tbuckley/cabot-search huggingface dataset:
mTORC1 activation assessed in metastatic sample to predict outcome in patients with metastatic breast cancer treated with everolimus-exemestan: Results from the SAFIRTOR study.
Authors: Thomas Denis Bachelot, Isabelle Treilleux, Camille Schiffler, Ivan Bieche, Mario Campone, Anne Patsouris, Monica Arnedos, Paul H. Cottu, Jean-Philippe Jacquin, Florence Dalenc, Valéry Attignon, Etienne Rouleau, Alain Morel, François Legrand, Marta Jimenez, Fabrice Andre
Journal: Journal of Clinical Oncology (2019)

1024 Background: Using samples from TAMRAD study (Treilleux, Ann Oncol, 2015), we previously reported that p4EBP1, a downstream protein of mTOR, was associated with higher benefit to everolimus (eve). SAFIRTOR study was designed to validate clinical utility of this biomarker. Methods: Patients (pts) with ER+, HER2 negative, AI resistant MBC were prospectively included (NCT02444390). All pts had a biopsy of a metastatic site and were then treated with standard eve + exemestane (exe) combination. The primary end point was to validate that p4EBP1 expression is associated with longer PFS in patients treated with eve. 120 evaluable pts were needed for the pre planed statistical analysis. All samples were collected and processed in a standardized procedure in order to allow phophoproteins IHC staining. In addition to p4EBP1, we explored prognostic value of pS6K, pAkt, PTEN and LKB1, together with genomic alterations assessed by NGS and CGH arrays. Results: 150 pts were included, 30 pts had no adequate sample, and further 13 had missing clinical data, 107 were evaluable for primary objective. Median age was 62, they had previously progressed on AI treatment, either in the adjuvant (22 pts) or the metastatic setting (83 pts). 20 were considered as primary hormone resistant, 87 as secondary resistant. The median Allread score for p4EBP1 was 5.5 (range: 0-6.5). Analysis of the primary endpoint showed that p4EBP1 staining above the median is associated with a longer PFS on eve+exe. (median PFS: 9.3 months, 95CI 6.3-13.1 for high p4EBP1 versus 5.8 months, 95CI 3.7-7.8 for low p4EBP1, p = 0.02). Prognostic value of high pEBP1 remained significant when assessed in a multivariate analysis along classical clinico-biological prognostic factors for MBC (HR 0.57, 95%CI 0.38-0.88, p = 0.01). In this AI resistant population, the tumor of 42 (46%), 33 (35%) and 5 (5.3%) pts carried an activating mutation for ESR1, PIK3CA and AKT1, respectively. None of these mutational statuses were correlated to outcome. Conclusions: This prospective study validates p4EBP1 expression analysis to select patients most likely to benefit from everolimus + exemestane. Clinical trial information: NCT02444390.
Immunologic responses in triple-negative breast cancer patients in a randomized phase IIb trial of nelipepimut-S plus trastuzumab versus trastuzumab alone to prevent recurrence.
Authors: Jessica Campf, Guy T. Clifton, Diane F. Hale, Timothy J. Vreeland, Annelies Hickerson, Jarrod P. Holmes, Jennifer Keating Litton, Rashmi Krishna Murthy, Jason Jerome Lukas, Elizabeth A. Mittendorf, George Earl Peoples
Journal: Journal of Clinical Oncology (2019)

