Faculty Bibliography

BACKGROUND:The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared to the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared to AJCC7. METHODS:We analyzed a cohort of 1,315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve (AUC) of 5-year survival to predict RFS/OS. All statistical tests were two-sided. RESULTS:Stage IIC continued to have worse outcomes than those for stage IIIA patients, with 5-year RFS of 26.5% (95%CI=12.8-55.1%) vs. 56.0% (95%CI=37.0-84.7%) by AJCC8 (P = 0.002). For stage I, removing mitotic index as T classification factor decreased its prognostic value, although not statistically significantly (RFS C-index=0.63 [95%CI=0.56-0.69] to 0.56 [95%CI=0.49-0.63], P = 0.07; OS C-index=0.48 [95%CI=0.38-0.58] to 0.48 [95%CI=0.41-0.56], P = 0.90). For stage II, prognostication remained constant (RFS C-index=0.65 [95%CI=0.57-0.72]; OS C-index=0.61 [95%CI=0.50-0.72]), and. For stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index=0.65 [95%CI=0.60-0.70] to 0.70 [95%CI=0.66-0.75], P = 0.01). CONCLUSIONS:Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS:Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS:Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS:Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAF^V600, NRAS^Q61, and TERT^-124C>T and TERT^-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%) and/or TERT (78%). Thirteen patients had TERT^mutant discordant tumors; seven of these had a single tumor with both TERT^-124C>T and TERT^-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one in different tumors and the other had a single tumor with both mutations. One patient with a BRAF^mutant primary lacked mutant BRAF in least one of their metastases. Overall, we identified mutational heterogeneity in 18/99 (18%) patients. These results suggest that some primary melanomas may be comprised of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Current guidelines recommend sentinel lymph node biopsy (SLNB) for patients undergoing mastectomy for a preoperative diagnosis of ductal carcinoma in situ (DCIS). We examined the factors associated with sentinel lymph node positivity for patients undergoing mastectomy for a diagnosis of DCIS on preoperative core biopsy (PCB). The Institutional Breast Cancer Database was queried for patients with PCB demonstrating pure DCIS followed by mastectomy and SLNB from 2010 to 2018. Patients were divided according to final pathology (DCIS or invasive cancer). Clinico-pathologic variables were analyzed using Pearson's chi-squared, Wilcoxon Rank-Sum and logistic regression. Of 3145 patients, 168(5%) had pure DCIS on PCB and underwent mastectomy with SLNB. On final mastectomy pathology, 120(71%) patients had DCIS with 0 positive sentinel lymph nodes (PSLNs) and 48(29%) patients had invasive carcinoma with 5(10%) cases of ≥1 PSLNs. Factors positively associated with upstaging to invasive cancer in univariate analysis included age (P = .0289), palpability (P < .0001), extent of disease on imaging (P = .0121), mass on preoperative imaging (P = .0003), multifocality (P = .0231) and multicentricity (P = .0395). In multivariate analysis, palpability (P = .0080), extent of disease on imaging (P = .0074) and mass on preoperative imaging (P = .0245) remained significant (Table 2). In a subset of patients undergoing mastectomy for DCIS with limited disease on preoperative evaluation, SLNB may be omitted as the risk of upstaging is low. However, patients who present with clinical findings of palpability, large extent of disease on imaging and mass on preoperative imaging have a meaningful risk of upstaging to invasive cancer, and SLNB remains important for management.

