Rachel V. Stankowski

Diabetes and cancer II: role of diabetes medications and influence of shared risk factors

An association between type 2 diabetes mellitus (DM) and cancer has long been postulated, but the biological mechanism responsible for this association has not been defined. In part one of this review, we discussed the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. Here we review the risk factors shared by cancer and DM and how DM medications play a role in altering cancer risk. Hyperinsulinemia stands out as a major factor contributing to the association between DM and cancer, and modulation of circulating insulin levels by DM medications appears to play an important role in altering cancer risk. Drugs that increase circulating insulin, including exogenous insulin, insulin analogs, and insulin secretagogues, are generally associated with an increased cancer risk. In contrast, drugs that regulate insulin signaling without increasing levels, especially metformin, appear to be associated with a decreased cancer risk. In addition to hyperinsulinemia, the effect of DM medications on other shared risk factors including hyperglycemia, obesity, and oxidative stress as well as demographic factors that may influence the use of certain DM drugs in different populations are described. Further elucidation of the mechanisms behind the association between DM, cancer, and the role of DM medications in modulating cancer risk may aid in the development of better prevention and treatment options for both DM and cancer. Additionally, incorporation of DM medication use into cancer prediction models may lead to the development of improved risk assessment tools for diabetic patients.

Type 2 diabetes mellitus, glycemic control, and cancer risk

Type 2 diabetes mellitus is characterized by prolonged hyperinsulinemia, insulin resistance, and progressive hyperglycemia. Disease management relies on glycemic control through diet, exercise, and pharmacological intervention. The goal of the present study was to examine the effects of glycemic control and the use of glucose-lowering medication on the risk of breast, prostate, and colon cancer. Patients diagnosed with type 2 diabetes mellitus (N=9486) between 1 January 1995 and 31 December 2009 were identified and data on glycemic control (hemoglobin A1c, glucose), glucose-lowering medication use (insulin, metformin, sulfonylurea), age, BMI, date of diabetes diagnosis, insurance status, comorbidities, smoking history, location of residence, and cancer diagnoses were electronically abstracted. Cox proportional hazards regression modeling was used to examine the relationship between glycemic control, including medication use, and cancer risk. The results varied by cancer type and medication exposure. There was no association between glycemic control and breast or colon cancer; however, prostate cancer risk was significantly higher with better glycemic control (hemoglobin A1c⩽7.0%). Insulin use was associated with increased colon cancer incidence in women, but not with colon cancer in men or breast or prostate cancer risk. Metformin exposure was associated with reduced breast and prostate cancer incidence, but had no association with colon cancer risk. Sulfonylurea exposure was not associated with risk of any type of cancer. The data reported here support hyperinsulinemia, rather than hyperglycemia, as a major diabetes-related factor associated with increased risk of breast and colon cancer. In contrast, hyperglycemia appears to be protective in the case of prostate cancer.

Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors.

Before the advent of the human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody trastuzumab, HER2-positive breast cancers were difficult to treat and had a poor prognosis. Adjuvant trastuzumab is now an important part of the treatment regimen for many women with HER2-positive breast cancer and has undoubtedly resulted in a significant improvement in prognosis, but it is associated with a risk for cardiotoxicity. In this review, we describe the prevalence, patient characteristics, and risk factors for cardiotoxicity associated with use of adjuvant trastuzumab. Understanding risk factors for trastuzumab-induced cardiotoxicity and appropriate patient monitoring during trastuzumab treatment allows for safe and effective use of this important adjuvant therapy.

Cardiovascular consequences of cocaine use.

The cardiovascular consequences of cocaine use are numerous and can be severe, with mechanisms of cardiotoxicity unique to cocaine that include sympathomimetic effects, blockade of sodium and potassium channels, oxidative stress and mitochondrial damage, and disruption of excitation-contraction coupling. In combination, these effects increase myocardial oxygen demand while simultaneously decreasing oxygen supply. Cocaine-associated chest pain is particularly common and, in some instances, associated with a more severe cardiac syndrome, such as myocardial infarction, myocardial ischemia, arrhythmia, cardiomyopathy, aortic dissection, or endocarditis. Therapy for cocaine-associated chest pain and myocardial infarction is similar to treatment in non-cocaine users, except for differences in the use of benzodiazepines and phentolamine and avoidance of beta-blockers in the acute setting. In this review, we discuss the most up-to-date literature regarding the mechanisms of cocaine-associated cardiotoxicity and clinical consequences, diagnosis, and treatment; we also discuss relevant controversies while proposing several important areas for future research.

Mammography utilization: patient characteristics and breast cancer stage at diagnosis.

OBJECTIVE Missed mammograms represent missed opportunities for earlier breast cancer diagnosis. The purposes of this study were to identify patient characteristics associated with missed mammograms and to examine the association between missed mammograms and breast cancer stage at diagnosis. MATERIALS AND METHODS Mammography frequency and cancer stage were retrospectively examined in 1368 cases of primary breast cancer diagnosed at our clinic from 2002 to 2008. RESULTS Regardless of age (median, 62.7 years), 1428 women who underwent mammography were more likely to have early-stage (stage 0-II) breast cancer at diagnosis than were those who did not undergo mammography (p < 0.001). Similarly, the number of mammographic examinations in the 5 years before diagnosis was inversely related to stage: 57.3% (94/164) of late-stage cancers were diagnosed in women missing their last five annual mammograms. In a multivariate analysis, family history of breast cancer was most predictive of undergoing mammography (odds ratio, 3.492; 95% CI, 2.616-4.662; p < 0.0001) followed by number of medical encounters (odds ratio, 1.022; 95% CI, 1.017-1.027; p < 0.0001). Time to travel to the nearest mammography center was also predictive of missing mammograms: Each additional minute of travel time decreased the odds of undergoing at least one mammographic examination in the 5 years before cancer diagnosis (odds ratio, 0.990; 95% CI, 0.986-0.993; p < 0.0001). CONCLUSION Missing a mammogram, even in the year before a breast cancer diagnosis, increases the chance of a cancer diagnosis at a later stage. Interventions to encourage use of mammography may be of particular benefit to women most likely to miss mammograms, including those with no family history of breast cancer, fewer encounters with the health care system, and greater travel distance to the mammography center.

Survival Comparisons for Breast Conserving Surgery and Mastectomy Revisited: Community Experience and the Role of Radiation Therapy

Objectives Evidence suggests superiority of breast conserving surgery (BCS) plus radiation over mastectomy alone for treatment of early stage breast cancer. Whether the superiority of BCS plus radiation is related to the surgical approach itself or to the addition of adjuvant radiation therapy following BCS remains unclear. Materials and Methods We conducted a retrospective cohort study of women with breast cancer diagnosed from 1994–2012. Data regarding patient and tumor characteristics and treatment specifics were captured electronically. Kaplan-Meier survival analyses were performed with inverse probability of treatment weighting to reduce selection bias effects in surgical assignment. Results Data from 5335 women were included, of which two-thirds had BCS and one-third had mastectomy. Surgical decision trends changed over time with more women undergoing mastectomy in recent years. Women who underwent BCS versus mastectomy differed significantly regarding age, cancer stage/grade, adjuvant radiation, chemotherapy, and endocrine treatment. Overall survival was similar for BCS and mastectomy. When BCS plus radiation was compared to mastectomy alone, 3-, 5-, and 10-year overall survival was 96.5% vs 93.4%, 92.9% vs 88.3% and 80.9% vs 67.2%, respectively. Conclusion These analyses suggest that survival benefit is not related only to the surgery itself, but that the prognostic advantage of BCS plus radiation over mastectomy may also be related to the addition of adjuvant radiation therapy. This conclusion requires prospective confirmation in randomized trials.