556 Background: Breast cancer (BC) patients (pts) expressing low levels of HER2 by (immunohistochemistry (IHC) 1-2+) are not eligible for trastuzumab (Tz). However, in a randomized phase 2b trial, triple negative BC (TNBC) pts demonstrated a significantly better DFS with nelipepimut-S (NPS) + Tz vs Tz alone. Here, we assess the ex vivo and in vivo immune responses (IR) in both arms. Methods: Disease-free pts (n = 275) with HER2 IHC 1-2+, non-amplified BC who were node positive and/or had TNBC were randomized 1:1 to granulocyte-macrophage-colony stimulating factor (GM-CSF) or NPS+GM-CSF. ±NPS was given every 3 weeks x 6 followed by 4 boosters every 6 months (mo). All pts received Tz concurrently for 1 year per label regimen and were followed for recurrence. IR were evaluated ex vivo by clonal expansion of NPS-specific cytotoxic T lymphocytes (CTL) by dextramer-staining/flow cytometry at time points over 3 years. In vivo IR were assessed by delayed type hypersensitivity (DTH) reactions periodically. Results: The trial enrolled 97 TNBC pts; 60 had 4 timepoints available for analysis (37 NPS + Tz pts; 23 Tz pts). The NPS+Tz group exhibited increases in CTL frequencies vs baseline: 208%, 303%, 379% at 18, 24 and 30 mo, respectively. NPS+Tz pts’ mean CTL frequencies increased from 0.029 ±0.001% at baseline to 0.112±0.026% at 30 mo (p = 0.01) compared to Tz pts who were 0.027 ±0.001% at baseline and 0.057 ±0.016% at 30 mo (p = 0.71). Only 4 NPS+Tz pts recurred as compared to 13 in the Tz arm. While limited by low numbers, recurrent NPS + Tz pt did not mount an IR by ex vivo assessment (range: 0.0 - 0.026%) or by DTH (all measurements: 0 mm), while non-recurrent pts mounted both clonal CTL expansion (range: 0.000- 0.33%) and enhanced DTH (range: 0.0- 80.5mm). Conclusions: NPS+Tz combination is more efficacious in generating time-dependent antigen (NPS)-specific CTL by both ex vivo and in vivo measures vs Tz. Based on these preliminary data, it appears that both ex vivo and in vivo IR to NPS were attenuated in pts with TNBC recurrence. Further analysis of read-outs from these assays to validate the relationship of IRs to clinical effect seen with NPS+Tz in TNBC pts is underway. Clinical trial information: NCT02297698.
CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages
Authors: Pengling Jiang, Wenjuan Gao, Tiansi Ma, Rongrong Wang, Yongjun Piao, Xiaoli Dong, Peng Wang, Xuehui Zhang, Yanhua Liu, Weijun Su, Rong Xiang, Jin Zhang, Na Li
Journal: Theranostics (2019)

Rationale: Bone is one of the most common metastatic sites of breast cancer. CD137 (4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study. Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo. Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 blocking antibody (NP-αCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis. Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.
Case 13-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Kenneth B. Miller, Nancy L. Harris
Journal: New England Journal of Medicine (1987)

Presentation of Case First admission. A 20-year-old man was admitted to the hospital because of facial swelling and leukemia.He was well until two weeks earlier, when he began to notice swelling about the left ear, accompanied by a headache. The swelling spread to involve the left earlobe and the upper portion of the neck. One day before admission chills and fever developed, and on the following day he went to another hospital, where he was found to be febrile and to have a white-cell count of 66,000. Cefoxitin and tobramycin were administered by vein, and he was referred . . .
A phase II study of pembrolizumab for HPV-associated papilloma patients with laryngeal, tracheal, and/or pulmonary involvement.
Authors: Sara I. Pai, Aaron D Friedman, Ramon Franco, Ashok Muniappan, Jong Chul Park, Nicholas Paul Campbell, Seth B. Krantz, Phillip C Song, Michiel Bove, Thomas L Carroll, William C Faquin, Anne M. O'Neill, Lori J. Wirth
Journal: Journal of Clinical Oncology (2019)

