Citations

Abstract Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510–41. ©2017 AACR.

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. Methods: With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. Results: 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). Conclusions: ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text]

98 Background: Concomitant with widespread adoption of axillary ultrasound (AUS) with ultrasound-guided needle biopsy (USNB) of suspicious lymph nodes (LN) for preoperative nodal staging of breast cancer patients, utilization of breast MRI, which includes axillary imaging, has increased. Little is known about the added value of MRI imaging of the axilla in this context. We undertook this study to assess the role of breast MRI in preoperative axillary nodal staging. Methods: We studied 988 consecutive invasive breast cancers in patients undergoing primary operation including axillary surgery, without neoadjuvant therapy, from 2010-2011. Results: 505 patients (51%) underwent MRI of which 168 (33%) demonstrated suspicious findings in the axilla. Abnormal axillary MRI findings included cortical thickening, edema, enhancement, hilar effacement, and/or altered shape and size. 114 patients had findings concordant with AUS. 54 patients had suspicious LNs on MRI either without a preceding AUS (33 cases) or after an initially negative AUS (21 cases). Second look AUS was performed in 29 of these cases and was abnormal in 3 (10%) in whom USNB confirmed metastatic adenopathy. Of the 54 cases with MRI-detected suspicious LNs 20 (37%) were node positive at operation with a pN stage of N0 (63%), N0i+ (5%), N1mic (4%), N1 (20%), N2 (6%), N3 (2%); extranodal extension was seen in 7 of 20 node-positive patients (35%). Conclusions: Second look AUS, when performed secondary to suspicious axillary MRI findings, identified LN metastasis preoperatively in 10% of patients. When MRI is done to evaluate the breast in newly diagnosed breast cancer patients, axillary findings can enhance the accuracy of preoperative nodal staging. We recommend second look AUS when MRI demonstrates suspicious axillary LN findings. [Table: see text]

49 Background: Predicting nodal positivity can guide surgical planning in breast cancer. Memorial Sloan-Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose that addition of distance of tumor from the nipple (DFN) can improve their performance. Methods: With IRB approval clinical T1/T2 tumors with pre-biopsy ultrasound were reviewed. MSKCC and MDACC nomogram predictions and the AUC-ROC were calculated. The addition of DFN was examined using multiple logistic regression and comparison of AUC-ROC values. Results: 401 breast cancers with clinical T1 (85%) or T2 (15%) tumors in 395 patients were included; of which 79/401 (19.7%) were node positive. Tumors were significantly closer to the nipple in those with positive nodes. 17/33 (51.5%) tumors within 2 cm of the nipple were node-positive versus 62/368 (16.8%) tumors > 2 cm from the nipple (p<0.0001). The MSKCC and MDACC nomograms each demonstrated good discrimination between node positive and negative patients with AUC-ROC values of 0.71 (95% CI: 0.64-0.77) and 0.74 (95% CI: 0.68-0.81), respectively. When added to the MSKCC nomogram, DFN ≤2 cm contributed significantly (OR 4.78, p=0.0001) to prediction of node positivity and improved the AUC-ROC to 0.73 (95% CI: 0.67-0.80). Similarly, DFN ≤2 cm was significant (OR 4.73, p=0.0002) when added to the MDACC nomogram and improved the AUC to 0.76 (95% CI: 0.70-0.82). Within nomogram probability categories, the proportion with positive nodes was consistently higher with DFN ≤2 cm. Conclusions: Tumor distance from nipple is associated with nodal positivity. When added to nomograms it improves prediction of node positivity. DFN should be considered when considering likelihood of nodal positivity for treatment planning. [Table: see text]

497 Background: As activating RAS mutations have been shown to predict lack of benefit from anti-EGFR therapies in advanced CRC, NCCN guidelines recommend testing for KRAS exon 2 and non-exon 2 mutations; however, these alterations are thought to explain only a subset of de novo resistance to targeted therapy. In a large set of CRC assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we assessed the frequency of less common KRAS short insertions that may predict failure of anti-EGFR therapy. Methods: 4,422 CRC cases were assayed with CGP performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 650X for at least 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified, including base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Pertinent available prior molecular testing results and clinical history was reviewed for selected cases. Results: Out of 4,422 CRC cases analyzed, KRAS short variants were identified in 50.9% of cases. A majority of cases contained a KRAS alteration at either codon G12 (35.5%) or G13 (9.1%), while alterations at codons Q61 or A146 were identified in 2.2% and 3.1% of cases, respectively. KRAS insertions were identified in 8 ( < 0.5%) cases. All KRAS insertions identified fell within codons 9-13, and 6/8 cases harbored V9_G10 insertions. Out of 6 patients with prior KRAS testing results available, 5 (83%) were negative by previous testing. Conclusions: CGP identifies KRAS insertions within or adjacent to hotspot regions in CRC cases which have previously tested negative for KRAS mutations. Given the importance of KRAS alterations in predicting lack of response to anti-EGFR therapies in CRC, accurate detection of these alterations in the course of clinical care is essential for effective treatment. CGP offers the possibility of identifying KRAS insertions that may impact efficacy of anti-EGFR targeted therapy and should be considered when previous focused testing for KRAS mutations is negative.

