David M. Euhus

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.

Breast Cancer Screening

Breast cancer screening has become a controversial topic. Understanding the points of contention requires an appreciation of the conceptual framework underpinning cancer screening in general, knowledge of the strengths and limitations of available screening modalities, and familiarity with published clinical trial data. This review is data intense with the intention of presenting enough information to permit the reader to enter into the discussion with an ample knowledge base. The focus throughout is striking a balance between the benefits and harms of breast cancer screening.

Contralateral Prophylactic Mastectomy: Challenging Considerations for the Surgeon

Abstract The use of both bilateral prophylactic mastectomy and contralateral prophylactic mastectomy (CPM) has increased significantly during the last decade. Various risk models have been developed to identify patients at increased risk for breast cancer. The indications for bilateral prophylactic mastectomy for patients without a diagnosis of breast cancer include high risk from mutation in BRCA or other breast cancer predisposition gene, very strong family history with no identifiable mutation, and high risk based on breast histology. Additionally, the use of CPM has more than doubled in the last decade, and this increase is noted among all stages of breast cancer, even in patients with ductal carcinoma in situ (stage 0). The risk of contralateral breast cancer often is overestimated by both patients and physicians. Nevertheless, specific risk factors are associated with an increased risk of contralateral breast cancer, including BRCA or other genetic mutation, young age at diagnosis, lobular histology, family history, and prior chest wall irradiation. Although CPM reduces the incidence of contralateral breast cancer, the effect on disease-free survival and, more importantly, overall survival is questionable and underscored by the fact that the reason most patients choose CPM is to achieve “peace of mind.” Newer and effective reconstructive options have made the procedure more attractive. This panel addresses the indications and rationale for bilateral prophylactic mastectomy and CPM, the decision-making process by patients, and ethical considerations. Changes in the physician–patient relationship during the past few decades have altered the approach, and ethical considerations are paramount in addressing these issues.

Genetic Testing Today

AbstractBackground The commercial introduction of next-generation sequencing has made it possible to test for mutations in all known or suspected breast cancer predisposition genes in one panel, at one time, for about the same cost as a BRCA gene test. Clinicians are increasingly presented with the challenge of advising patients with mutations in rare breast cancer predisposition genes.MethodsLiterature review and personal experience with panel tests.ResultsPanel tests are more likely to identify a variant of uncertain clinical significance than a deleterious mutation. In addition, not all of the genes included in panel tests are unequivocally linked to increased breast cancer risk, and for most genes the penetrance is highly variable, making it difficult to translate a specific mutation into an absolute breast cancer risk. The three-generation cancer family history should be used to select truly high-risk families for panel testing, and then referred to again when the results are received in order to guide risk-management decisions. Knowing a breast cancer patient’s mutation status can influence decisions about local–regional and systemic therapy, but turnaround times for many tests are still too long to incorporate them into the initial evaluation of a new breast cancer.ConclusionThe commercialization of next-generation sequencing has the potential to greatly enhance the identification and management of individuals with an inherited predisposition to breast cancer. A period of uncertainty is anticipated before the full potential of this new technology is realized.

Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

New Insights into the Surgical Management of Breast Cancer

William Halstead is considered by many as the father of modern breast surgery. He popularized the notion that breast cancer progresses in an orderly fashion and that appropriately timed radical surgery can interrupt this progression to save lives. This view dominated for nearly 100 years and still persists to one extent or another in the minds of physicians and patients alike. Rapid advances in breast cancer biology have highlighted the heterogeneity of breast cancer and paradigm-shifting clinical trials have successfully challenged prevailing wisdom to effect a seed change in breast cancer surgery. Advances in radiation and systemic therapies permit more limited surgery for most patients. Recurrence rates of all kinds are on the decline; yet, paradoxically, use of bilateral mastectomy is increasing.

Breast Cancer Prevention

Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women.

Prediction of Cancer Prevention: From Mammogram Screening to Identification of BRCA1/2 Mutation Carriers in Underserved Populations

Background The US Preventative Service Task Force recommends that physicians perform a genetic risk assessment to identify women at risk for BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) syndrome. However, outcomes data after a diagnosis of HBOC syndrome especially in diverse populations, are minimal. Here we asked if genetic screening of high-risk underserved women identified in the mammogram population reduces cancer incidence. Methods We evaluated 61,924 underserved women at screening mammography for family histories suggestive of HBOC syndrome over the course of 21 months. Data were collected retrospectively from patients at two safety net hospitals through chart review. A computer model was used to calculate the long-term effect of this screening on cancer incidence by assessing both the mutation detection rate and the completion of prophylactic surgeries in BRCA1/2 mutation carriers. Findings We identified 20 of the 85 (23.5%) expected BRCA1/2 mutation carriers in the underserved population. The frequencies of prophylactic mastectomies and oophorectomies in the mutation carriers were 25% and 40%, respectively. Using these data, our model predicted only an 8.8% reduction in both breast and ovarian cancer in the underserved patients. This contrasts with a 57% reduction in breast cancer and 51% reduction in ovarian cancer in an insured reference population. Our data indicate that underserved patients with HBOC syndrome are difficult to identify and when identified are limited in their ability to adhere to NCCN guidelines for cancer prevention. Interpretation Screening for women at risk for HBOC syndrome in mammogram populations will only prevent cancers if we can increase compliance with management guidelines. This study provides prototypic baseline data for step-wise analysis of the efficacy of the use of family history analysis in the mammography setting for detection and management of HBOC syndrome.