2502 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 &amp; 11. RRP proliferates in the respiratory tract impacting breathing, swallowing, and voice and carries a 1-4% risk of malignant transformation. There is no curative therapy for RRP. Given the tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts &gt; 12 years of age were treated with pembro 200mg every 3 weeks. Adjuvant surgical debridement of RRP was permitted for airway obstruction but not dysphonia. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease in response out of 21 (assuming &gt; 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). Serial biopsies (up to 8 biopsies/patient over the 24 months of treatment) to identify biomarkers of response and mechanisms of immune resistance (PD-L1 expression, mutations in HLA class I antigen presentation machinery, and tumor mutational burden) are underway. Results: Accrual is complete (n = 21 pts accrued between May 2016 and Jan 2019). Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. As of February 1, 2019, ORR is 43% (9/21) (.95 two-stage CI: 22%-66%) (4 of 11 with juvenile-onset RRP and 5 of 10 with adult-onset RRP disease responded). No complete responses have been observed. Fatigue was the most frequent treatment related adverse event (TRAEs); Grade 3 TRAEs included uveitis and hypophysitis, both were reversible upon pembro discontinuation. The frequency of surgical interventions was reduced in all pts undergoing surgery for airway palliation prior to study entry. Conclusions: Pembro reduces the need for routine surgical interventions based on the response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.
Mother nurture: the link between gardening and health
Authors: Juliet Dobson
Journal: BMJ (2019)

Mark Thomas

With overgrown shrubs, rambling roses, and a relaxed look and feel, the High Maintenance Garden stands out from the manicured perfection of the show gardens and floral marquees at the Chelsea Flower Show.

Created by Sue Hayward for the Motor Neurone Disease Association, this is a garden being reclaimed by …
Blood-based genomic profiling of cell-free DNA (cfDNA) to identify microsatellite instability (MSI-H), tumor mutational burden (TMB) and Wnt/B-Catenin pathway alterations in patients with gastrointestinal (GI) tract cancers.
Authors: James Isaacs, Andrew B. Nixon, Emily Bolch, Katie Quinn, Kimberly Banks, Brent Allen Hanks, John H. Strickler
Journal: Journal of Clinical Oncology (2019)

3552 Background: MSI-H cancers are responsive to immune checkpoint blockade (ICB), but nearly half of all patients experience primary or early treatment resistance. Activation of the WNT/B-Catenin pathway can lead to immune exclusion and may drive resistance to ICB. Methods: 12 patients had stage III (N = 1) or IV (N = 11) MSI-H GI tract (small bowl, colon, or rectal) cancers. Blood samples were obtained after (N = 5) or during (N = 5) ICB. 2 patients did not receive ICB. Blood samples from 8 patients with microsatellite stable (MSS) metastatic colorectal cancer were included as controls. The Guardant Health (Redwood City, CA) Omni 2.0 mb panel was used to analyze cfDNA. We analyzed MSI-H status, TMB, and mutations within the WNT/B-Catenin pathway, including APC, RNF43 and CTNNB1. Results: Of 12 patients with MSI-H GI cancers, 1 sample failed enrichment due to hemolysis. MSI-H was not detected in 2 patients with a history of MSI-H in tissue; however these patients had a complete response to ICB at the time of blood collection. The Omni panel identified MSI-H in the remaining 9 patients with MSI-H disease in tissue. Among 8 control patients with MSS disease in tissue, MSI-H was not detected. Median TMB (mutations/Mb) was greater for MSI-H specimens (109; range 30-807) than for MSS specimens (13; range 6-24). All 8 patients with MSS GI cancers were identified to have APC mutations, and none were found to have CTNNB1 or RNF43 mutations. Of 9 evaluable MSI-H GI cancers, 2 had APC mutations alone. The remaining 7 carried RNF43 mutations (G659fs). All patients with RNF43 mutations were found to have disease progression while on ICB. Among these 7 patients with RNF43 mutations, 6 had additional mutations in APC or CTNNB1. Conclusions: Blood based genomic profiling can identify MSI-H cancers. Patients with MSI-H cancers resistant to ICB in this cohort have mutations in RNF43 as well as additional mutations in APC or CTNNB1, suggesting that co-activation of the WNT/B-Catenin pathway may be biologically important. Further study of the role of WNT/B-Catenin pathway activation in ICB resistance will be pursued using tumor tissue from this cohort.
Quality of end-of-life care for veterans with metastatic cancer and advanced chronic kidney disease.
Authors: Shakira Jeanene Grant, Claire A Richards, Nicholas Burwick, Paul L Hebert, Ann A O'Hare
Journal: Journal of Clinical Oncology (2019)

