Sarah J. Lord

Accuracy and Surgical Impact of Magnetic Resonance Imaging in Breast Cancer Staging: Systematic Review and Meta-Analysis in Detection of Multifocal and Multicentric Cancer

PURPOSE We review the evidence on magnetic resonance imaging (MRI) in staging the affected breast to determine its accuracy and impact on treatment. METHODS Systematic review and meta-analysis of the accuracy of MRI in detection of multifocal (MF) and/or multicentric (MC) cancer not identified on conventional imaging. We estimated summary receiver operating characteristic curves, positive predictive value (PPV), true-positive (TP) to false positive (FP) ratio, and examined their variability according to quality criteria. Pooled estimates of the proportion of women whose surgery was altered were calculated. Results Data from 19 studies showed MRI detects additional disease in 16% of women with breast cancer (N = 2,610). MRI incremental accuracy differed according to the reference standard (RS; P = .016) decreasing from 99% to 86% as the quality of the RS increased. Summary PPV was 66% (95% CI, 52% to 77%) and TP:FP ratio was 1.91 (95% CI, 1.09 to 3.34). Conversion from wide local excision (WLE) to mastectomy was 8.1% (95% CI, 5.9 to 11.3), from WLE to more extensive surgery was 11.3% in MF/MC disease (95% CI, 6.8 to 18.3). Due to MRI-detected lesions (in women who did not have additional malignancy on histology) conversion from WLE to mastectomy was 1.1% (95% CI, 0.3 to 3.6) and from WLE to more extensive surgery was 5.5% (95% CI, 3.1 to 9.5). CONCLUSION MRI staging causes more extensive breast surgery in an important proportion of women by identifying additional cancer, however there is a need to reduce FP MRI detection. Randomized trials are needed to determine the clinical value of detecting additional disease which changes surgical treatment in women with apparently localized breast cancer.

Magnetic Resonance Imaging Screening of the Contralateral Breast in Women With Newly Diagnosed Breast Cancer: Systematic Review and Meta-Analysis of Incremental Cancer Detection and Impact on Surgical Management

PURPOSE Preoperative magnetic resonance imaging (MRI) is increasingly used for staging women with breast cancer, including screening for occult contralateral cancer. This article is a review and meta-analysis of studies reporting contralateral MRI in women with newly diagnosed invasive breast cancer. METHODS We systematically reviewed the evidence on contralateral MRI, calculating pooled estimates for positive predictive value (PPV), true-positive:false-positive ratio (TP:FP), and incremental cancer detection rate (ICDR) over conventional imaging. Random effects logistic regression examined whether estimates were associated with study quality or clinical variables. RESULTS Twenty-two studies reported contralateral malignancies detected only by MRI in 131 of 3,253 women. Summary estimates were as follows: MRI-detected suspicious findings (TP plus FP), 9.3% (95% CI, 5.8% to 14.7%); ICDR, 4.1% (95% CI, 2.7% to 6.0%), PPV, 47.9% (95% CI, 31.8% to 64.6%); TP:FP ratio, 0.92 (95% CI, 0.47 to 1.82). PPV was associated with the number of test positives and baseline imaging. Few studies included consecutive women, and few ascertained outcomes in all subjects. Where reported, 35.1% of MRI-detected cancers were ductal carcinoma in situ (mean size = 6.9 mm), 64.9% were invasive cancers (mean size = 9.3 mm), and the majority were stage pTis or pT1 and node negative. Effect on treatment was inconsistently reported, but many women underwent contralateral mastectomy. CONCLUSION MRI detects contralateral lesions in a substantial proportion of women, but does not reliably distinguish benign from malignant findings. Relatively high ICDR may be due to selection bias and/or overdetection. Women must be informed of the uncertain benefit and potential harm, including additional investigations and surgery.

When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials?

