Time Of Metastasis Diagnosis Research Articles

Perceptions of prognosis and goals of care in patients receiving radiation therapy.

30 Background: We aimed to gain insight into the experiences and perceptions of patients with advanced metastatic cancer surrounding palliative radiation therapy (RT). Methods: In-depth structured interviews were conducted from 9/2016 to 10/2018 with 17 patients with bone or lung metastases receiving their first course of palliative RT. Patient answers about understandings of goals of care and disease prognosis were recorded and analyzed through qualitative content analysis. Medical records were reviewed to obtain demographic and clinical data. Results: The median age of patients was 64 years (range: 21-82). The median survival from time of metastatic diagnosis was 17.6 months (range: 1-46). When asked about goals of RT, qualitative analysis revealed that half (53%) linked receiving palliative RT to improving their quality of life, however 35% believed RT would completely get rid of their tumor. Words that were used commonly throughout patient answers included alleviating pain (41%), cure (29%), and reducing tumor growth (24%). All patients reported they received their information about goals of care from their medical teams. When asked about prognosis, 53% said prognosis had been discussed with them, whereas 76.5% said they were interested in information about prognosis. When asked “What do you believe lies ahead?,” about half (47%) expressed uncertainty about the future, while others (41%) were focused on the next steps in treatment. In the patients interested in learning more about their prognosis, there was a strong preference for this information to come from their medical teams. Conclusions: More than half of patients accurately identified the goal of RT as improving their quality of life, however some patients believed that the palliative RT would cure their tumor. This highlights the ongoing gap in patient provider communication and the need for improvement in this area. Inaccurate perceptions of goals of treatment and prognosis may motivate some patients to pursue unnecessarily aggressive treatments, which could affect quality of life without improving survival. Referrals to radiation oncologists present a potential opportunity to reopen discussions on goals of care and prognosis to adjust patient expectations.

Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, “clinical benefit” was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

Abstract 4468: Role of statins and PSA nadir after androgen-deprivation therapy in overall survival of patients with metastatic prostate cancer

Abstract Statins are known to reduce prostate cancer (CaP) aggressiveness in both localized and metastatic disease. Studies have indicated that the use of statin drugs to lower cholesterol levels was associated with decreased risk of localized CaP, less frequent high grade CaP and lower CaP volume, suggesting that statin use has a protective effect against localized CaP. However, less is known about a role for statins in metastatic CaP (mCaP). While it is known that hypercholesterolemia is associated with the development of castration resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) in patients with bone metastasis, it is not known whether the sequence of statin and ADT affects outcome. Charts of 162 patients with mCaP treated at the VA Northern California Health Care System (VANCHCS) with ADT and statins between 1992 and 2016 were analyzed. Overall survival (OS) was followed until 12/2016. Dates were noted from the medical records entered into the Computerized Patient Record System (CPRS). Time to event outcomes (with the exception of time to Nadir PSA, which was not censored) were analyzed using Cox proportional hazard models. PSA Nadir and time to PSA Nadir were analyzed using linear models, with outcomes log transformed. All models include age at PSA diagnosis and year of metastatic diagnosis as covariates. Of the 162 total patients, 110 were on ADT following biochemical recurrence (BCR) at the time of diagnosis with distant metastasis (ADT before mets, ABM) while 50 were diagnosed with a distant metastatic lesion at the time of ADT administration (mets before ADT, MBA). 46.3% of the patients did not receive statin treatment whereas 41.4% received statins prior to diagnosis with distant metastasis, and 12.3% started statins after metastasis diagnosis (29% prior to ADT treatment and 24.7% after starting on ADT). There was no effect of statins on OS among those who had a diagnosis of metastasis prior to initial ADT (MBA group). On the other hand, among those who developed metastases while on ADT (ABM group), statin use significantly increased OS (based on the time of metastasis diagnosis). However, within this group, the largest benefit was in the patients that received statins after starting ADT (HR = 0.51, p=0.022). The same group (subgroup within the ABM group who initiated statins after ADT) also took longer to reach PSA nadir following ADT compared to those who never received statins (R=1.79, p=0.031) and also took longer to be diagnosed with mCaP following ADT compared to those who had never been (HR=0.45, p=0.003). These advantages were not seen in patients in the ABM group who were already on statins at the time of ADT initiation, and no advantages of statins were seen in the MBA group. Our data indicate that treatment with statins initiated after the patient has undergone ADT is beneficial to patients who develop distant metastases while on ADT treatment. Citation Format: Salma Siddiqui, Blythe P. Durbin-Johnson, Stanley A. Yap, Ralph W. deVere White, Paramita M. Ghosh. Role of statins and PSA nadir after androgen-deprivation therapy in overall survival of patients with metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4468.