e18281 Background: Patients with cancer receive less aggressive interventions and higher quality end-of-life care than those with advanced chronic kidney disease (ACKD). However, the relationship between ACKD and cancer and patterns and quality of end-of-life care is poorly understood. Methods: Among a retrospective cohort of all patients with ACKD (estimated glomerular filtration rate &lt; 20 mL/min/1.73m 2 ) who died in Veterans Affairs facilities between 2009-2015 ( N = 9993), we compared dialysis treatment patterns, end-of-life care and family rated quality of care among those who did and did not have a diagnosis of metastatic cancer during the year before death. Data sources included Veterans Affairs clinical and administrative data, Medicare claims, and the United States Renal Data System registry. Family ratings of end-of-life care were based on responses to the Bereaved Family Survey (BFS). We fit logistic regression models and converted the coefficients to predicted probabilities Results: Overall, 1,237(12.4%) patients had a diagnostic code for metastatic cancer during the year before death. These patients were less likely than other patients to have been treated with dialysis before death. In analyses adjusted for patient characteristics and dialysis receipt, patients with metastatic cancer were less likely than other patients to receive intensive procedures (predicted probability: 18.2% vs. 36.2%) and to be admitted to the intensive care unit (ICU) within 30 days of death (30.7% vs. 50.1 %), or die in the ICU (16.2% vs. 33%). These patients were also more likely to receive a palliative care consultation within 90 days of death (46.6% vs. 37%) and to have hospice services at the time of death (55.3% vs. 33.4 %). Family-rated overall quality of care was higher for those with metastatic cancer (59.6% vs. 54.1%). Family members of patients with metastatic cancer also provided more favorable ratings for five individual BFS items including provider listening, informational, emotional support before death and pain control. All comparisons were statistically significant (i.e., P &lt; 0.05). Conclusions: Within a national cohort of US Veterans with ACKD, the presence of metastatic cancer was associated with less dialysis utilization, less intensive medical care, and significantly higher bereaved family ratings of end-of-life care.
Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations
Authors: Emma E. Dutton, Dominika W. Gajdasik, Claire Willis, Remi Fiancette, Emma L. Bishop, Ana Camelo, Matthew A. Sleeman, Margherita Coccia, Arnaud M. Didierlaurent, Michio Tomura, Fernanda Pilataxi, Christopher A. Morehouse, Gianluca Carlesso, David R. Withers
Journal: Science Immunology (2019)

Innate lymphoid cells recirculate through peripheral lymph nodes and contribute to early IFN-γ production after immunization.
Incidence and prognostic factors in patents (pts) with mutant BRAF (mBRAF) metastatic colorectal cancer (mCRC) in Russia.
Authors: Mikhail Fedyanin, Kheda Elsnukaeva, Irina Demidova, Daniil Stroyakovskiy, Yury Shelygin, Alexey Tsukanov, Alexey Ponomorenko, Maria V Panina, Vitaliy Shubin, Fedor Vladimirovich Moiseenko, Larisa Bolotina, Anna Kudryavtseva, Maxim Filipenko, Mikhail Voscoboev, Liubov Yu Vladimirova, Oleg Ivanovich Kit, Anna Stroganova, Svetlana Dranko, Anastasia Senderovich, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2019)

