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DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features

Lin, Lawrence Hsu; Tran, Ivy; Yang, Yiying; Shen, Guomiao; Miah, Pabel; Cotzia, Paolo; Roses, Daniel; Schnabel, Freya; Darvishian, Farbod; Snuderl, Matija
Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.
PMID: 37595637
ISSN: 1530-0285
CID: 5607792

Macrophage density is an adverse prognosticator for ipsilateral recurrence in ductal carcinoma in situ

Darvishian, Farbod; Wu, Yinxiang; Ozerdem, Ugur; Chun, Jennifer; Adams, Sylvia; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Troxel, Andrea B; Schnabel, Freya; Roses, Daniel
INTRODUCTION/BACKGROUND:There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood. METHODS:We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables. RESULTS:The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively]. CONCLUSIONS:macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
PMID: 35489232
ISSN: 1532-3080
CID: 5217782

Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease

Uppal, Abhineet; Stern, Stacey; Thompson, John F; Foshag, Leland; Mizzollo, Nicola; Nieweg, Omgo E; Hoekstra, Harald J; Roses, Daniel F; Sondak, Vernon K; Kashani-Sabet, Mohammed; Coventry, Brendon J; Cochran, Alistair J; Fujita, Manabu; Sim-Shin, Myung; Elashoff, David; Elashoff, Robert M; Faries, Mark B
BACKGROUND:Recommended treatment for patients with sentinel lymph node (SLN)-positive melanoma has recently changed. Randomized trials demonstrated equivalent survival with close observation versus completion lymph node dissection (CLND), but increased regional node recurrence. We evaluated factors related to in-basin nodal recurrence after lymphadenectomy (LND) for SLN-positive or macroscopic nodal metastases. METHODS:An institutional database and the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were analyzed independently. Exclusions were multiple primaries, multi-basin involvement, or in-transit metastases. Patient demographics, primary tumor thickness and ulceration, lymph nodes retrieved, and use of adjuvant radiotherapy were analyzed. Multivariate analyses were performed to determine factors predicting in-basin nodal recurrence (significance p ≤ 0.05). RESULTS:The retrospective cohort (577 patients) showed an in-basin failure rate of 6.6% after CLND for a positive SLN and 13.1% after LND for palpable disease (p = 0.001). This recurrence risk persisted after adjustment for patient, tumor, and LND factors [hazard ratio (HR) 2.32; p = 0.004]. In the MSLT-I cohort (326 patients), the failure rate after CLND following SLNB was 6.2%, but 10.1% after LND for palpable recurrence in observation patients. After adjustment for other factors, macroscopic disease was associated with an increased risk of recurrence after LND (HR 2.24; p = 0.05). CONCLUSION/CONCLUSIONS:After LND for melanoma, in-basin recurrence is infrequent, but a clinically significant fraction will fail. Failure is less likely if dissection is performed for clinically occult disease. Further research is warranted to evaluate the long-term regional control and quality of life associated with nodal basin observation, which has now become standard practice.
PMID: 31863416
ISSN: 1534-4681
CID: 4243782

Sentinel lymph node positivity in patients undergoing mastectomies for ductal carcinoma in situ (DCIS)

Price, Alison; Schnabel, Freya; Chun, Jennifer; Kaplowitz, Elianna; Goodgal, Jenny; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Mema, Eralda; Moy, Linda; Darvishian, Farbod; Roses, Daniel
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.
PMID: 31957944
ISSN: 1524-4741
CID: 4272692

Pregnancy-associated breast cancer in a contemporary cohort of newly diagnosed women

Gooch, Jessica C; Chun, Jennifer; Kaplowitz, Elianna; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Roses, Daniel; Schnabel, Freya
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.
PMID: 31448522
ISSN: 1524-4741
CID: 4054182

A Nomogram to Predict Factors Associated with Lymph Node Metastasis in Ductal Carcinoma In Situ with Microinvasion

Gooch, Jessica C; Schnabel, Freya; Chun, Jennifer; Pirraglia, Elizabeth; Troxel, Andrea B; Guth, Amber; Shapiro, Richard; Axelrod, Deborah; Roses, Daniel
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.
PMID: 31529311
ISSN: 1534-4681
CID: 4097972

Tumor-Infiltrating Lymphocytes in a Contemporary Cohort of Women with Ductal Carcinoma In Situ (DCIS)

