Current Cancer Therapy Reviews - Volume 11, Issue 4, 2015

The HSP response is implicated in conferring to breast and gynecologic malignancies different sensitivities to anticancer therapies including chemotherapy, endocrine therapy and immunotherapy (we are in the need of more studies about radiotherapy). The heat shock proteins are mainly implicated in cell death mechanisms, in cell differentiation including epithelial-mesenchymal transition, in tumor dormancy, in angiogenesis, metastasis formation, and in the escape of immunosurveillance. Considering the ample functions where the HSPs are implicated and that the HSP response is quite complex it is not surprising that the HSP response affects the anticancer therapies. Several of the HSPs have different predominant roles according to the molecular partners with which they interact, thus it is difficult to dissect the molecular mechanisms to find the sensitivity to the therapies. In this review we present the implications of some the major HSPs (HSP27, HSP70 and HSP90) with drug resistance and present some of the main partners that are also implicated in drug resistance like p53, PTEN and MDR. We have given priority to the incorporation of clinical data where the HSPs have been studied using standard chemotherapies and new therapeutic strategies. It is clear that in order to have a significant understanding of the degree of drug resistance/sensitivity presented by a particular patient we need to examine the molecular status of several key molecular markers involved in the drug resistance pathways and that in this context the study of the HSP response should be incorporated. One of the other major problems in this field is that an inhibitor of one particular HSP will not be enough to achieve a significant anticancer response. Now that we know the complexity of this field we need to design strategies aiming to inhibit several molecular HSP pathways simultaneously without significantly affecting the normal cells, this is the principal challenge for the near future.

Preclinical laboratory science has revealed multiple new targets for breast cancer therapy. Clinical trials targeting key signaling pathways are underway and a number of new drugs have been approved for treatment. Targeting of growth factor receptors by monoclonal antibodies and tyrosine kinase inhibitors were among the first to be approved, but new small molecules inhibiting the phosphatidylinositol 3-kinase signaling pathway have also shown promise. This review will evaluate potential new targets and specifically targets in hormone receptor positive and triple negative breast cancer.

Chemoresistance is a major cause of breast cancer recurrence and death. Currently, drug-resistant disease is treated by selection of another drug(s), without understanding the molecular mechanism(s) involved in a given patient’s chemoresistance. Better understanding of chemoresistance may enable a more informed selection of chemotherapeutic agents and improve patient outcomes. The article reviews mechanisms of resistance to common chemotherapeutic agents in breast cancer: anthracyclines, taxanes and antimetabolites. Gene amplification of YWHAZ, encoding an anti-apoptotic protein, and LAPTM4B, encoding lysosomal-associated protein transmembrane 4B, decrease sensitivity to anthracyclines. Overproduction of p-170 glycoprotein, encoded by MDR1 gene, pumps these drugs out of cancer cells. Overexpression of topoisomerase II-alpha (TOP2A), which relaxes supercoiled DNA for replication, is associated with more aggressive tumors. Taxanes paclitaxel and docetaxel bind beta-tubulin, disrupting microtubule stability, causing cell cycle arrest and apoptosis. Taxane resistance is hypothesized to be due to increased tubulin expression, altered expression of microtubule-associated proteins, alternative tubulin isoforms, or overexpression of Tau protein which stabilizes microtubules. Overexpression of MDR1 gene and Pgp (permeability glycoprotein) cause efflux of taxanes from cells. Knockdown of YWHAZ and LAPTM4B genes in cell lines has increased sensitivity to anthracyclines. Overcoming taxane resistance may employ microtubule-inhibiting agents not vulnerable to known mechanisms of resistance, such as eribulin, which has been studied in the phase III EMBRACE clinical trial. Strategies to overcome resistance to antimetabolites capecitabine and gemcitamine include: dose escalation, pharmacologic manipulation of drug metabolism, and design of new antimetabolites. A clearer understanding of resistance would enable developing more informed, rational treatment strategies than the current trial-and-error method.

Trastuzumab has been clearly demonstrated to improve overall survival for both early and metastatic HER2 positive breast cancer. However, despite the improved clinical outcomes seen with the addition of HER2 targeted therapy to conventional cytotoxic agents, the response rates remain between 30-55% and the majority of patients with advanced breast cancer experience disease progression within 1 year. In this review article, we provide a summary of the key mechanisms of resistance to trastuzumab, including the truncated form of HER2 (p95HER2), compensatory up-regulation of receptor cross-talk, genetic mutations and aberrancies in molecular pathways that allow tumor cells to evade cell cycle regulations. In recent years, treatment options for patients with trastuzumab-resistant disease have been developed and approved, including lapatinib and T-DM1. Ongoing research is evaluating multiple other therapeutic regimens that include novel HER2- targeting agents for the treatment of resistant disease. We will review these newer therapies as well as the scientific rationale behind treatment regimens that have been studied in patients with trastuzumab-resistant HER2 positive breast cancer.