Abstract P2-08-16: Impact of germline BRCA mutation status on survival in women with metastatic triple negative breast cancer

Abstract Background: 15-20% of patients with triple negative breast cancer (TNBC) harbor deleterious germline (g) BRCA1/2 mutations. Recent data suggests that in metastatic TNBC (mTNBC) gBRCA1/2 mutations are associated with response to PARP inhibitors (PARPi) and platinum chemotherapy. However, diagnosis of mTNBC is associated with short overall survival (OS) with no available biomarkers that can identify mTNBC patients with better prognosis. Aim: Utilizing data from a prospective registry, the objective of this study was to investigate whether presence of gBRCA1/2 mutation impacts overall survival for patients with mTNBC treated prior to clinical availability of PARPi. Methods: 643 patients with stage I-IV TNBC were enrolled in an IRB approved multisite prospective registry between 2011 to 2018. Clinical, demographic, and treatment information was collected and patients were followed for recurrence and survival. 100/643 patients had metastatic breast cancer (de novo stage IV disease or metastatic recurrence). OS (from the time of diagnosis of metastatic disease to death from any cause) was estimated according to the Kaplan-Meier method and compared among groups by log-rank test. Results: For the 100 mTNBC patients, the median age at diagnosis of metastatic disease was 55 years, 17% were African American, 20% had novo stage IV and 80% had relapsed disease. 84% had visceral disease, 12% had bone-only disease, and 4% had lymph node only disease. Metastatic treatment: 87% received chemotherapy, 7% received radiation only without chemotherapy and 6% did not receive any treatment. No patients received treatment with PARP inhibitor. Among de-novo stage IV patients, 35% (7/20) had breast surgery for removal of primary tumor during their course of metastatic treatment. For all 100 patients, 12% (n=12) had gBRCA mutation; 72% (n=72) had no gBRCA mutation; and 16% (n=16) had unknown BRCA mutation status. When compared with non-carriers, gBRCA carriers were younger at time of metastatic diagnosis (median age 49 vs. 57 years, p=0.02). There was no difference in prevalence of visceral disease, de-novo stage IV disease or median lines of metastatic chemotherapy among gBRCA carriers and non-carriers. At a median follow up of 31 months, median OS for all patients is 21 months (95% CI 13-23 months). Median OS is 18 months (95% CI 15-27 months) for non-carriers and has not yet been reached for gBRCA mutation carriers (p=0.023). 3-year estimated OS is 63% in gBRCA carriers compared to 28% in non-carriers (p=0.02). On multivariate Cox regression analysis, gBRCA carrier status was associated with reduced risk of death (HR=0.33; 95%CI [0.23-0.91], p=0.033) Conclusions: gBRCA mutation associated mTNBC patients have a clinically significant improved OS at 3 years compared to mTNBC patients without BRCA mutations (3-year OS of 63% vs 28%). Further research is needed to understand tumor and host biological reasons for this observation. Outcomes of gBRCA mutation associated mTNBC are likely to be further improved with availability of PARPi. Given that patients with gBRCA mutation are at risk for second breast/ovarian cancers, these findings also underscore need for further research regarding the role of prophylactic surgeries mTNBC with gBRCA mutation. Citation Format: Larson K, Wang YY, Finke K, O'Dea AP, Khan Q, Nye L, Heldstab J, Godwin AK, Kimler BF, Sharma P. Impact of germline BRCA mutation status on survival in women with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-16.

Abstract P6-02-18: Hepatic complications of breast cancer

Abstract Background Breast cancer is the most common malignancy and the leading cause of cancer death in women in the United States. Nearly 30% of women with metastatic breast cancer will have liver metastases, with a median survival from time of 4.23 months from time of metastatic diagnosis. Hepatic involvement of breast cancer is common and can result from metastatic tumor burden or treatment with chemotherapy or radiation. Being able to recognize and diagnose hepatic involvement of breast cancer is of utmost importance, as it has a dramatic effect on patient prognosis and management. Learning Objectives To familiarize multidisciplinary clinical team members with the radiographic presentations of hepatic complications of breast cancer in a variety of imaging modalities including computed tomography, dual-energy computed tomography, ultrasound, and MR. This will facilitate accurate and prompt diagnosis and treatment of hepatic involvement of breast cancer. Abstract Our educational pictorial essay demonstrates the typical appearance of hepatic metastases on multiple imaging modalities, as well as atypical presentations such as hyperdense, hypervascular, or hypoechoic lesions and pseudoprogression. We will show examples of hepatic metastases presenting as pseudocirrhosis, left lobar atrophy, capsular retraction, as well as sequelae of pseudocirrhosis such as malignant ascites, varices, portal vein thrombosis, and biliary obstruction. We will discuss the radiographic appearance of the liver after being treated with locoregional liver-directed techniques such as surgical resection, ablation, and chemoembolization. Importantly, we will illustrate examples of hepatic complications from systemic therapy including steatohepatitis from tamoxifen, as well as hepatic fibrosis from gemcitabine. Conclusion Clinicians must have a thorough understanding of the hepatic complications of cancer to ensure excellent diagnostic accuracy and management.

Comprehensive genomic profiling in metastatic pancreatic adenocarcinoma, correlation with early death versus prolonged survival.