Pregnancy-associated breast cancer (PABC) refers to breast cancer (BC) diagnosed during pregnancy, lactation, or in the postpartum period. There is evidence that PABC is associated with a poorer prognosis, and that the development of the disease is influenced by the unique hormonal milieu of pregnancy. The purpose of this study was to investigate the clinicopathologic characteristics associated with PABC in a contemporary cohort of women with newly diagnosed BC. Our institutional Breast Cancer Database was queried for women diagnosed with BC between 2009-2018 who had at least one full-term pregnancy (FTP). Variables of interest included patient demographics and clinical and tumor characteristics. PABC was defined as breast cancer diagnosed within 24 months of delivery. Statistical analyses included Pearson's chi-square and logistic regression. Out of a total of 2202 women, 46 (2.1%) had PABC. Median follow-up in the total cohort was 5.5 years. After adjusting for age at first FTP, PABC was associated with younger age at diagnosis, older age at first FTP, non-Caucasian race, BRCA positivity, presentation with a palpable mass, higher pathologic stage, higher histologic grade, and ER-negative and triple-negative receptor status. The association of PABC with non-Caucasian race may be reflected in the increased proportion of triple-negative breast cancers in the PABC group. PABC was also associated with older age at first FTP. As more women delay childbearing, risk for PABC may increase. Our findings suggest that women who become pregnant at older ages should be followed carefully during pregnancy and the postpartum period, especially if they are BRCA mutation carriers. The optimal approach for monitoring older women during pregnancy and the postpartum period is unclear.

Introduction The use of neoadjuvant chemotherapy (NAC) has enabled more patients to be eligible for breast-conservation surgery (BCS). Achieving negative lumpectomy margins, however, may be challenging after NAC due to changes in tissue density and the potential for residual carcinoma to be scattered in the tumor bed. Data regarding patients undergoing BCS after NAC has shown variable re-excision rates. MarginProbe (Dune Medical Devices Ltd, Israel) has been shown to identify positive resection margins intraoperatively and reduce the number of re-excisions in primary BCS, but has not been previously studied in NAC+BCS cases. The purpose of our study was to investigate the clinicopathologic characteristics, including margin status, and re-excision rates in patients who had NAC+BCS with and without the use of MarginProbe at our institution. Methods The Institutional Breast Cancer Database was queried for all patients who received NAC and had subsequent BCS from 2010-2019. Variables of interest included demographics, tumor characteristics, pathologic complete response (pCR), MarginProbe use, treatment and outcomes. Statistical methods included Chi-Square and Fisher's Exact tests. Results A total of 214 patients had NAC in our study population, and 61 (28.5%) of those patients had NAC+BCS. The median age was 53.5 years. A total of 19 (31.1%) patients had pCR. Of the remaining 42 patients, 9 (21%) had close or positive margins that required re-excision. Re-excision was associated with a larger residual tumor size (p=0.025), and ER-positive disease before NAC (p=0.041). Breast density and the presence of palpable disease did not differ between the groups. MarginProbe use was associated with a lower re-excision rate in patients with NAC+BCS (6% vs. 31%, respectively). Conclusion The use of NAC may enable more patients to undergo BCS. Patients with larger residual tumor burden and ER-positive disease were at an increased risk for inadequate margins at the time of surgery. The use of Margin-Probe was associated with a lower re-excision rate. Techniques to reduce the need for re-excision will support the use of BCS after NAC

Background/Objective: According to the US Census data, adoptees account for 2.5% of the US population (7.8 million). However, the number of adoptees diagnosed with breast cancer is unknown. Many adoptees face the unique challenge of lacking access to their family health history and limited access to screening and risk-reducing interventions. This important health disparity among adoptees has raised awareness in the importance genetic testing (GT), although it does not completely fill the disparity gap of lacking family history. The National Society of Genetic Counselors (NSGC) released an updated position statement in 2018 that supported the use of genetic testing, including genome-wide testing, for adopted adults. The purpose of our study was to investigate the adoptees in a cohort of newly diagnosed breast cancers and to look at the clinicopathologic characteristics, including the uptake of genetic testing, and to see if there were any differences compared to the non-adopted breast cancer patients.
Method(s): The Institutional Breast Cancer Database was queried for all patients diagnosed with breast cancer between 2010-2018. Variables of interest included adoption status and other clinical and tumor characteristics. Statistical analyses included descriptive and Pearson's Chi Square tests.
Result(s): Out of 3,507 patients newly diagnosed with breast cancer, 34 (1%) were adopted. The median age at diagnosis for the total population was 60 years (range 23-96 years). When we compared the adopted and non-adopted groups, age was not statistically different (p=0.817); race was not statistically different (p=0.077), although there was a slightly higher proportion of Hispanics in the adopted vs. non-adopted cohorts (15% vs. 6%). When we looked at genetic testing, 56% of the adoptees were tested compared to 45% of non-adopted patients, but this was not significant (p=0.229). All adopted patients were negative for BRCA1/2 and other mutations. Interestingly, 29% of the adopted patients had a first-degree relative with breast cancer compared to 31% of non-adopted patients. The tumor characteristics between the adopted and non-adopted cohorts were not statistically different. The majority had early stage (Stage 0, I, II) disease (93%), invasive ductal and lobular carcinoma (73%), and ER/PR-positive and HER2-negative cancers (71%).
Conclusion(s): In a contemporary cohort of newly diagnosed breast cancer patients, we found no difference between the adopted and non-adopted patients based on age, race, education, and tumor characteristics. However, there was a higher proportion of adopted patients who got genetic testing compared to the non-adopted cohort. Both groups also reported a similar proportion of having a first-degree relative with breast cancer, which indicates the increased communication between the adoptees and their biological parents

INTRODUCTION/BACKGROUND:Ductal carcinoma in situ (DCIS) with foci of invasion measuring ≤ 1 mm (DCISM), represents < 1% of all invasive breast cancers. Sentinel lymph node biopsy (SLNB) has been a standard component of surgery for patients with invasive carcinoma or extensive DCIS. We hypothesize that selective performance of SLNB may be appropriate given the low incidence of sentinel node (SN) metastasis for DCISM. We investigated the clinicopathologic predictors for SN positivity in DCISM, to identify which patients might benefit from SLNB. METHODS:A retrospective review of the National Cancer Database was performed for cases from 2012 to 2015. Clinical and tumor characteristics, including SN results, were evaluated, and Pearson's Chi square tests and logistic regression were performed. RESULTS:Of 7803 patients with DCISM, 306 (4%) had at least one positive SN. Patients with positive SNs were younger, more often of Black race, had higher-grade histology and larger tumor size, and were more likely to have lymphovascular invasion (LVI; all p < 0.001). In an adjusted model, the presence of LVI was associated with the highest odds ratio (OR) for node positivity (OR 8.80, 95% confidence interval 4.56-16.96). CONCLUSIONS:Among women with DCISM, only 4% had a positive SN. Node positivity was associated with more extensive and higher-grade DCIS, and the presence of LVI was strongly correlated with node positivity. Our data suggest that LVI is the most important factor in determining which patients with DCISM will benefit from SN biopsy.

BACKGROUND:Growing evidence suggests that the tumor immune microenvironment influences breast cancer development and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer is correlated with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) are less understood. METHODS:Our institutional database of 668 patients with pure DCIS from 2010 to 2018 was queried. TILs were evaluated by International TILs Working Group guidelines. Percentage of TILs was assessed from the densest focus (hotspot) in one high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses (to define sparse versus dense TILs), logistic, and Cox regression models. RESULTS:Sixty-nine patients with DCIS and TILs were evaluated, of whom 54 (78%) were treated by breast-conserving surgery. Thirteen (19%) patients had ipsilateral recurrence. Each recurrence (n = 13) was matched to four controls (n = 56) based on date of surgery. Median follow-up was 6.7 years. TILs were defined as sparse (< 45%) or dense (≥ 45%). Dense TILs were associated with younger age (p = 0.045), larger tumor size (p < 0.001), high nuclear grade (p = 0.010), comedo histology (p = 0.033), necrosis (p = 0.027), estrogen receptor (ER) negativity (p = 0.037), and ipsilateral recurrence (p = 0.001). Nine patients with dense TILs had mean time to recurrence of 73.5 months compared with four patients with sparse TILs with mean time to recurrence of 97.9 months (p = 0.003). CONCLUSIONS:Dense TILs were significantly associated with age, tumor size, nuclear grade, comedo histology, necrosis, and ER status and was a significant predictor of recurrence in patients with pure DCIS.