trials include head-to-head comparisons between the AIs in early-stage breast cancer; the results of these trials are eagerly anticipated and should further optimize the use of AIs.

The impact of adjuvant endocrine therapy on reducing the risk of distant metastases in hormone-responsive breast cancer.

SUMMARY: The primary goal of systemic adjuvant therapy for breast cancer is to control the risk of recurrence following surgery, thereby improving long-term survival. For many years, tamoxifen has served as the standard adjuvant endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. The entry of the third-generation aromatase inhibitors (AIs) exemestane, anastrozole and letrozole as adjuvant therapy has introduced several different treatment options. Indirect comparisons suggest that appreciable differences may exist between the AIs in terms of early risk reduction, especially the risk for early distant metastases. Possible differences in efficacy may be related to differences in potency. Two ongoing trials directly comparing two AIs - the Femara versus Anastrozole Clinical Evaluation and MA.27 - may provide further information.

Lenalidomide-Associated ITP.

Lenalidomide is a potent immunomodulatory agent being used increasingly for treatment of hematologic malignancies including multiple myeloma and myelodysplasia. The common toxicities of lenalidomide, including dose-limiting myelosuppression, are well described. However, the immunomodulatory properties of lenalidomide may give rise to unexpected autoimmune complications. Herein, we describe a case of immune thrombocytopenic purpura (ITP) associated with use of lenalidomide.

Second primary ipsilateral breast cancer with contralateral axillary involvement: a case report and literature review.

After breast-conserving surgery for an initial breast cancer, the incidence of lymphatic drainage to sites other than the ipsilateral axilla, such as the contralateral axilla, increases significantly at the time of a second primary ipsilateral breast cancer. Given the likelihood of altered lymphatic drainage, and in the absence of distant metastatic sites, consideration should be given to treating patients with a second primary ipsilateral breast cancer and contralateral axillary lymph node involvement with curative intent. This clinical issue may become more common as the incidence of second primary ipsilateral breast cancer would be expected to increase due to widespread adoption of breast-conserving surgery, improved prognosis for patients with an initial early-stage breast cancer, and highly sensitive screening modalities such as magnetic resonance imaging.

Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.

PURPOSE: A phase II study of dasatinib, an inhibitor of multiple oncogenic tyrosine kinases including Src, was conducted to evaluate 16-week progression-free rate and tolerability in patients with previously treated metastatic breast cancer (MBC). Real-time assessment of potential tissue biomarkers of Src inhibition was used to optimize dosing. EXPERIMENTAL DESIGN: Eligibility criteria required that patients have measurable MBC, biopsiable tumor, and unlimited prior therapies. For the analysis of change in protein biomarkers of Src inhibition, focal adhesion kinase, paxillin, and p-Src, patients underwent metastatic biopsies at baseline and 4 weeks. Patients who tolerated the starting dose of dasatinib (50 or 70 mg orally twice daily) for the first 28-day cycle, and displayed suboptimal Src inhibition, were escalated to a higher dose (70 or 100 mg). RESULTS: The trial was closed early with 31 patients because of a statistical boundary that required at least 4 (13%) patients without disease progression to continue accrual. These 31 patients had a median of 2 prior lines of chemotherapy for MBC. The most notable toxicity was pleural effusions in 16 patients (52%). Twenty patients had evaluable metastatic biopsies. None of the tumors showed the predefined optimal level of Src inhibition at week 4. CONCLUSIONS: Single-agent dasatinib did not exhibit significant antitumor activity in patients with heavily pretreated MBC. There were no clinically meaningful decreases before and after dasatinib exposure between exploratory tissue biomarkers of Src inhibition which may be attributable to challenges in defining biomarker endpoints for multitargeted tyrosine kinase inhibitors.