282 Background: PDAC has a very poor prognosis and around 50% of the patients die within two months of their diagnosis and around 10% live beyond one year. In this study we sought to find biomarkers differentiating patients with early death from those with more prolonged survival. Methods: Tumors from our patients with PDAC were examined using NexGen sequencing (evaluating somatic mutations in 592 genes), immunohistochemistry, and in-situ hybridization (Caris Life Sciences). Tumor mutational burden, microsatellite instability, copy number variation, and gene fusion assessment were done in a subset of samples. Extremes in clinical outcome were defined as death in < 4 months and > 12 months from metastasis diagnosis. Fischer’s exact tests were used to associate the categorical clinical data and genomic factors with the extremes of clinical outcome. A t-test was used to associate the continuous clinical factors with the extreme outcomes. Hierarchical clustering using the Ward amalgamation and binary distance metric was used to define cluster based upon the genomic factors. Results: From October 2014 to August 2018, we evaluated 115 patients. 15 patients with PDAC died < 4 months and 39 died > 12 month from the time of metastasis diagnosis. Compared to the patients with prolonged survival, patients with an early death were significantly older (Average 67.5 vs. 60.5 years old, P = 0.03) and had significantly higher neutrophil counts (average 9.6 vs. 5.1, P = 0.001) and monocyte counts (average 1 vs. 0.6, P = 0.01). No genomic alteration differentiated the groups with extreme outcomes. None of the clusters defined upon the genomic factors differentiated the two outcome groups. Using classification model to predict early death vs prolonged survival, no factor evaluated by the genomic profiling was discriminatory between the groups. Conclusions: We did not find a pattern of genomic alteration difference in PDAC patients between the short-term versus the long-term survivals using Next Generation Sequencing. The short-term survivals were older and had higher neutrophil and monocyte counts at the time of metastatic disease diagnosis.

Abstract 3024: Genomic characterization of organ-specific metastasis from prospective clinical sequencing of 20,000 cancer patients

Abstract We investigated genomic differences in sequenced biopsies of patients with metastatic cancer to identify associations between somatic alterations and anatomic site of metastasis. We analyzed data from 20,000 patients treated at Memorial Sloan Kettering Cancer Center, covering >50 cancer types and >20 metastatic sites. Tumors were sequenced using MSK-IMPACT, a targeted sequencing assay that identifies somatic mutations, copy number changes and structural rearrangements in 468 cancer genes using tumor and matched normal DNA. We identified tumor types such as prostate cancer, lung adenocarcinoma, uterine endometrioid carcinoma, head and neck cancer and gastrointestinal stromal tumors, for which the primary biopsies differed significantly from the metastatic biopsies at the genomic level, suggesting a need for sample stratification in clinical studies. We also identified site-specific enrichment of individual somatic alterations for tumors from the same cancer type, including therapeutically relevant targets. For example, when evaluating patients with esophagogastric cancer, we found an enrichment of HER2 amplified tumors, which are candidates for trastuzumab therapy, in sequenced lung metastases as opposed to biopsies sequenced at other metastatic sites (8/16, 50% vs. 20/145, 14%; p<0.001). Looking at sequenced metastases of lung adenocarcinoma (n=468), we found that brain metastases (n=34) exhibit increased aneuploidy (median fraction of genome altered 0.55 vs. 0.44; p<0.001, purity-controlled results) and adrenal gland metastases (n=21) exhibit increased mutational burden (13.3 mut/Mb vs. 6.1 mut/Mb; p<0.001) when compared to metastases sequenced at other anatomic sites. Other examples of novel findings include enrichment of amplifications in the MITF-ETV1 pathway in melanoma patients with brain metastatic disease (13/63, 21% vs. 10/234, 4%; p<0.001) and enrichment of 20q chromosomal amplifications in patients with microsatellite stable colorectal tumors that exhibit oligo-metastatic (as opposed to poly-metastatic) patterns at first time of metastasis diagnosis (158/223, 71% vs. 28/58, 48%; p=0.002). We provide a detailed analysis of associations between genomic features and metastatic patterns within a clinical sequencing setting. Our work has the potential to directly influence the management of patients with metastatic cancer by enabling clinicians to (a) estimate the risk of future metastasis based on the genomic profile of early stage tumors, (b) choose the appropriate site for biopsy in cases where mutation identification will influence the selection of targeted therapy, (c) optimize the use and frequency of imaging modalities for metastasis surveillance and (d) investigate and functionally characterize novel genomic alterations that have a role in metastasis and can lead to improved therapies. Citation Format: Francisco Sanchez-Vega, Walid K. Chatila, Karuna Ganesh, Alexander Penson, Niedzica Camacho, Philip Jonsson, Ed Reznik, Jianjiong Gao, Rona Yaeger, Michael F. Berger, Barry S. Taylor, Nikolaus Schultz. Genomic characterization of organ-specific metastasis from prospective clinical sequencing of 20,000 cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3024.