60 Background: Indications for nipple-sparing mastectomy (NSM) with immediate reconstruction have expanded. For cancer patients, NSM is thought best-suited for early stage patients, with nodal involvement initially viewed as a relative contraindication. We undertook this study to evaluate the use and early outcomes of NSM in node-positive (LN+) breast cancer. Methods: We identified 240 cancers in 226 patients (14 bilateral) scheduled for NSM and operated on at our institution 1/2009-6/2014. Data on intraoperative conversion from NSM, recurrence and follow-up was abstracted from the medical record. Chi-square and long-rank tests were used for statistical analysis. P-values < 0.05 were considered significant. Results: Of 240 cancers, 182 were LN- and 58 were LN+. More LN+ patients had T2/T3 tumors (27/58, 47%) than LN- patients (31/182, 17%), p < 0.0001, but ER and HER2 status was similar. Of 58 LN+ cases, 19 (33%) were cN1 confirmed by positive LN cytology and 39 (67%) were cN0 but LN+ at operation. 10 patients LN+ at diagnosis received neoadjuvant therapy (NT) followed by operation (at which 6 were pLN+ and 4 rendered ypN0); 39 cN0 (4 NT, 35 primary surgery) and 9 cN1 primary surgery patients were pLN+ at operation with a median of 1 LN+. NSM was successful in 13/14 LN+ NT patients (93%) and 39/44 LN+ primary surgery patients (89%), p = 0.64. Six LN+ patients (10%) were converted to skin-sparing mastectomy (SSM) at initial operation based on frozen section pathology (n = 5) or at a second operation (n = 1) vs 13/182 LN- patients (7%), p = 0.44. Among cancer patients treated with NSM, 7 locoregional recurrences (5 in LN+, 2 in LN- patients) occurred at 25 mos median follow-up. 3-year locoregional disease-free estimates were 87% (95% CI 75-100%) for LN+ vs 99% (95% CI 97-100%) for LN- patients, p = 0.007. One nipple-areolar recurrence occurred, in a LN- patient. 3-year breast cancer-specific survival was 97% (95% CI 92-100%) in LN+ vs 99% (95% CI 98-100%) in LN- patients, p = 0.40. Conclusions: Conversion from planned NSM to SSM did not differ significantly between LN+ and LN- patients. Short-term oncologic outcomes were satisfactory. These data suggest that NSM may be appropriate for carefully selected LN+ breast cancer patients.

247 Background: There are no prospective and few large retrospective studies of male breast cancer (MBC). This study’s aim was to describe our institutional experience with MBC and evaluate the ability of the AJCC staging system to stratify survival. Methods: All MBC cases were identified from our institution’s cancer registry from 1984-2008. Data collected included tumor characteristics, lymph node status, treatment, age, and survival. Results: During the study period 166 MBC cases were identified. Median age at diagnosis was 62 years (range 27-87). Most common presentation was a palpable breast mass (77%). Stage at diagnosis was stage 0 (6%), stage 1 (27%), stage 2 (36%), stage 3 (17%), stage 4 (5%), and unknown (9%). Procedure performed was mastectomy in 148 patients (89%), lumpectomy in 10 patients (6%) and unknown in 8 patients (5%). Median tumor size was 2.0 cm (range 0.2-11.0 cm). Most common histology was invasive ductal carcinoma (91%). Estrogen and progesterone receptor status assessed at diagnosis was positive in 93% and 86% of cases tested respectively. HER2/neu status was positive in 6 of 47 cases tested (13%). Nodal staging was performed by axillary dissection (AD) (70%), sentinel node biopsy (SN) alone (11%), SN and AD (11%) and no axillary staging (8%); 43% were node positive, 47% node negative and 10% unknown. Adjuvant chemotherapy was given to 40 patients (24%), adjuvant hormonal therapy to 42 patients (25%) and adjuvant radiation therapy was used in 33 cases (20%). With a median follow-up of 5.5 years, 86 patients (52%) have died: 44 due to breast cancer, 23 due to causes unrelated to breast cancer, and in 19 the cause of death is unknown. Median overall survival was 9.3 years. Median cancer-specific survival was 16.0 years. For patients initially diagnosed at stage 2, 3, and 4 median cancer-specific survival was 12.9, 7.2, and 0.8 years respectively. Median cancer-specific survival was significantly different for stages 2 vs. 3 (p = 0.03) and 3 vs. 4 (p = 0.0006). Conclusions: MBC most commonly presents as a palpable mass, is hormone responsive, and is most commonly treated with mastectomy. The TNM system appropriately stratifies men with MBC by duration of survival.

333 Background: Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Methods: Six patients with pancreatic SCC at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data was analyzed, and the literature on pancreatic SCC was reviewed. Results: Median age at diagnosis was 50 years (range 27-60). Half of the patients were male, and half were known smokers. All six masses were limited to the pancreatic head. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There was no perioperative mortality, although three patients had postoperative complications. All six patients received adjuvant chemotherapy therapy, five of whom were given cisplatin and etoposide. Of these five patients, three were known to have received radiation, while the remaining two had a plan for radiation at an outside facility. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Conclusions: Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed improved survival rates when compared to prior experiences with both resected and unresectable cases. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation. No significant financial relationships to disclose.