personalized adjuvant therapies lessons from the past the opening address by the st gallen 2013 award recipient

Abstract For several decades, personalized adjuvant therapies have been prescribed based on features that predict response to specific types of treatment. In this summary four specific issues regarding adjuvant therapies are described. Each one developed using information from past experience and is ready to be challenged by future findings from clinical trials and maturation of follow-up data. 1) Accuracy of determination of steroid hormone receptors and of HER2-status was the key feature in International Breast Cancer Study Group (IBCSG) and Breast International Group (BIG) trials. 2) Investigations on ovarian function suppression in IBCSG clinical trials led to the design of two trials (SOFT and TEXT), which are likely to lead to improved adjuvant therapy for premenopausal women with breast cancer. 3) Data from the BIG 1–98 trial of letrozole vs tamoxifen for postmenopausal patients with endocrine-responsive breast cancer provided information on which patients might obtain increased benefit from aromatase inhibitors and which might achieve similar treatment outcome with tamoxifen alone. 4) Finally, low-dose, frequently administered cytotoxics (metronomic chemotherapy) were tested in advanced disease with surprisingly favorable disease control and very low incidence of side effects. Personalized treatments are likely to improve substantially with increasingly accurate determination of their targets and by using risk- and toxicity-modulated therapies

Neoadjuvant chemotherapy for breast cancer: any progress?

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lessons on responsiveness to adjuvant systemic therapies learned from the neoadjuvant setting

Summary Aims Recommended principles for the choice of therapies in operable breast cancer include the recognition of diverse subtypes of breast cancer and, based on genetic signature and immunohistochemistry, the identification of targets and related factors predictive of response. We review recent developments in the knowledge of established predictive factors in the neo-adjuvant setting. Methods and Results Experimental and clinical studies have shown that the degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) of the primary tumor defines distinct biological entities that require a differentiated approach to neoadjuvant treatment and clinical trial investigation. In particular, tumors that express high levels of both steroid hormone receptors in a majority of cells derive no or low benefit from preoperative chemotherapy, while the absence of expression of ER and PgR was significantly correlated with the probability of pathologic complete remission (pCR). It was also demonstrated that the pCR rate to primary chemotherapy is significantly lower in invasive lobular carcinoma, frequently characterized by a high expression of steroid hormone receptors, if compared with the ductal histotype. Direct or indirect measures of high cell proliferation (elevated Ki-67 labeling index and high grade) identified patients with tumors responsive to chemotherapy in the preoperative setting. These factors might therefore assist in the identification of patients who might benefit from chemotherapy, in particular those patients with endocrine responsiveness. HER2 overexpression or amplification represents a target for neoadjuvant treatment with the humanised monoclonal antibody against its extracellular domain, but is also a factor predictive of response to neoadjuvant systemic therapies. A statistically significant positive correlation between HER2 positivity and pCR rate in patients treated with neoadjuvant chemotherapy was recently shown. Conclusions Results from studies in the neoadjuvant setting indicate that the use of factors predictive of response may permit a more effective application of therapies identifying patients likely to obtain substantial benefit from treatment

New criteria for selecting elderly patients for breast cancer adjuvant treatment studies.

Learning Objectives After completing this course, the reader will be able to: List the factors that should be considered when choosing the appropriate adjuvant treatment for an elderly women with operable breast cancer.Discuss the possible explanations that account for the underrepresentation of elderly patients in breast cancer clinical trials.Describe the clinical trials that are being specifically conducted in elderly patients with early breast cancer to evaluate different forms of adjuvant treatments. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

immunizing against breast cancer a new swing for an old sword

Summary Therapeutic potential of vaccination has been explored in many clinical trials involving patients with breast cancer. A large variety of cancer immunogens have been tested. The majority of clinical vaccination studies have been carried out in patients with metastatic breast cancer, characterized by extremely aggressive malignant tumors, resistant to all standard cytotoxic treatments and with longest-lasting disease. With active specific immunotherapy, tumor-associated antigens coupled to appropriate adjuvant can elicit a powerful antitumor responses. The potential advantages of therapeutic cancer vaccines are that they can augment an established immunogenic response to the tumor (which is generally weak in breast cancer), they target specific tumor antigens (although there are few), they are potentially non-toxic, they can be combined with conventional therapies and/or other immunotherapies, and they elicit immunologic memory to prevent recurrence of the tumor. It is unclear whether therapeutic vaccines for cancer prolong survival. Data of clinical activity have been observed by using vaccines targeting HER-2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen (CEA), and carbohydrate antigen given after stem cell rescue. A better understanding of the relation between innate and adaptive immune responses, and of the immune escape mechanisms employed by tumor cells, the discovery of mechanisms underlying immunological tolerance, and acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumour growth are necessary for leading to a more comprehensive immunotherapeutic approach in breast cancer

autologous fat transplantation in patients with breast cancer silencing or fueling cancer recurrence