Abstract PD8-07: Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer

Abstract Background: Resistance to endocrine therapy remains a challenge for patients with metastatic hormone receptor positive breast cancer. Mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in patients with endocrine resistance and correlates with reduced survival. The occurrence of mutations in the gene for progesterone receptor (PGR), another important biomarker in breast cancer, has not been reported. Objective: Determine the frequency of mutations in ESR1 and PGR in patients with newly diagnosed metastatic ER+ breast cancer treated with adjuvant endocrine therapy at our institution, and identify whether these mutations are associated with worse patient survival. Methods: This is an IRB-approved, HIPAA-compliant retrospective study of patients with ER+ metastatic breast cancer identified from our comprehensive cancer center registry. Eligible patients must have received at least 6 months of adjuvant endocrine therapy with biopsy-proven diagnosis of metastatic or locally recurrent disease. Next-generation sequencing of the coding regions of ESR1 and PGR was performed on extracted tumor genomic DNA. Analysis was limited to protein coding mutations. Clinicopathologic data was collected and correlated with the genomic information for each patient. Associations between mutation status and clinicopathologic factors were analyzed using Fisher's exact test. Kaplan-Meier method with log-rank test was used to analyze overall survival (OS) from time of metastatic diagnosis. Results: The study included 35 women (35-88 yr old). Metastatic sites included bone (N=13), brain (N=6), chest wall (N=2), liver (N=4), lung/pleura (N=4), and lymph nodes (N=6). PGR mutations were identified in 66% of patients (23/35; 95%CI 48-81%), and were more common than ESR1 mutations (10/35; 29%; 95%CI 15-46%). Mutations in both PGR and ESR1 were identified in 26% (9/35), and neither mutation was identified in 31% (11/35). Neither mutation was associated with prior adjuvant aromatase inhibitor or tamoxifen therapy. There was no significant association between ESR1 or PGR mutations and metastatic site, although 75% (3/4) of patients with liver metastases had an ESR1 mutation compared to 23% (7/31) without liver metastases (p=0.061). The differences in median OS between ESR1 wildtype vs mutant (1.6 mo vs 1.0 mo, p=0.14) and PGR wildtype vs mutant (2.6 mo vs 1.3 mo, p=0.56) were not significant. However, patients with both mutations may have worse median OS compared patients with neither or only one mutation (1.0 mo vs 1.6 mo vs 4.0 mo, p = 0.073). Conclusions: The overall survival of metastatic ER+ breast cancer patients with ESR1 or PGR mutations were not statistically significant compared with those without mutations. Despite the small sample size, there is a trend that patients with mutations in both genes may have worse survival. To the best of our knowledge, the PGR mutation rate in metastatic breast cancer has not previously been reported. Interestingly in our data set, PGR mutations were identified more commonly than mutations in ESR1. The significance of PGR mutations is not known, nor whether this could be a future indicator of treatment resistance or a target for therapy. Citation Format: Fowler AM, Rassman S, DeGrave M, Ong I, Powers GL, Salem K, Kumar M, Woo K, Mahajan AM. Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-07.

Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma.

The current study was conducted to better characterize the association between overall survival (OS) from metastatic thyroid cancer and the rate of structural disease progression. In this retrospective study, the average tumor volume doubling time (midDT) of 2 dominant lung metastases was used to group patients into 6 clinically relevant cohorts. OS was calculated from the time of metastasis diagnosis and from the time the pulmonary lesions crossed over the 1-cm diameter threshold. The tumor growth rate was remarkably constant in lung metastases from thyroid cancer over a median follow-up of 8.5 years (median correlation coefficient, 0.92; coefficient of determination, 0.85). Patients with a midDT ≤1 year were found to have worse OS compared with those with a higher midDT (log-rank P = .01). The 5-year OS rate from the 1-cm diameter time point was 20% for patients with a midDT ≤1 year (15 patients), 50% for patients with a midDT of 1 to 2 years (19 patients), 53% for patients with a midDT of 2 to 3 years (9 patients), 80% for patients with a midDT of 3 to 4 years (6 patients), and 80% for patients with a midDT of ≥4 years or who were negative (12 patients). Within the group of patients with a midDT ≤1 year, the 2-year OS rate from the 1-cm diameter point was 88% in the patients treated with multikinase inhibitors (8 patients) versus 43% in the nontreated group (7 patients) (P = .13). The midDT of lung metastases appears to be a good prognostic indicator of OS in patients with metastatic thyroid cancer. Unlike the thyroglobulin DT, the midDT alone can be used to predict eligibility for multikinase inhibitor therapy. Cancer 2017;123:2955-64. © 2017 American Cancer Society.

