Career Advancement: Meeting the Challenges Confronting the Next Generation of Endocrinologists and Endocrine Researchers.

CONTEXT: Challenges and opportunities face the next generation (Next-Gen) of endocrine researchers and clinicians, the lifeblood of the field of endocrinology for the future. A symposium jointly sponsored by The Endocrine Society and the Endocrine Society of Australia was convened to discuss approaches to addressing the present and future Next-Gen needs. EVIDENCE ACQUISITION: Data collection by literature review, assessment of previously completed questionnaires, commissioning of a new questionnaire, and summarization of symposium discussions were studied. EVIDENCE SYNTHESIS: Next-Gen endocrine researchers face diminishing grant funding in inflation-adjusted terms. The average age of individuals being awarded their first independent investigator funding has increased to age 45 years. For clinicians, a workforce gap exists between endocrinologists needed and those currently trained. Clinicians in practice are increasingly becoming employees of integrated hospital systems, resulting in greater time spent on nonclinical issues. Workforce data and published reviews identify challenges specifically related to early career women in endocrinology. Strategies to Address Issues: Recommendations encompassed the areas of grant support for research, mentoring, education, templates for career development, specific programs for Next-Gen members by senior colleagues as outlined in the text, networking, team science, and life/work integration. Endocrine societies focusing on Next-Gen members provide a powerful mechanism to support these critical areas. CONCLUSIONS: A concerted effort to empower, train, and support the next generation of clinical endocrinologists and endocrine researchers is necessary to ensure the viability and vibrancy of our discipline and to optimize our contributions to improving health outcomes. Collaborative engagement of endocrine societies globally will be necessary to support our next generation moving forward.

Induction of apoptosis in hormone refractory breast cancer: horizontal modulation is superior to vertical.

Women with estrogen receptor positive (ER+) breast cancer receive treatment with tamoxifen or aromatase inhibitors as adjuvant hormone therapy, but their tumors frequently exhibit de novo or acquired resistance. Current strategies being developed to overcome resistance involve a combination of growth factor pathway inhibitors in addition to hormone therapy. Unfortunately, prolongation of responses with these new approaches is measured only in months. We reasoned that a pro-apoptotic strategy would be preferable since cell death would abrogate the process of adaptive reprogramming and eliminate the resistant cells rather than inhibiting their growth. Our hypothesis was that combinations of pro-apoptotic agents could be designed that would act synergistically as opposed to a merely additively. We examined two model strategies to determine which would result in the greatest synergy: a vertical approach that involved the targeting of two or more steps in a single pathway and a horizontal one, targeting steps in more than one parallel pathway. We found that combinations involving horizontal activation resulted in greater synergy than vertical. Combination index and isobologram analyses revealed that the horizontal combination of the small molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) along with T-DM1 displayed the strongest synergy for inducing apoptosis in hormone refractory breast cancer cells. Both the reprogrammed, hormone resistant cells and the wild type responded to certain combinations with synergistic enhancement of apoptosis. These data suggest that combinations using T-DM1 are promising for further in vivo studies both in xenografts and in patients.

Standardization of steroid hormone assays: why, how, and when?

Lack of standardization of high-quality steroid hormone assays is a major deficiency in epidemiologic studies. In postmenopausal women, reported levels of serum 17beta-estradiol (E(2)) are highly variable and median normal values differ by approximately a 6-fold factor. A particular problem is the use of E(2) assays for prediction of breast cancer risk and osteoporotic fractures, where assay sensitivity may be the most important factor. Identification of women in the lowest categories of E(2) levels will likely provide prognostic information that would not be available in a large group of women in whom E(2) levels are undetectable by less sensitive assays. Detailed and costly methods involving extraction and chromatography in conjunction with RIA provide generally acceptable E(2) results in postmenopausal serum, whereas less tedious, direct immunoassays suffer from inadequate specificity and sensitivity. Studies comparing the two types of methods generally report higher E(2) values with the direct methods as a result of cross-reactivity with other steroids and reduced correlation with biological variables such as body mass index. Similar problems exist with measurements of E(2) and estrone in men, and estrone and testosterone in women. Interest in mass spectrometry-based assays is increasing as potential gold standard methods with enhanced sensitivity and specificity; however, these assays require costly instrumentation and highly trained personnel. Taking all of these issues into consideration, we propose establishment of standard pools of premenopausal, postmenopausal, and male serum, and utilization of these for cross-comparison of various methods on an international basis. An oversight group could then establish standards based on these comparisons and set agreed upon confidence limits of various hormones in the pools. These criteria would allow validation of sensitivity, specificity, precision, and accuracy of current steroid hormone assay methodology and provide surrogates until a true gold standard can be developed.

Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model.

The majority of candidates for breast cancer prevention have not accepted tamoxifen because of the perception of an unfavorable risk/benefit ratio and the acceptance of raloxifene remains to be determined. One means of improving this ratio is to identify women at very high risk of breast cancer. Family history, age, atypia in a benign biopsy, and reproductive factors are the main parameters currently used to determine risk. The most powerful risk factor, mammographic density, is not presently employed routinely. Other potentially important factors are plasma estrogen and androgen levels, bone density, weight gain, age of menopause, and fracture history, which are also not currently used in a comprehensive risk prediction model because of lack of prospective validation. The Breast Cancer Prevention Collaborative Group (BCPCG) met to critically examine and prioritize risk factors that might be selected for further testing by multivariate analysis using existing clinical material. The BCPCG reached a consensus that quantitative breast density, state of the art plasma estrogen and androgen measurements, history of fracture and height loss, BMI, and waist-hip ratio had sufficient priority for further testing. As a practical approach, these parameters could be added to the existing Tyrer-Cuzick model which encompasses factors included in both the Claus and Gail models. The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time.

Risk of breast cancer with progestins: critical assessment of current data.

Whether progestins protect against the risk of breast cancer or enhance that risk has been a major area of controversy over the past several years. Observational studies have reported conflicting results and experimental studies examining whether progestins exert mitogenic or anti-mitogenic actions on breast tissue report divergent results. Based upon a wide range of animal, epidemiologic and clinical data, most investigators agree that estrogens contribute to the development of breast neoplasms. However, the additional effect of progestins on this risk has been the subject of substantial discussion and controversy. A variety of experiments have been carried out using human breast cancer cells grown in vitro and as xenografts in nude mice. These studies demonstrated both mitogenic and anti-mitogenic effects depending upon the precise experimental conditions. Two potential reasons for these differences include differential metabolism of progestins into inhibitory pregnenes or stimulatory 5-alpha-reduced pregnanes or the presence of a protein (GPR 30) which allows the anti-mitogenic effects of progestins to be manifest. Based upon the conflicting nature of the results in experimental studies, we believe that only data in patients provide substantial insight into the actions of progestins on the intact human breast. Studies have now demonstrated that cell proliferation and breast density is higher during the luteal than during the follicular phase of the menstrual cycle. In postmenopausal women, long-term exposure to estrogen plus a progestin results in a marked enhancement of proliferation of the terminal duct lobular units as well as in breast density. These data, taken together, provide substantial evidence that progestins are mitogenic on the human breast when given long term to postmenopausal women. To critically evaluate the observational studies regarding breast cancer risk from progestins, we developed a set of stringent criteria for acceptance of individual studies. Four of the five studies meeting these criteria reported a greater risk of breast cancer with combination estrogen/progestin regimens than with estrogen alone. More importantly, the first randomized, prospective, controlled trial of the risk of breast cancer with an estrogen/progestin combination (the Women's Health Initiative Study) has now been published. This study reported a 26% increased relative risk of breast cancer with the estrogen/progestin combination. Based upon these data, we believe that progestins do add to the risk of breast cancer over and above that imparted by estrogen alone. The attributable risk during use for 5 years or less is small but increases logarithmically during long-term use. The majority of data regarding progestins are derived from regimens using MPA. However, we conclude from our analysis that the burden of proof regarding progestins has now shifted. One must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful.