Adedayo A. Onitilo

Breast Cancer Subtypes Based on ER/PR and Her2 Expression: Comparison of Clinicopathologic Features and Survival

OBJECTIVE To compare the clinicopathologic features and survival in the four breast cancer subtypes defined by immunohistochemistry (IHC) expression of estrogen receptor (ER) or progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2): ER/PR+, Her2+; ER/PR+, Her2-; ER/PR-, Her2+; and ER/PR-, Her2-. METHODS A 7-year retrospective study of 1134 invasive breast cancer subjects. Clinical and pathologic features and survival of the four subtypes were compared. RESULTS Using ER/PR+ and Her2- as a reference, ER/PR-, Her2- had the worst overall survival (hazard ratio, 1.8; 95% confidence interval [CI], 1.06-3.2) and the worst disease-free survival (hazard ratio, 1.5; 95% CI, 0.8-3.0). In ER/PR+, Her2-, chemotherapy conferred significant overall and disease-free survival advantages. Subtype comparison revealed statistically significant differences in outcomes. CONCLUSION The triple negative subtype has the worst overall and disease free survival. Efforts should be directed at standardization of current testing methods and development of more reliable and reproducible testing.

Variability in Reexcision Following Breast Conservation Surgery

CONTEXT Health care reform calls for increasing physician accountability and transparency of outcomes. Partial mastectomy is the most commonly performed procedure for invasive breast cancer and often requires reexcision. Variability in reexcision might be reflective of the quality of care. OBJECTIVE To assess hospital and surgeon-specific variation in reexcision rates following partial mastectomy. DESIGN, SETTING, AND PATIENTS An observational study of breast surgery performed between 2003 and 2008 intended to evaluate variability in breast cancer surgical care outcomes and evaluate potential quality measures of breast cancer surgery. Women with invasive breast cancer undergoing partial mastectomy from 4 institutions were studied (1 university hospital [University of Vermont] and 3 large health plans [Kaiser Permanente Colorado, Group Health, and Marshfield Clinic]). Data were obtained from electronic medical records and chart abstraction of surgical, pathology, radiology, and outpatient records, including detailed surgical margin status. Logistic regression including surgeon-level random effects was used to identify predictors of reexcision. MAIN OUTCOME MEASURE Incidence of reexcision. RESULTS A total of 2206 women with 2220 invasive breast cancers underwent partial mastectomy and 509 patients (22.9%; 95% CI, 21.2%-24.7%) underwent reexcision (454 patients [89.2%; 95% CI, 86.5%-91.9%] had 1 reexcision, 48 [9.4%; 95% CI, 6.9%-12.0%] had 2 reexcisions, and 7 [1.4%; 95% CI, 0.4%-2.4%] had 3 reexcisions). Among all patients undergoing initial partial mastectomy, total mastectomy was performed in 190 patients (8.5%; 95% CI, 7.2%-9.5%). Reexcision rates for margin status following initial surgery were 85.9% (95% CI, 82.0%-89.8%) for initial positive margins, 47.9% (95% CI, 42.0%-53.9%) for less than 1.0 mm margins, 20.2% (95% CI, 15.3%-25.0%) for 1.0 to 1.9 mm margins, and 6.3% (95% CI, 3.2%-9.3%) for 2.0 to 2.9 mm margins. For patients with negative margins, reexcision rates varied widely among surgeons (range, 0%-70%; P = .003) and institutions (range, 1.7%-20.9%; P < .001). Reexcision rates were not associated with surgeon procedure volume after adjusting for case mix (P = .92). CONCLUSION Substantial surgeon and institutional variation were observed in reexcision following partial mastectomy in women with invasive breast cancer.

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

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.

Tumor-Related Hyponatremia

Hyponatremia is an important and common electrolyte disorder in tumor patients and one that has been reported in association with a number of different primary diagnoses. The correct diagnosis of the pathophysiological basis for each patient is important because it significantly alters the treatment approach. In this article, we review the epidemiology and presentation of patients with hyponatremia, the pathophysiologic groups for the disorder with respect to sodium and water balance and the diagnostic measures for determining the correct pathophysiologic groups. We then present the various treatment options based on the pathophysiologic groups including a mathematical approach to the use of hypertonic saline in management. In cancer patients, hyponatremia is a serious comorbidity that requires particular attention as its treatment varies by pathophysiologic groups, and its consequences can have a deleterious effect on the patient’s health.

Ablation of the thyroid remnant and I-131 dose in differentiated thyroid cancer: a meta-analysis revisited.

Postoperative ablation of functioning thyroid tissue has become established in the management of differentiated thyroid cancer as the long-term risk of recurrence and death is reduced. This beneficial effect results from the destruction of potentially malignant cells or occult multifocal disease that may occur in up to 30% of patients with papillary tumors1–4 Furthermore, the specificity of thyroglobulin as a tumor marker is increased and the sensitivity of subsequent whole body scans seems improved because residual thyroid tissue may compete with recurrent or metastatic thyroid cancer cells for radioiodine uptake.5 Indeed, it has been demonstrated that patients with successful ablation of remnant thyroid tissue have a better prognosis than those with unsuccessful ablation (disease-free survival of 87% versus 49% after 10 years, while thyroid cancer-related survival was 93% versus 78%).6 This suggests that it is important to achieve complete ablation as soon as possible after diagnosis in order to ensure the best possible prognosis for a patient. In 2000,7 we demonstrated that the optimal dose (specific activity of I-131 administered) required to achieve ablation is a high dose of approximately 100 mCi, and thus lower doses are not as beneficial as the conventional doses of 75 to 100 mCi (2775–3700 MBq) in terms of successful remnant ablation. Recently, Hackshaw et al8 carried out another meta-analysis including studies published since 2000, and surprisingly, report that from the published data it is not possible to reliably determine whether ablation success rates using 30 mCi are similar to using 100 mCi. Our analysis7 published in 2000 predicted that the risk estimates were stable. We did not think additional data would refute these findings, but rather would further narrow down the confidence intervals (CI) of the risk estimate. Thus, we performed this analysis again using the same data extracted by Hackshaw et al.8 The methods used were the same as previously described7 and the quantification was on the dichotomous variable “risk of failure of remnant ablation after I-131.” There were a total of 2,584 patients (as opposed to our previous report which consisted of 967 patients), and of these, 1,094 patients who were given low doses and 1,490 patients who were given high doses were extracted from the 22 datasets that contained both a low-dose and high-dose group as reported in the study by Hackshaw et al.8 Of these 22 datasets, six were randomized controlled trials with mixed surgical status (group 2),9–14 four were cohorts with near-total thyroidectomy (group 1)7,15–17 and 12 were cohorts with mixed surgical status (group 3).7,18–28 Because of the concern about combining data from studies with markedly different designs, separate analyses were done for each group, as well as a pooled analysis. Since the test for heterogeneity was almost statistically significant (Cochran Q for heterogeneity, P=0.08), a random effects model was used as it does not assume that a common (fixed) treatment effect exists but rather that the true treatment effects in the individual studies may be different from each other. Such an analysis assumes the distribution of different true effects in each study is normally distributed, and we can estimate the summary of the different effects. However, we did not find a significant difference in results using a fixed or random effects model, and the CIs in the cumulative plot narrow with each additional study, suggesting that it may be reasonable to combine the studies into one stratum. Most studies used a high dose of 2775–3700 MBq (75–100 mCi). The summary high-dose to low-dose group relative risk (RR) of non-ablation after the first dose was 0.58 (95% CI, 0.46–0.74) for the cohort studies in group 1 and 0.88 (95% CI, 0.78–1) for those in group 3 using the random effects model. RR was 0.68 (95% CI, 0.43–1.07) for the randomized controlled trials (group 2) using the random effects model. The subgroup summary and individual study RRs and 95% CIs, listed by year of publication, are depicted individually in figure 1A ▶. A cumulative analysis is depicted in figure 1B ▶, while figure 1C ▶ displays the result of a cumulative analysis by subgroup. The pooled RR for all studies is 0.73 (95% CI, 0.62–0.85) which is identical to the risk estimate we reported previously (RR=0.73; 95% CI, 0.61–0.87).7 This indicates that despite the inclusion of additional studies from the last 7 years, and more than doubling the patient pool, these estimates remain stable and affirm our previous findings.7 Thus, we cannot agree with the findings of Hackshaw et al.8 In summary, our analyses indicate that high-dose patients have about one-third less risk of non-ablation than low-dose patients, more so if extent of surgery is near-total and less so if incomplete surgery is performed. Figure 1. Standard meta-analysis and cumulative meta-analysis. (A) The standard meta-analysis plot of the risk ratios for non-ablation in a comparison of high-dose radioiodine (treatment group) with low-dose radioiodine (control group). The point estimates for ... We have not attempted here to redefine the pertinent issues in meta-analysis such as eligibility criteria, restriction of sample size or length of follow-up, eligibility based on similarity of treatments or outcomes or study quality, as these have been addressed in the original meta-analyses.7,8 Nevertheless, we must draw attention to a few important study differences that exist. The most important, as mentioned previously, is confounding caused by the extent of surgery. This, however, should bias the end result towards less effect for the high-dose group unless more patients with subtotal surgery were given lower doses. This seems unlikely as clinicians are prone to give higher doses to patients with subtotal surgery. However, as both high and low doses are less effective in less complete surgery, groups 2 and 3 demonstrate blunted risk differences. An additional confounding factor would be the timing of post-ablation scans. If those patients given higher doses were scanned later than those given lower doses, a biased estimate of risk reduction could be determined. There was no reason to suspect that this had occurred in any study included in this analysis. One issue that certainly needs to be considered in the interpretation of this synthesis is the possibility of selection bias in the same direction across the studies, thus falsely exaggerating the risk estimates. In hospital-based cohort studies, it may be difficult to ensure comparability of the low-dose and high-dose groups, since selection bias as a result of unknown referral patterns cannot be easily overcome. However, we would assume that lower risk patients get lower doses and vice-versa, leading to non-differential bias resulting in a trend towards no difference rather than an exaggerated effect for higher doses. Finally, publication bias certainly may have influenced these results as indicated by Hackshaw et al,8 but this is a subject where negative results with larger doses would certainly qualify for publication due to the controversy that exists. We would like to repeat our previous conclusion7 that, while it is true a higher dose means higher costs of admission to the hospital and patient inconvenience, comparing this and the rather insignificant side effects of the higher dose to that of a lower dose should focus in the first instance on an estimate of the benefits of successful ablation. Wong et al4 used a decision analytic perspective to determine that successful ablation probably reduces cancer recurrence rates by 54%, and the change in life expectancy gained by successful ablation is about equal to that gained by coronary artery bypass graft in patients with two vessel coronary artery disease. The question of cost and inconvenience with high-dose therapy is similar to the question of choice of surgeon in coronary artery bypass graft. The stage of the tumor, extent of surgery and age of the patient are all factors in this decision-making process. We conclude that after increasingly meticulous near-total surgery and careful patient selection, the available data continue to favor higher doses of radioiodine (in the region of 2775–3700 MBq) for remnant ablation, especially after near-total thyroidectomy.

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.

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.

Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer

Purpose:The aim of this study was to examine Lynch syndrome screening of patients with metastatic colorectal cancer in integrated health-care-delivery organizations.Methods:We determined the availability of Lynch syndrome screening criteria and actual Lynch syndrome screening in the medical records of 1,188 patients diagnosed with metastatic colorectal cancer between 2004 and 2009 at seven institutions in the Cancer Research Network.Results:We found infrequent use of Lynch syndrome screening (41/1,188). Family history was available for 937 of the 1,188 patients (79%). There was sufficient information to assess Lynch syndrome risk using family history–based criteria in 719 of the 937 patients (77%) with family history documentation. In 391 individuals with a family history of a Lynch syndrome–associated cancer, 107 (27%) could not be evaluated due to missing information such as age of cancer onset. Eleven percent of patients who met the Bethesda criteria and 25% of individuals who met the Amsterdam II criteria were screened for Lynch syndrome. Recommended guidelines were adhered to during screening, but no testing method was preferred.Conclusion:The information required for Lynch syndrome screening decisions is routinely collected but seldom used. There is a critical gap between collection of family history and its use to guide Lynch syndrome screening, which may support a case for implementation of universal screening guidelines.Genet Med 15 12, 933–940.Genetics in Medicine (2013); 15 12, 933–940. doi:10.1038/gim.2013.43