Abstract 172: Managing metastatic breast cancer via serial monitoring with circulating cell-free tumor DNA next generation sequencing testing

Abstract Background: Metastatic breast cancer (MBC) is an incurable disease with complex molecular features including somatic mutations that evolve in relation to genomic instability and selective treatment pressure. Patients with treatment-refractory MBC may benefit from tumor genomic evaluation using next generation sequencing (NGS). Furthermore, analysis of circulating tumor DNA (ctDNA) in patients with advanced disease offers the possibility of non-invasive molecular monitoring. Methods: A patient with MBC was tested at each progression with a ctDNA NGS panel (Guardant360™) that includes all NCCN-recommended somatic genomic variants for solid tumors and sequences complete exons of >50 genes to report single nucleotide variants (SNVs), fusions, amplifications, and indels with high sensitivity and ultra-high specificity (>99.9999%). The patient was diagnosed with invasive breast cancer at age 44 and treated with surgery and hormonal therapy. At age 61, she had axillary adenopathy and liver metastases. Treatment details are in Table 1. Results: ctDNA analysis was performed at the time of metastatic diagnosis and at 5 additional time points over the course of treatment. All samples revealed an ERBB2 exon 19 indel (p.Leu755_Glu757delinsSer), and multiple SNVs and gene amplifications. ERBB2 amplification was seen in 4 of 6 samples. Mutant allele fractions (Table 1) correlated with clinical response to treatment and progression. Conclusions: Analysis of ctDNA in this patient identified an ERBB2 exon 19 indel, which are present in 2-4% of non-small cell lung cancers but 1-2% in breast cancer. Treatment with anti-HER2 monoclonal antibody or dual anti-EGFR/ERBB2 tyrosine kinase inhibitor therapies may show clinical benefit. ctDNA analysis can detect emergence of actionable resistance mutations with the advantage of serial evaluation, allowing capture of inter- and intra-tumor heterogeneity and illustration of molecular progression and response. Table 1.Blood DrawDisease status at time of blood drawMutant allele fraction of ERBB2 indel (* = ERBB2 amplification)Treatment1Initial diagnosis9%trastuzumab, pertuzumab and docetaxel (TPD), cycle 12Stable disease1%*TPD cycle 23Progressing10%*TPD cycle 34Progressing62%*trastuzumab, emtansine (TDM1) 3 cycles5Progressing70%*vinorelbine, trastuzumab, everolimus6Partial response1%flourouracil, epirubicin, cyclophoasphamide Citation Format: Laura Austin, Rebecca Nagy, Oliver Zill, Richard B. Lanman, AmirAli Talasaz, Massimo Cristofanilli. Managing metastatic breast cancer via serial monitoring with circulating cell-free tumor DNA next generation sequencing testing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 172.

Metastatic solid tumors to the jaw and oral soft tissue: A retrospective clinical analysis of 44 patients from a single institution.

Metastatic solid tumors to the oral cavity are rare, frequently indicative of an end-stage disease process, and associated with poor survival rates. We performed a 20-year retrospective clinical analysis of our institution's cases of solid metastases to the oral cavity, and investigated these patients' clinical outcomes. A retrospective study of patients with metastatic solid tumors to the oral cavity over a 20-year period (October 1996 to September 2015) was conducted at Memorial Sloan Kettering Cancer Center. Patients were selected if they had a histopathologically confirmed diagnosis. Demographic, pathologic, and clinical information were reviewed to identify patient outcomes. A total of 44 patients with metastatic non-melanocytic non-hematopoietic tumor to the oral cavity were identified: 24 males and 20 females (39 adults and 5 children) with a mean age of 54.3 years. In all, 24 cases involved the jaw and 20 cases involved the oral soft tissue. Eight patients (18.2%) had oral cavity metastases as the first indication of an occult malignancy. In adult patients, the common primary sites were the lungs (n=9, 20%), kidney (n=7, 16%), breast (n=5, 11%), and colon (n=4, 9%); and in pediatric patients the adrenal gland (3/5) was the most common site. Of the adult patients, 33 (84.6%) died of disease. From the time of metastasis diagnosis, patients with jaw metastases had a median and mean survival of 12 months and 27.7 months, respectively. In comparison, patients with oral soft tissue metastases had a median survival time of 5 months, and mean of 8 months. One pediatric patient (20%) died of disease 8 months after metastasis diagnosis. Metastatic solid tumors to the oral cavity can be the first sign of a malignancy. Pediatric patients with oral cavity metastases have a better prognosis compared to adult patients. In this series, adults with oral soft tissue involvement had shorter survival times compared to patients with jaw involvement.

Abstract P3-12-12: Incidence of internal mammary node, sternum, and manubrium failure as detected by FDG-18 PET/CT

Abstract Introduction: Elective radiotherapy to the internal mammary (IM) lymph nodes remains an ongoing subject of debate. While the incidence of occult IM involvement on extended mastectomy ranges from 15-65%, reported rates of IM failure are substantially lower (approximately 1%). Interest in this subject has resurfaced recently as randomized trials have shown a survival benefit to adjuvant regional node irradiation including the IM chain. The mechanism by which extended field radiotherapy leads to improved systemic outcomes has not been clearly demonstrated and the degree of benefit directly attributable to IM irradiation remains to be seen. We hypothesized that the IM lymphatic chain may provide a direct route for tumor cell dissemination into the the sternum or manubrium. As such, sternal metastases may be a manifestation of IM involvement rather than true hematogenous metastases. We sought to better elucidate patterns of failure by evaluating the incidence and timing of IM, sternal, or manubrial involvement identified by PET/CT imaging following diagnosis of metastatic breast cancer. Patients and Methods: Between 2007 and 2014, 96 patients with invasive breast cancer were found to have metastatic disease as diagnosed on FDG-18 PET/CT. Site of recurrence was scored as breast/chest wall, axilla/supraclav, IM chain, sternum/manubrium, or distant. IM or sternum/manubrium failure was scored as isolated (occurring without distant metastatic disease), synchronous (involved at initial diagnosis of distant metastatic disease), or metachronous (involved at any time after diagnosis of metastatic disease). Results: Isolated IM failures were observed in 3.1% of patients while isolated sternum/manubrium failures were recorded in 7.3% of patients. Isolated involvement of the sternum/manubrium or IM nodes occurred in 11.4%. The rate of synchronous IM failure was 11.4% with the rate of metachronous failure being 13.5%. The rate of synchronous sternum/manubrium failure was 17.7% with the rate of metachronous failure being 23.9%. The incidence of sternum/manubrium or IM involvement at the initial diagnosis of distant metastatic disease was 29.2% with the rate of involvement at any point increasing to 36.5%. Conclusion: The rate of internal mammary node failure by PET/CT at the time of metastatic diagnosis is higher than the incidence reported in previous trials. This discrepancy is likely due increased sensitivity of PET/CT and the difficulty of accurately assessing this region once patients have been found to have metastatic disease. Interestingly, sternum and manubrium were more often the first site of recurrence than the IM nodes. This could be due to a tropism of hematogenous metastases for these bones or could represent direct tumor cell dissemination from the internal mammary chain. This is of special interest as this region is incidentally included in the radiotherapy fields when targeting the IM nodes. Overall, our findings suggest that historic patterns of failure studies may underestimate the local benefit of internal mammary node radiotherapy. Citation Format: Grow JL, Choudhary G, Kuo P, Livingston RB, Gonzalez VJ. Incidence of internal mammary node, sternum, and manubrium failure as detected by FDG-18 PET/CT. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-12.

Incorporating trans-arterial radioembolization (TARE) in the treatment of metastatic pancreatic adenocarcioma: A single center experience.

346 Background: There is a lack of data on the potential efficacy of the incorporation of trans-arterial radioembolization (TARE) for metastatic pancreatic adenocarcinoma. We retrospectively evaluated the efficacy of TARE in the management of patients with liver dominant metastatic pancreatic adenocarcinoma Methods: Sixteen patients were treated with concurrent systemic therapy and TARE for liver-dominant pancreatic adenocarcinoma from February, 2014 to August, 2015. Electronic chart review was performed for this group of patients to assess response Results: Eleven male and 5 female patients were treated for liver dominant metastatic pancreatic adenocarcinoma with Yttrium-90 resin microspheres. The average age was 64 (50 - 77). All patients were treated with at least one line of systemic therapy. Five had prior or concurrent SBRT treatment for the primary lesion. Eleven patients had extra-hepatic disease with evidence of nodal, pulmonary and/or omental disease on pretreatment imaging. All patients had adequate hepatic reserve and functional status at treatment. Eight of the 16 patients were alive at the time of analysis. The median overall survival from diagnosis of liver metastases to time of analysis is 22 months (11 – 50, 95% CI). The median time of survival from TARE is 12.5 months (4 – not reached, 95% CI). The estimated survival rate at 6 months, 1 year, 2 year and 3 years from diagnosis is 100%, 84%, 39% and 26%. Follow up imaging was available on 13 patients. Local PR, SD and PD based on RECIST criteria were seen in 4 (31%), 7 (54%) and 2 (15%) patients. The average local and systemic PFS was 4.9 and 3.4 months, respectively Conclusions: We found promising results for the incorporation of TARE in the treatment of patients with metastatic pancreatic adenocarcinoma. In our cohort, the median overall survival from the time of metastatic diagnosis was 22 months, a significant improvement from the expected median survival. Although our data is promising, there are inherent weaknesses of our study due to the small number of patients and its retrospective nature. Further studies are needed to validate our findings. For this purpose, a prospective trial is currently being in development.

Metastases to the kidney: a comprehensive analysis of 151 patients from a tertiary referral centre.

To describe the presentation, treatment and outcomes of patients with metastatic tumours to the kidney treated at a tertiary referral centre. We retrospectively identified 151 patients diagnosed with a primary non-renal malignancy with renal metastasis. Clinical, radiographic and pathological characteristics were assessed. Overall survival (OS) was calculated using Kaplan-Meier methods. The median patient age was 56.7 years. The most common presenting symptoms were flank pain (30%), haematuria (16%) and weight loss (12%). Most primary cancers were carcinomas (80.8%). The most common primary tumour sites were lung (43.7%), colorectal (10.6%), head and neck (6%), breast (5.3%), soft tissue (5.3%) and thyroid (5.3%). Renal metastases were typically solitary (77.5%). Concordance between radiologist and clinician imaging assessment was 54.0%. Three ablations and 48 nephrectomies were performed. For non-surgical patients, renal metastasis diagnosis was made with fine-needle aspiration or biopsy. The median OS from primary tumour diagnosis was 3.08 years and the median OS from time of metastatic diagnosis was 1.13 years. For patients treated with surgery, median OS from primary tumour diagnosis was 4.81 years, and OS from metastatic diagnosis was 2.24 years. Metastases to the kidney are a rare entity. Survival appears to be longer in patients who are candidates for and are treated with surgery. Surgical intervention in carefully selected patients with oligometastatic disease and good performance status should be considered. A multidisciplinary approach with input from urologists, oncologists, radiologists and pathologists is needed to achieve the optimum outcomes for this specific patient population.

Can neutrophil-to-lymphocyte ratio be used to identify patients with metastatic renal cell carcinoma who may gain greater benefit from cytoreductive nephrectomy?

490 Background: Two randomized trials demonstrated survival benefits associated with cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the interferon era. However, the role of CN in the era of targeted therapies is yet to be defined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a clinically useful prognostic marker in several cancers including mRCC. In this multi-center retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. Methods: Patients with de novo mRCC diagnosed between 2006 and 2012 from three large Australian hospitals were identified using an electronic database. Data regarding clinicopathological features, MSKCC risk group, NLR at the time of metastatic diagnosis, treatments received and survival were collected. NLR ≥5 was used as the cutoff for statistical analyses. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses used the Cox proportional hazards method. Results: Our study identified 91 de novo mRCC patients. CN was performed in 46 (51%) patients. Patients who underwent CN were more likely to be younger (median age 59.0 vs. 64.6, p=0.019), and to have received systemic therapy post CN (91% vs. 76%, p=0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 mo vs. 10.9 mo, p=0.039). Patients with NLR <5 also had superior mOS (16.7 mo vs. 6.2 mo; HR 0.53; 95% CI; 0.24-0.84; p=0.013). While CN was associated with substantially improved survival in patients with both NLR <5 (mOS 31.1 mo vs. 7.0 mo; HR 0.41; 95% CI, 0.18-0.64; p=0.0009) and NLR ≥5 (mOS 10.9 mo vs. 2.3 mo; HR 0.33; 95% CI, 0.11-0.69; p=0.009), the absolute survival difference was greater in patients with baseline NLR <5. Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.31; 95% CI, 0.18-0.55; p<0.0001). Conclusions: CN is associated with significantly improved OS in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR.

The proportion and characterization of patients with metastatic renal cell carcinoma who are never treated or have delayed treatment with targeted therapy: Results from a large prospective cohort.

424 Background: The proportion and characterization of patients (pts) with metastatic renal cell carcinoma (mRCC) who never start or delay starting targeted therapy (TT) is unknown. It is important to understand and characterize these pts. Methods: Data from the Canadian Kidney Cancer information system (CKCis) database were utilized. CKCis data were collected prospectively from 14 REB-approved academic centers in Canada. The study population included pts with mRCC managed from 2006 (when VEGFR TT became available) to 2014. Results: 920 pts met the inclusion criteria, but 67 pts had <6 months (mo) follow up and were excluded. Thus, 853 pts make up the study cohort with a median follow up of 21 mo. The cohort was divided into 3 groups: early (started TT within 6 mo), delayed (started TT after 6 mo), and never (never started TT). The groups consisted of 406 pts (47.6%), 182 pts (21.3%), and 265 pts (31.1%), respectively. In those that started TT, median time to initiation was 3.2 mo; 69% by 6 mo, 82% by 12 mo, 92% by 24 mo, and 99.7% by 5 yrs. Multiple baseline characteristics were determined, compared, and will be presented. On univariable analysis, pts never treated were older, had a longer interval from original diagnosis to metastases (mets), fewer metastatic sites, fewer liver mets, more lung-only mets, more metastectomies, and less radiation (RT). On Cox regression analysis, pts were less likely to initiate TT if they were older, had earlier year of diagnosis of mets, had metastectomy, never had RT, fewer sites of mets, and brain mets. Median survival from time of metastatic diagnosis was 1.53 yrs, 3.54 yrs, and 1.41 yrs in the early, delayed, and never treated groups, respectively. Conclusions: 31% of pts with mRCC never received TT in this cohort of pts treated in academic centers, which may underrepresent the reality in the community. Baseline characteristics in the delayed treatment group were better and likely represent a more indolent biology. More data on the untreated group will be presented as it comprises a heterogenous group of pts: potentially those lost to follow up, those treated with metastectomy, pts too ill with limited survival, and pts felt to have excellent outcomes without treatment.

Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations

ObjectivesThe aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations. MethodsWe retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol. ResultsOf 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with <30 pack-years, and 14.9% were smokers with ≥30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥30 pack-years were significantly lower than never-smokers and smokers with <30 pack-years (DCR, 78.8% vs. 93.1%, p=0.016; ORR, 45.5% vs. 62.4%, p=0.020). Smokers with ≥30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p=0.001) and smokers with <30 pack-years (6.4 vs. 11.4 months, p=0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p=0.003). There was no survival difference between smokers with <30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15–3.05; p=0.012). ConclusionsCigarette smoking dosage of ≥30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations.

Prognostic value of quantitative fluorodeoxyglucose measurements in newly diagnosed metastatic breast cancer

The aim of this study was to determine the prognostic value of quantitative fluorodeoxyglucose (FDG) measurements (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) in patients with newly diagnosed metastatic breast cancer (MBC). An IRB-approved retrospective review was performed of patients who underwent FDG positron emission tomography (PET)/computed tomography (CT) from 1/02 to 12/08 within 60 days of diagnosis MBC. Patients with FDG-avid lesions without receiving chemotherapy in the prior 30 days were included. Target lesions in bone, lymph node (LN), liver, and lung were analyzed for SUVmax, MTV, and TLG. Medical records were reviewed for patient characteristics and overall survival (OS). Cox regression was used to test associations between quantitative FDG measurements and OS. A total of 253 patients were identified with disease in bone (n = 150), LN (n = 162), liver (n = 48), and lung (n = 66) at the time of metastatic diagnosis. Higher SUVmax tertile was associated with worse OS in bone metastases (highest vs. lowest tertile hazard ratio [HR] = 3.1, P < 0.01), but not in LN, liver or lung (all P > 0.1). Higher MTV tertile was associated with worse OS in LN (HR = 2.4, P < 0.01) and liver (HR = 3.0, P = 0.02) metastases, but not in bone (P = 0.22) or lung (P = 0.14). Higher TLG tertile was associated with worse OS in bone (HR = 2.2, P = 0.02), LN (HR = 2.3, P < 0.01), and liver (HR = 4.9, P < 0.01) metastases, but not in lung (P = 0.19). We conclude measures of FDG avidity are prognostic biomarkers in newly diagnosed MBC. SUVmax and TLG were both predictors of survival in breast cancer patients with bone metastases. TLG may be a more informative biomarker of OS than SUVmax for patients with LN and liver metastases.Measures of fluorodeoxyglucose (FDG) avidity are prognostic biomarkers in newly diagnosed metastatic breast cancer. Volumetric measurements, such as total lesion glycolysis (TLG), may be more informative biomarkers for survival than the more commonly used standardized uptake value (SUV).

Do anti-angiogenic therapies prevent brain metastases in advanced renal cell carcinoma?

BackgroundWe analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). MethodsData from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. ResultsOne hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR=0.58 [0.26-1.30], P=0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P=0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR=0.53 [0.22-1.32]). ConclusionIn this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Widespread Microscopic Gastrointestinal Metastases: An Unusual Presentation of Breast Cancer

Purpose: Breast cancer is second only to melanoma in malignancies that metastasize to the gastrointestinal tract in women. In most cases, primary breast malignancy has been described at the time of metastatic diagnosis, and in many cases, evidence of metastatic disease has been confirmed by endoscopy or radiologic studies. We describe a rare case of diffuse microscopic gastrointestinal metastases as the initial presentation of breast cancer. Case Report: A 55-year-old white female presented with several months of nausea, emesis, and diarrhea. Her past medical history was notable only for gastroesophageal reflux disease. She had a known family history of breast cancer. The patient underwent upper endoscopy and colonoscopy. The gastric, duodenal, and colonic mucosa appeared grossly normal. Random biopsies taken from these areas were positive for malignant cells in all three locations. Stains of these cells were positive for Estrogen Receptors, Progesterone Receptors, GCDFP-15, and Mammoglobin, indicating adenocarcinoma of breast origin. The patient had had a routine screening mammography six months prior which was interpreted as benign, and consistent with fibrocystic disease. Subsequent mammography demonstrated the same findings. A PET scan and nuclear bone scan were negative for metastatic disease elsewhere. Her CA 27-29 level was elevated. The patient was treated with chemotherapy, after which her GI symptoms resolved. Discussion: 14-35% of patients who die from breast cancer have evidence of luminal gastrointestinal metastases at autopsy. To our knowledge, this is only the second case report of breast cancer presenting de novo as luminal metastases. In the other de novo case report, the primary breast malignancy was later identified. In this case, the primary tumor was never discovered. Additionally, the luminal metastases were discovered by random biopsies, with no gross evidence of abnormalities on endoscopy. Our case highlights several pertinent clinical points. Clinicians must be aware that breast cancer has a high incidence of metastases to the GI tract. Endoscopy with random biopsies should be considered in any patient with a history of breast cancer who presents with GI symptoms, to evaluate for obvious or occult metastatic disease. If malignant cells are identified on histology, immunohistochemical analysis should be performed to differentiate between metastatic and primary disease.