Are Axillary Lymph Nodes Still Relevant in Breast Cancer

The importance of axillary nodal metastases in breast cancer has been recognized at least since the time of Wilhelm Fabry (1560–1634), who described axillary nodal excision in conjunction with primary tumor surgery. Understanding precisely what axillary metastases mean has been a work in progress for centuries. By the 18th century breast cancer progression was envisioned as an orderly process beginning in the breast, spreading to nodal basins, and then disseminating to distant sites. In the late 19th century William Halstead popularized the notion that radical nodal surgery could interrupt this progression and save lives. This view was challenged by Devitt in 1962 based on retrospective data that failed to show a survival advantage for radical nodal surgery. He astutely recognized that ‘‘...breast cancer patients do not do poorly because they have regional lymph node metastases, rather they have these metastases when they do poorly’’. The randomized prospective NSABP B-04 trial, which was first reported in 1977, confirmed that the addition of axillary dissection to mastectomy does not improve distant diseasefree or overall survival. In a 1980 review Bernard Fisher asserted that ‘‘...breast cancer is a systemic disease, likely at its inception,’’ and ‘‘The positive lymph node is the reflection of an interrelationship that permits the development of metastases rather than the instigator of distant disease’’. Identifying a lymph node metastasis is only the crudest possible indicator that a primary tumor possesses the machinery to thrive outside of the breast in a host who lacks the capacity to prevent it. Though there is considerable overlap between the tumor skill set required to generate a lymph node metastasis and the skill set required to proliferate in a distant organ, the study by Gangi et al. in this issue of the Annals reminds us that lymph node metastases are neither necessary nor sufficient for the generation of lethal distant metastatic disease. The specific observation was that tumor subtype, approximated by immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2/neu, did not independently predict lymph node positivity, though young age, larger tumors, higher grade, and lymphovascular invasion did. Breast cancer intrinsic subtype, ascertained by gene expression profiling, is known to predict breast cancer outcome. Immunohistochemistry provides only an inexact approximation of these intrinsic subtypes, and the 3-marker panel used by these investigators is inferior to larger panels that include EGFR, cytokeratins, and Ki67. The authors focus on triple negative breast cancer, which is a reasonable immunohistochemistry classification, but it must be recognized that this defines a fairly heterogeneous group of tumors and additional markers are required to more closely approximate the truly poor prognosis basal phenotype. Nevertheless, the conclusion that triple negative breast cancer, though associated with a poor prognosis, is not associated with a higher rate of lymph node metastases is consistent with prior studies suggesting that basal phenotype breast is actually associated with a lower rate of lymph node metastases than hormone-sensitive subtypes. These tumors clearly possess the machinery to disseminate and grow in distant organs, but some feature of the tumor-host interaction frequently precludes establishment of nodal metastases. Whether this reflects a deficiency in the tumors or an efficiency in the nodes is not known. Axillary nodal status has long been recognized as one of the strongest predictors of breast cancer recurrence and mortality. In the wake of rapid advances in molecular profiling, this role is appropriately being challenged, but much work is still required if we are to obtain the same information about tumor-host interactions through other Society of Surgical Oncology 2014

Validation of a personalized risk prediction model for contralateral breast cancer

PurposeWomen diagnosed with unilateral breast cancer are increasingly choosing to remove their other unaffected breast through contralateral prophylactic mastectomy (CPM) to reduce the risk of contralateral breast cancer (CBC). Yet a large proportion of CPMs are believed to be medically unnecessary. Thus, there is a pressing need to educate patients effectively on their CBC risk. We had earlier developed a CBC risk prediction model called CBCRisk based on eight personal risk factors.MethodsIn this study, we validate CBCRisk on independent clinical data from the Johns Hopkins University (JH) and MD Anderson Cancer Center (MDA). Women whose first breast cancer diagnosis was either invasive and/or ductal carcinoma in situ and whose age at first diagnosis was between 18 and 88 years were included in the cohorts because CBCRisk was developed specifically for these women. A woman who develops CBC is called a case whereas a woman who does not is called a control. The cohort sizes are 6035 (with 117 CBC cases) for JH and 5185 (with 111 CBC cases) for MDA. We computed the relevant calibration and validation measures for 3- and 5-year risk predictions.ResultsWe found that the model performs reasonably well for both cohorts. In particular, area under the receiver-operating characteristic curve for the two cohorts range from 0.61 to 0.65.ConclusionsWith this independent validation, CBCRisk can be used confidently in clinical settings for counseling BC patients by providing their individualized CBC risk. In turn, this may potentially help alleviate the rate of medically unnecessary CPMs.