Abstract Lipotransfer can be considered a technical revolution in plastic surgery and widely performed for esthetic surgery. Recently the lipofilling has been indicated in breast reconstruction and deformity correction after breast conservative treatment. However, there is lack of understanding concerning the interactions between the potential tumor beds and the lipoaspirates grafts. Current literature underlines the efficacy of the technique as well as its safety. Nevertheless, many experimental studies provide data on the endocrine, paracrine, and autocrine activities of the transplanted fat tissues. Adipocyte, pre-adipocyte and progenitor cell secretions can stimulate angiogenesis and cell growth. The "tumor–stroma interaction" can potentially induce cancer reappearance by "fueling" dormant breast cancer cells in tumor bed. There is lack of translational research that proves this concern in clinical aspect. No study on the effects of lipotransfer on human cancer breast cells in vivo is available. We provide direct and indirect effects of lipotransfer in breast cancer patients, highlighting pro and con related issues. To confirm the safety of lipotransfer in breast cancer patients we need clinical studies with control group based on long term follow up

developing an effective breast cancer vaccine challenges to achieving sterile immunity versus resetting equilibrium

Abstract Introduction Evading immune destruction is an emerging hallmark of cancer. Immunotherapy of cancer is categorized as either specific stimulation of the immune system by active immunization, with cancer vaccines, or passive transfer of humor or cellular materials, such as, tumor specific antibodies (including immunomodulators) or adoptive cell therapy that inhibit the function of- or directly kill tumor cells. Modulation of immune response in cancer patients is the result of a balanced activity of T regulators and T effector cells. Methods and results We will present the current information and the prospects for the future of immunotherapy in patients with breast cancer including tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy. Discussion Active immunotherapy in breast cancer and its implementation into clinical trials has largely been a frustrating experience in the last decades. After many years of controversy, the concept that the immune system regulates cancer development is experiencing a new resurgence. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. It has been also clear that the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Conclusion What do we know about tumor immunogenicity and how might we therapeutically improve tumor immunogenicity? The first vaccine and the first immunomodulating agent were recently approved by the US Food and Drug Administration (FDA) for the treatment of prostate cancer (sipuleucel-T) and melanoma (ipilimumab), respectively. The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signalingsignaling pathways that regulate immune responses in the tumor microenvironment

International Web-based consultation on priorities for translational breast cancer research

Background Large numbers of translational breast cancer research topics have been completed or are underway, but they differ widely in their immediate and/or future importance to clinical management. We therefore conducted an international Web-based consultation of breast cancer professionals to identify the topics most widely considered to be of highest priority. Methods Potential participants were contacted via two large e-mail databases and asked to register, at a Web site, the issues that they felt to be of highest priority. Four hundred nine questions were reduced by a steering committee to 70 unique issues, and registrants were asked to select the 6 questions they considered to be the most important. Results Votes were recorded from 420 voters ( 2,520 votes) from 48 countries, with 48% of voters coming from North America. Half of the voters identified themselves as clinicians, with the remainder being academics, research scientists, or pathologists. The highest priority was to identify molecular signatures to select patients who could be spared chemotherapy, which gained about 50% more votes than the second topic and was consistently voted top by voters in North America, Europe, and the rest of the world. Research scientists voted the determination of the role of stem cells in breast cancer development, progression, and treatment sensitivity as the most important issue, but this was considered the sixth priority for clinicians and fourth overall. Conclusion This exercise may bring a greater focus of research resources onto issues voted as top priorities

Biopsy of liver metastasis for women with breast cancer: Impact on survival

Abstract Background Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain. Patients and methods One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One-hundred matched control patients with LM from BC and no biopsy were selected. Results Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58–1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38–0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69–1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER ( n = 5), overexpression of HER2 ( n = 12) or both ( n = 1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28–1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06–0.62)]. Conclusions Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options