Diagnostic tests are used to confirm, exclude, classify, or monitor disease to guide treatment. Their clinical value depends on whether the information they provide leads to improved patient outcomes; this can be assessed by randomized trials that compare patient outcomes from the new diagnostic test versus the old test strategy. However, randomized trials of test-and-treatment strategies are not routinely performed. They are not required for marketing approval, and they are not always feasible because they require large sample sizes. As a result, new diagnostic tests frequently enter clinical practice without evidence of improved patient outcomes. Studies of diagnostic test accuracy can show how well diagnostic strategies that include a new test identify the presence or absence of disease compared with an old test strategy by comparing each with the results of a reference standard test. However, if clinicians use only information about test accuracy to decide whether to adopt a new diagnostic test, they sometimes may harm patients (for example, if subsequent treatments are unsafe or ineffective). It is therefore worthwhile to investigate how best to decide if clinicians can rely on evidence about test accuracy or if they need to wait for patient outcome results from randomized trials. Fryback and Thornbury (1) described a hierarchy of 6 levels of evidence for the assessment of a diagnostic test: 1) the technical quality of test information; 2) diagnostic accuracy; 3) change in the referring physicians diagnostic thinking; 4) change in the patient management plan; 5) change in patient outcomes; and 6) societal costs and benefits. This framework does not provide guidelines about if and when lower levels of evidence are adequate to assess a test and always requires randomized trials for conclusions about improved patient outcomes. Some researchers have suggested that accuracy studies alone may sometimes suffice (2-6). We provide a practical framework to help clinicians decide whether a new diagnostic test can be adopted on the basis of evidence of test accuracy alone or if they need to wait for results from randomized trials. A Framework for Deciding if Evidence of Test Accuracy Will Suffice Studies of diagnostic test accuracy can suffice if clinicians already have evidence from randomized trials showing that treatment of the cases detected by the diagnostic test improved patient outcomes (Figure 1). This approach may seem straightforward; however, it requires a clear understanding of the proposed use and benefits of the new test, as well as careful consideration of whether the cases detected are representative of the patients included in treatment trials. Figure 1. Trial evidence versus linked evidence of test accuracy and treatment efficacy. The benefits of a new diagnostic test will vary according to how it is used. Investigators of a new diagnostic test need to explicitly state who will be tested, where the new test will fit in the existing diagnostic pathway, and what tests it will supplement or replace. This information will allow them to identify the expected benefits of adopting the new test and, therefore, the most relevant questions to ask to assess its value. Test attributes generally fall into 3 categories: 1) The test is safer or is less costly; 2) the test is more specific (excludes more cases of nondisease) and thus avoids unnecessary treatment; and 3) the test is more sensitive (detects more cases of disease) and thus promotes more appropriate treatment. We propose a simple sequence of questions to guide decisions about whether evidence of test accuracy will suffice for each of these 3 categories (Figure 2). The first step in assessing a new diagnostic test is to classify it according to whether it is more sensitive than the old test. We describe the key concepts of this framework using simple examples to describe situations where the new test offers better safety or specificity with similar sensitivity, followed by consideration of situations where the test is more sensitive. We also consider other, more complex scenarios. In each of these examples, we have some existing evidence of treatment efficacy for cases detected by an old test, and therefore, the rationale for testing has already been established. Figure 2. Assessing new tests using evidence of test accuracy, given that treatment is effective for cases detected by the old test. When a New Test Has Similar Sensitivity to an Old Test If a new diagnostic and old diagnostic test have similar sensitivity, it is generally reasonable to assume that they will detect the same true cases of disease. However, a new test may offer other positive attributes, such as better safety or more specificity than an old test. If studies of test accuracy show that the new test offers other positive attributes without a loss of sensitivity, it is logical to assume that cases detected by either test will show the same response to treatment. Therefore, new trials assessing treatment efficacy in the cases detected by the new test are not needed. When a new test and an old test show similar sensitivity and specificity, the value of the new test corresponds to the benefits of avoiding the adverse events or costs associated with the old test. For example, Doppler ultrasonography has been adopted as a less invasive replacement for venography for diagnosis of deep venous thrombosis (7). Given that trials have shown that treatment of this condition is effective (8), studies of test accuracy showing that Doppler ultrasonography and venography have similar sensitivity and specificity suffice to determine the value of the new test (Table, example 1). Table. New Diagnostic Test Assessment Framework and Examples If a new test is more specific than an old test, it avoids the harms of unnecessary further investigation or treatment. In this scenario, evidence showing that the new test has similar sensitivity but better specificity than the old test will suffice to determine the new tests value. For example, new immunochemical fecal occult blood testing kits have been proposed to offer increased specificity, without a loss of sensitivity, for detecting human blood, reducing the high false-positive rate of the older guaiac-based test kits (9). Given that trials have already shown the benefit of detecting colorectal cancer with guaiac test kits, studies of test accuracy will suffice to determine whether the immunochemical tests have increased specificity without any substantial loss in sensitivity (Table, example 2). Our assessment is more complex when we consider a new test that involves a tradeoff between positive and negative attributes. We deal with this situation later. When the New Test Is More Sensitive than the Old Test If a new test is more sensitive than an old test but has similar specificity, its value is directly related to the treatment response in the extra cases detected. If treatment response has already been assessed by treatment trials enrolling patients detected by the new test, decisions to use the test will be based on whether these trials showed that treatment improves patient outcomes. In this instance, evidence of test accuracy linked with evidence of treatment efficacy replaces the need for new randomized trials (Figure 1). There will also be a good match between tested and treated populations if the results for patients identified by a new test are analyzed in a treatment trial as potential predictors of treatment response. For example, trials of adjuvant tamoxifen among women with early breast cancer have shown that the estrogen receptor status of the tumor determines its response to treatment (10). These trials demonstrate the clinical value of testing for estrogen receptor status, as well as the effectiveness of tamoxifen therapy. However, more commonly, treatment trials have only enrolled cases detected by an old test. In these situations, clinicians need to consider whether the results apply to cases detected by the new test. Assessing Whether the Extra Cases Detected by a New, More Sensitive Test Respond to Treatment Clinicians first need to ask whether the extra cases detected by a new diagnostic test represent the same spectrum or subtypes of disease as those included in treatment trials. If they do, then randomized trials may not be required (Figure 2). If they do not, or if clinicians cannot be certain that they do, then clinicians also need to ask whether treatment response is known to be similar across the range of disease spectrum or subtype. These considerations are important regardless of the magnitude of the difference in sensitivity between tests. At one extreme, a good match between tested and treated populations is possible if the reference standard used to determine test sensitivity and specificity is also the starting point for trials conducted in similar populations. For example, computed tomography colonography is more sensitive for the detection of large colorectal polyps when scanning is performed with the patient in prone and supine positions versus supine positioning alone, without reduced specificity (11). Treatment trials showing improved survival following the early detection and treatment of colorectal polyps have been based on cases detected by colonoscopy, the reference standard for the computed tomography colonography accuracy studies. All of these tests are used to identify the same disease characteristic (adenomatous colorectal polyps) and spectrum of disease (classified by polyp size), so it is reasonable to conclude that computed tomography colonography with dual positioning will improve patient outcomes compared with supine positioning alone (Table, example 3). At the other extreme, a good match between tested and treated populations will not be possible if a new test measures a different biological characteristic to define disease and leads to a different selection of cases for treatment. For example, a new nucl

Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Womens Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case–control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER − PR − tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

Introduction: We performed a meta‐analysis to assess the role of immune checkpoint inhibitors as second‐line therapy in EGFR‐mutant advanced NSCLC. Methods: Randomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention‐to‐treat population and EGFR mutation–defined subgroups. We used the fixed‐effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided. Results: In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild‐type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR‐mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment‐mutation interaction p = 0.03). Conclusion: In EGFR‐mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first‐line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second‐line treatment for these patients.

A 2-Hour Diagnostic Protocol for Possible Cardiac Chest Pain in the Emergency Department: A Randomized Clinical Trial

IMPORTANCE Patients with chest pain represent a high health care burden, but it may be possible to identify a patient group with a low short-term risk of adverse cardiac events who are suitable for early discharge. OBJECTIVE To compare the effectiveness of a rapid diagnostic pathway with a standard-care diagnostic pathway for the assessment of patients with possible cardiac chest pain in a usual clinical practice setting. DESIGN, SETTING, AND PARTICIPANTS A single-center, randomized parallel-group trial with blinded outcome assessments was conducted in an academic general and tertiary hospital. Participants included adults with acute chest pain consistent with acute coronary syndrome for whom the attending physician planned further observation and troponin testing. Patient recruitment occurred from October 11, 2010, to July 4, 2012, with a 30-day follow-up. INTERVENTIONS An experimental pathway using an accelerated diagnostic protocol (Thrombolysis in Myocardial Infarction score, 0; electrocardiography; and 0- and 2-hour troponin tests) or a standard-care pathway (troponin test on arrival at hospital, prolonged observation, and a second troponin test 6-12 hours after onset of pain) serving as the control. MAIN OUTCOMES AND MEASURES Discharge from the hospital within 6 hours without a major adverse cardiac event occurring within 30 days. RESULTS Fifty-two of 270 patients in the experimental group were successfully discharged within 6 hours compared with 30 of 272 patients in the control group (19.3% vs 11.0%; odds ratio, 1.92; 95% CI, 1.18-3.13; P = .008). It required 20 hours to discharge the same proportion of patients from the control group as achieved in the experimental group within 6 hours. In the experimental group, 35 additional patients (12.9%) were classified as low risk but admitted to an inpatient ward for cardiac investigation. None of the 35 patients received a diagnosis of acute coronary syndrome after inpatient evaluation. CONCLUSIONS AND RELEVANCE Using the accelerated diagnostic protocol in the experimental pathway almost doubled the proportion of patients with chest pain discharged early. Clinicians could discharge approximately 1 of 5 patients with chest pain to outpatient follow-up monitoring in less than 6 hours. This diagnostic strategy could be easily replicated in other centers because no extra resources are required. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12610000766011.

Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis

PURPOSE We examined the impact of different epidermal growth factor receptor (EGFR) mutations and clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated non-small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy. PATIENTS AND METHODS This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-variance-weighted method. All statistical tests were two sided. RESULTS In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged PFS overall (HR, 0.37; 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the benefit was 50% greater (HR, 0.24; 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution (HR, 0.48; 95% CI, 0.39 to 0.58; Pinteraction < .001). Never-smokers had a 36% greater benefit (HR, 0.32; 95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50; 95% CI, 0.40 to 0.63; Pinteraction < .001). Women had a 27% greater benefit (HR, 0.33; 95% CI, 0.28 to 0.38) than men (HR, 0.45; 95% CI, 0.36 to 0.55; treatment-sex interaction P = .02). Performance status, age, ethnicity, and tumor histology did not significantly predict additional benefit from EGFR TKIs. CONCLUSION Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.

Breast Cancer Risk and Hormone Receptor Status in Older Women by Parity, Age of First Birth, and Breastfeeding: A Case-Control Study

Background: Early age at first birth and multiparity reduce the risk of estrogen receptor-progesterone receptor (ERPR)–positive breast cancer, whereas breastfeeding reduces the risk of both ERPR-positive and ERPR-negative cancers. Methods: We used multivariable logistic regression analysis to investigate whether age at first birth (<25 or ≥25 years) and breastfeeding (ever/never) modify the long-term effect of parity on risk of ERPR-positive and ERPR-negative cancer using 1,457 incident breast cancer cases and 1,455 controls ages ≥55 years who participated in the Womens Contraceptive and Reproductive Experiences Study. Results: Women who gave birth before age 25 years had a 36% reduced risk of breast cancer compared with nulligravida that was not observed for women who started their families at an older age (Pheterogeneity = 0.0007). This protective effect was restricted to ERPR-positive breast cancer (Pheterogeneity = 0.004). Late age at first birth increased the risk of ERPR-negative cancers. Additional births reduced the risk of ERPR-positive cancers among women with an early first birth (Ptrend = 0.0001) and among women who breastfed (Ptrend = 0.004) but not among older mothers or those who never breastfed. In women with a late first birth who never breastfed, multiparity was associated with increased risk of breast cancer. Conclusions: These findings suggest that the effect of parity on a womans long-term risk of breast cancer is modified by age at first full-term pregnancy and possibly by breastfeeding. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1723–30)

Reproductive factors and risk of breast carcinoma in a study of white and African-American women.

Few studies have investigated the association between reproductive factors and the risk of breast carcinoma among African‐American women. The authors assessed whether the number of full‐term pregnancies, age at first full‐term pregnancy, and total duration of breastfeeding were associated with similar relative risk estimates in white and African‐American women in a large multicenter, population‐based case–control study of breast carcinoma.

Markers of systemic inflammation predict survival in patients with advanced renal cell cancer.

Background:The host inflammatory response has a vital role in carcinogenesis and tumour progression. We examined the prognostic value of inflammatory markers (albumin, white-cell count and its components, and platelets) in pre-treated patients with advanced renal cell carcinoma (RCC).Methods:Using data from a randomised trial, multivariable proportional hazards models were generated to examine the impact of inflammatory markers and established prognostic factors (performance status, calcium, and haemoglobin) on overall survival (OS). We evaluated a new prognostic classification incorporating additional information from inflammatory markers.Results:Of the 416 patients, 362 were included in the analysis. Elevated neutrophil counts, elevated platelet counts, and a high neutrophil–lymphocyte ratio were significant independent predictors for shorter OS in a model with established prognostic factors. The addition of inflammatory markers improves the discriminatory value of the prognostic classification as compared with established factors alone (C-statistic 0.673 vs 0.654, P=0.002 for the difference), with 25.8% (P=0.004) of patients more appropriately classified using the new classification.Conclusion:Markers of systemic inflammation contribute significantly to prognostic classification in addition to established factors for pre-treated patients with advanced RCC. Upon validation of these data in independent studies, stratification of patients using these markers in future clinical trials is recommended.