Darvishian, Farbod; Ozerdem, Ugur; Adams, Sylvia; Chun, Jennifer; Pirraglia, Elizabeth; Kaplowitz, Elianna; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Price, Alison; Troxel, Andrea; Schnabel, Freya; Roses, Daniel
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.
PMID: 31240590
ISSN: 1534-4681
CID: 3954082

Tumor-infiltrating lymphocytes in a contemporary cohort of women with DCIS [Meeting Abstract]

Price, A; Darvishian, F; Ozerdem, U; Schnabel, F; Chun, J; Kaplowitz, E; Pirraglia, E; Troxel, A; Adams, S; Roses, D
Background/Objective: Growing evidence suggests that tumor immune-microenvironment influences breast cancer carcinogenesis and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer correlates with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) is less understood.
Method(s): Our institutional database was queried for pure DCIS from 2010-2018 (n=668). Local recurrences (n=13) were matched 1:4 to patients without recurrence. TILs were evaluated by the International TILs Working Group Guidelines. Percentage of TILs was assessed from the densest focus in 1 high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses, logistic, and Cox regression models.
Result(s): Sixty-nine patients, including the 13 recurrences were evaluated. Fifty-four (78%) were treated by breast-conserving surgery (BCS). The median follow-up was 6.7 years. TILs were defined as sparse (<45%) and dense (>=45%). Dense TILs was associated with younger age (p=0.045), larger tumor size (p<0.001), high nuclear grade (p<0.001), comedo histology (p=0.016), necrosis (p=0.038), and recurrence (p=0.001). Nine patients with dense TILs had a mean time to recurrence of 74 months compared to 4 patients with sparse TILs who had a mean time to recurrence of 93 months (p=0.044) (Figure).
Conclusion(s): We found that dense TILs in DCIS was significantly associated with age, tumor size, grade, and histology. Most importantly, dense TILs are a significant predictor of recurrence in patients with DCIS, which underlies the prognostic importance of the immune microenvironment of early breast cancers. (Figure Presented)
ISSN: 1534-4681
CID: 3926482

Obesity Paradox in Early Stage Melanoma: Long-Term Follow-up in MSLT-I [Meeting Abstract]

Rand, J. G.; Kirchoff, D.; Deutsch, G.; Stern, S.; Thompson, J.; Cochran, A.; Mozzillo, N.; Nieweg, O.; Roses, D.; Hoekstra, H.; Sondak, V.; Coventry, B.; Kashani-Sabet, M.; Smithers, M.; Paul, E.; Kraybill, W.; Elashoff, R.; Lee, D.; Faries, M. B.
ISSN: 1068-9265
CID: 3705502

A novel immunization strategy using cytokine/chemokines induces new effective systemic immune responses, and frequent complete regressions of human metastatic melanoma

Valentine, Fred T; Golomb, Frederick M; Harris, Matthew; Roses, Daniel F
Immune responses have been elicited by a variety of cancer vaccines, but seldom induce regressions of established cancers in humans. As a novel therapeutic immunization strategy, we tested the hypothesis that multiple cytokines/chemokines secreted early in secondary responses ex-vivo might mimic the secretory environment guiding new immune responses. The early development of immune responses is regulated by multiple cytokines/chemokines acting together, which at physiologic concentrations act locally in concert with antigen to have non-specific effects on adjacent cells, including the maturation of dendritic cells, homing and retention of T cells at the site of antigen, and the differentiation and expansion of T cell clones with appropriate receptors. We postulated that repeated injections into a metastasis of an exogenous chemokine/cytokine mixture might establish the environment of an immune response and allow circulating T cell clones to self- select for mutant neo-epitopes in the tumor and generate systemic immune responses. To test this idea we injected some metastases in patients with multiple cutaneous melanoma nodules while never injecting other control metastases in the same patient. New immune responses were identified by the development of dense lymphocytic infiltrates in never-injected metastases, and the frequent complete regression of never-injected metastases, a surprising observation. 70% of subjects developed dense infiltrates of cytotoxic CD8 cells in the center and margin of never-injected metastases; 38% of subjects had complete and often durable regressions of all metastases, without the use of check-point inhibitors, suggesting that, as a proof-of-principle, an immunization strategy can control advanced human metastatic melanoma.
PMID: 29308310
ISSN: 2162-4011
CID: 2905762