e15035 Background: m BRAF mCRC has the aggressive phenotype. The incidence of such mutation in Europe and the USA is around 8-14%, in Asian countries - 4-8%. The purpose of this population-based study was to determine the incidence and identifying prognostic factors in pts with mBRAF mCRC in Russia. Methods: A multicenter retrospective analysis of clinical data and treatment results of pts with mBRAF mCRC was performed. The main method for determining mutations was a PCR. The main efficacy endpoint was progression free survival (PFS) at the 1 st line. Multivariate analysis was performed using Cox regression model. Results: 437 out of 8646 pts (5%) with a known mutational status had m BRAF (V600E). Clinical data were collected from 119/437 (27.2%): female - 65.5%, average age - 60 years (28-86), MSI-H -10%; the right-sided primary tumor – in 65%, left-sided – in 17%, rectum – in 18%; the primary tumor was removed in 76%; adjuvant chemotherapy was administered in 30%; lung metastases – in 15 %, liver - 45%, peritoneal metastases – in 38%; metastasectomy was performed in 13% pts. The first line was administered in 86 (72%) pts: FOLFIRI / XELIRI - 17 (20%), FOLFOX / XELOX - 50 (58%), FOLFOXIRI - 12 (14%), monotherapy of fluoropyrimidines – in 7 (8%). Bevacizumab was added to chemotherapy at 1 st line in 25 (29%) patients, anti-EGFR – in 8 (9%) pts. PFS at the 1 st line was 7 months: XELOX / FOLFOX - 7, FOLFOXIRI - 7, FOLFIRI / XELIRI - 6 and fluoropyrimidines - 2 months (HR 0.9, 95% CI 0.6-1.1, p = 0.3). None of the clinical or morphological factors except the presence of metastases in the retroperitoneal lymph nodes (HR 2.6, 95% CI 1.3-5.4, p = 0.006) did not have an independent negative prognostic value. Conclusions: In contrast to Western countries the incidence of mBRAF gene in the population of pts with mCRC in the Russia is low and we found a high incidence of localization of the primary tumor in the rectum. We didn’t reveal any prognostic factors except metastases in the retroperitoneal lymph nodes, and didn’t reveal any differences between the usual duplets and standard regimen for such mutation - FOLFOXIRI in term of 1 st line PFS. This suggests we need a prospective randomized study to determine the optimal regimen of chemotherapy at 1 st line for mBRAF mCRC pts.
RAS Mutations Are Not Created Equal
Authors: G. Aaron Hobbs, Channing J. Der
Journal: Cancer Discovery (2019)

In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart different structural and biochemical consequences on KRAS function and that the same KRAS mutation displays tissue-distinct signaling and biological consequences.See related article by Poulin et al., p. 738.
Unraveling the molecular profile underpinning pancreatic tropisms in metastatic clear cell renal cell carcinoma.
Authors: Nirmish Singla, Oreoluwa Onabolu, Layton Woolford, Christina Stevens, Vanina Tcheuyap, Tiffani McKenzie, Qurratulain Yousuf, Yuanqing Ma, Jacob Choi, Ze Zhang, Zhiqun Xie, Tao Wang, Renee McKay, Alana Christie, Ivan Pedrosa, Christopher Przybycin, Payal Kapur, Brian I. Rini, James Brugarolas
Journal: Journal of Clinical Oncology (2019)

e16096 Background: The tropism of cancer metastases is poorly understood yet holds prognostic value. Clear cell renal cell carcinoma (ccRCC) exhibits a broad pattern of metastases, making it an optimal model to study organotropism. Notably, when ccRCC metastasizes to the pancreas (PM) independently of other sites, it is associated with favorable outcomes in patients for unclear reasons. Here, we comprehensively analyzed the clinical and molecular profile of patients with PM. Methods: RCC patients with PM from UTSW and Cleveland Clinic were identified. Clinicopathologic data and oncologic outcomes were analyzed. Whole exome sequencing (WES), RNAseq, and histologic assessment of primary and metastatic tumors from PM patients were conducted. Results: 31 RCC patients with PM were identified. We observed remarkably favorable outcomes in our PM cohort, with a median overall survival (OS) of 10.7 years from metastatic diagnosis and a long latency between initial diagnosis and development of metastasis (median 69 months in patients who were non-metastatic at diagnosis). OS was independent of both metastatic tumor burden and known IMDC prognostic factors. We discovered that tumors from PM patients were markedly uniform and clustered together by gene expression analysis. WES and DNA copy number analyses revealed a high frequency of VHL and PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of 9p, 14q and 4q losses and BAP1 mutations, characteristic of indolent ccRCC. Furthermore, the genomic and histologic features of tumors from patients with PM can be recapitulated in patient-derived xenograft models. Conclusions: To our knowledge, this is the first report to unravel molecular determinants of organotropism, and we highlight that organotropism can be an independent prognostic factor. Understanding tumor heterogeneity may help refine prognostic models for metastatic RCC and hold implications for improved personalization of therapy.