Breast cancer incidence before and after diagnosis of type 2 diabetes mellitus in women: increased risk in the prediabetes phase

The physiological changes associated with type 2 diabetes mellitus begin before disease onset, yet few have examined the incidence of cancer both before and after diabetes onset. We examined the temporal relationship between diabetes and breast cancer risk. Breast cancer risk was assessed in a retrospective cohort study using patient data from the Marshfield Clinic electronic medical record including 5423 women who developed diabetes between 1 January 1995 and 31 December 2009 (reference date) and 26 346 nondiabetic women matched by age, smoking history, residence, and reference date. Breast cancer risk was assessed before and after reference date, adjusting for matching variables, BMI, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number of women needed to be exposed to diabetes for one additional person to be harmed – that is, develop breast cancer (NNEH). HR for breast cancer before diabetes diagnosis was 1.16 (95% CI 1.03–1.31, P=0.0150) and NNEH was 99 at time of diabetes onset. HR for breast cancer after diabetes diagnosis was not significant at 1.07 (95% CI 0.90–1.28, P=0.422), and NNEH was 350 at 10 years post diabetes onset. Diabetic women are at the greatest increased risk of breast cancer near the time of diabetes diagnosis. The comparative NNEH increased shortly after diagnosis and as the duration of diabetes increased. Breast cancer risk appears to be increased during the prediabetes phase, waning after diagnosis, raising important issues regarding timing of breast cancer prevention interventions in women with diabetes.

Adequate Lymph Node Recovery Improves Survival in Colorectal Cancer Patients

Current recommendations suggest recovery of 12 lymph nodes during surgical resection for colorectal cancer (CRC) for proper staging and prognostication. Adequate lymph node recovery has been associated with improved patient survival, with results inconsistent.

All-Cause Mortality Is Decreased in Women Undergoing Annual Mammography Before Breast Cancer Diagnosis

OBJECTIVE The value of annual mammography remains an area of debate because of concerns regarding risk versus benefit. The potential for harm due to overdiagnosis and treatment of clinically insignificant cancers may not be captured by breast cancer-specific mortality. Instead, we examined all-cause mortality as a function of missed annual mammography examinations before breast cancer diagnosis. MATERIALS AND METHODS Primary breast cancer cases diagnosed in the Marsh-field Clinic Health System from 2002 through 2008 were identified for retrospective review, and whether annual mammography examinations had been performed in the 5 years before diagnosis was assessed. RESULTS Analyses were performed on 1421 women with breast cancer. After adjustment of data for age, comorbidity status, a family history of breast cancer, insurance status, medical encounter frequency, and the calendar year, women who had missed any of the previous five annual mammography examinations had a 2.3-fold increased risk of all-cause mortality compared with subjects with no missed mammography examinations (hazard ratio=2.28; 95% CI, 1.58-3.30; p<0.0001). Additionally, an analysis by the number of missed annual mammography examinations showed a progressive increase in hazard as the number of missed mammography studies increased. CONCLUSION These results suggest that annual mammography before breast cancer diagnosis is predictive of increased overall survival. A stepwise decline in overall survival was noted for each additional missed mammography examination. These results are similar to findings in the literature for breast cancer-specific mortality and illustrate the importance of recommending annual mammography to all eligible women.

Breast Cancer Biomarkers: Risk Assessment, Diagnosis, Prognosis, Prediction of Treatment Efficacy and Toxicity, and Recurrence

Breast cancer is the most common cancer amongst women in the United States and around the world. Although widespread use of adjuvant chemotherapeutic and hormonal agents has improved mortality from breast cancer, it remains challenging to determine on an individual basis who will benefit from such treatments and who will be likely to encounter toxicities. With the rising costs of healthcare and the introduction of new targeted therapies, use of biomarkers has emerged as a method of assisting with breast cancer diagnosis, prognosis, prediction of therapeutic response, and surveillance of disease during and after treatment. In the following review, prognostic and therapeutic biomarkers, their utility in the management of patients with breast cancer, and current recommendations regarding their clinical use will be discussed.