Uterine epithelial cancers are the most common type of gynecologic cancer in the United States. The American Cancer Society estimated 53,000 new cases of uterine cancers in 2014 with 8,600 deaths from advanced or recurrent cases, 99% of which are endometrial cancer. The 5-year survival rate of low-stage, low-grade endometrioid adenocarcinoma is greater than 90%. In contrast, advanced stage endometrioid adenocarcinomas and Type II (serous and carcinosarcoma) endometrial cancers have a much poorer prognosis, with the 5-year survival rate of advanced stage uterine carcinosarcoma as low as 9%. Together, these endometrial cancers with poor prognoses comprise almost half of all cases in the US, creating a significant medical obstacle for management. The authors present a review of endometrial cancer pathology, diagnosis and treatment. Included on the topic of treatment are: surgery, endocrine therapy, and chemotherapy with commentary on pertinent phase II and III clinical trials. The discussion covers single and multi-agent chemotherapy. Also covered are current clinical trials using targeted therapies such as mTOR inhibitors, angiokinase inhibitors, and HER2-directed agents. The review concludes with thoughts on future directions in therapeutic management of this disease.

Ovarian cancer represents the second most common gynecologic cancer in the United States, with an estimated 22,000 new diagnoses and 14,000 deaths attributed in 2014 [1]. While the term loosely encompasses a large and varied assortment of malignancies, greater than 90% of ovarian cancers are epithelial carcinomas. Again within this category, there are a number of different histologic subtypes however, 60-70% of ovarian cancers are high-grade serous carcinomas. Overall, high-grade serous carcinomas account for 90% of deaths due to ovarian cancer. Early stage diagnosis has good prognosis with a predicted 5-year survival rate of over 90%. In contrast, late stage diagnosis has a 5-year survival of only 30%, a number which has not significantly changed over the past roughly half century [2]. Unfortunately the majority of ovarian cancers tend to be diagnosed in late stage (stage 3), due in part to both lack of a cost-effective early detection screening method and the non-specificity of symptoms. The incidence of ovarian cancer is 9.4 cases per 100,000 women. In contrast, the rarer fallopian tube and primary peritoneal carcinomas represent a much smaller proportion, with an incidence of 0.41 and 0.46 cases per 100,000, respectively [3, 4]. Due to relatively recently elucidated histologic findings as well as molecular similarities, evidence indicates that these three serous carcinomas may stem from the same origin. Together, epithelial serous ovarian, fallopian and primary peritoneal carcinomas comprise the “extrauterine serous adenocarcinomas” and are staged and managed consistently with ovarian serous cancer [5]. Following is a review of the diagnosis and treatment of these deadly malignancies, with commentary on future therapeutic directions.

Uterine sarcomas comprise endometrial stroma tumors (EST) and uterine leiomyosarcomas (ULMS), with ESTs accounting for less than 2% and ULMS accounting for approximately 1% of uterine neoplasms. Recent classifications of ESTs denote as many as four categories: benign endometrial stromal nodule (ESN), low-grade endometrial stromal sarcomas (ESS), high-grade endometrial stromal sarcomas (HGESS), and undifferentiated uterine sarcomas (UUS). The designation UUS has been suggested to encompass undifferentiated endometrial sarcomas (UES) and undifferentiated uterine sarcomas of other tissue origins. The prognosis for ESS is good. Although a third of cases recur, the 5-year survival rate for Stage I disease can be as high as 98%. In contrast the prognosis for UES is poor, with a 5-year survival rate for Stage I disease at 57%. Few patients with UES survive two years. ULMS represents the most common single type of uterine sarcoma and is associated with a poor prognosis. Recurrence rates are estimated at 50-70% and the 5-year survival rate for Stage I approximates 51%. The authors present a review of these tumors from the vantage point of clinical work up and diagnosis, treatment options, and adjuvant therapy including hormonal therapy, radiation therapy, and chemotherapy. Included are accounts of pertinent phase II and III clinical trials. The article concludes with commentary on future treatment directions for these rare tumors.