Massachusetts General Hospital Cancer Center Research Articles

RNA-based fusion testing in gastrointestinal (GI) carcinomas: A single-institution experience.

RNA-based fusion testing in gastrointestinal (GI) carcinomas: A single-institution experience.

Patient-Reported Outcomes, Tumor Markers, and Survival Outcomes in Advanced GI Cancer

Patient-reported outcomes (PROs), such as quality of life (QOL) and symptoms, are often associated with clinical outcomes in patients with cancer. In practice, oncologists use serum tumor markers (TMs) (ie, carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA 19-9]) and imaging to monitor clinical outcomes in patients with gastrointestinal cancer. To examine associations of 1-month changes in PROs and TMs with treatment response and survival among patients with gastrointestinal cancer. This cohort study enrolled patients at Massachusetts General Hospital Cancer Center with at least 1 month follow-up from May 2019 to December 2020. Included patients were beginning first-line systemic therapy, aged 18 years or older, and had been diagnosed with metastatic pancreaticobiliary, colorectal, or gastroesophageal cancer. Data analyses took place from January 2021 to January 2022. PROs were collected, including QOL (Functional Assessment of Cancer Therapy General [FACT-G]), physical symptoms (Edmonton Symptom Assessment System [ESAS]), and psychological symptoms (Patient Health Questionnaire-4 [PHQ4] total, PHQ4-depression, and PHQ4-anxiety), as well as TMs (CEA and CA 19-9), at the time of chemotherapy initiation and 1 month later. Associations of 1-month changes in PROs and TMs with treatment response (clinical benefit vs disease progression) at first scan, progression-free survival (PFS), and overall survival (OS), adjusted for baseline values using regression models. This study included 159 patients, with 134 patients (84.3%) evaluable for analysis. Patients had a median (range) age of 64.0 (28.0-84.0) years and 86 (64.2%) were male. One-month PRO changes (FACT-G: OR, 1.07; 95% CI, 1.03-1.11; P = .001; ESAS-total: OR, 0.97; 95% CI, 0.94-1.00; P = .02; ESAS-physical: OR, 0.96; 95% CI, 0.92-1.00; P = .03; PHQ4-depression: OR, 0.67; 95% CI, 0.49-0.92; P = .01) were significantly associated with treatment response, but PHQ4-total or TMs were not. Changes in FACT-G (HR, 0.97; 95% CI, 0.95-0.99; P = .003), ESAS-total (HR, 1.03; 95% CI, 1.01-1.05; P = .004), ESAS-physical (HR, 1.03; 95% CI, 1.00-1.05; P = .02), PHQ4-depression (HR, 1.22; 95% CI, 1.01-1.48; P = .04), and CEA (HR, 1.00; 95% CI, 1.001-1.004; P = .001) were associated with PFS, but changes in PHQ4-total or TMs were not. Changes in ESAS-total (HR, 1.03, 95% CI, 1.01-1.06; P = .006) and ESAS-physical (HR, 1.04, 95% CI, 1.01-1.06; P = .015) were associated with OS, but changes in TMs were not associated with OS. These findings suggest that 1-month changes in PROs can be associated with treatment response and survival in patients with advanced gastrointestinal cancer. Notably, 1-month changes in TMs were not consistently associated with these outcomes. These findings highlight the potential for monitoring early changes in PROs to associate with clinical outcomes while underscoring the need to address the QOL and symptom concerns of patients with advanced cancer.

Study protocol for NeuroCARE: a randomised controlled trial of a psychological intervention for caregivers of patients with primary malignant brain tumours

IntroductionCaregivers of patients with primary malignant brain tumours experience substantial psychological distress while caring for someone with a progressive, life-limiting neurological illness. However, there are few interventions aimed at addressing...

Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Belzutifan treatment of Von Hippel-Lindau (VHL) related central nervous system (CNS) hemangioblastomas (HBs): A single institution experience.

2078 Background: Patients with inactivating germline mutations in the VHL gene develop CNS (brain and/or spine) HBs and/or renal cancers, pheochromocytomas and pancreatic neuroendocrine tumors. The oral HIF2a inhibitor belzutifan has been approved by FDA for the treatment of VHL-related HBs. We present here data on a cohort of VHL patients with CNS HBs treated with belzutifan in a single institution. Methods: Adult VHL patients, with radiologically documented CNS (brain and/or spine) HBs that displayed documented growth within the last 6 months prior to therapy, were treated with an initial dose of 120 mg belzutifan orally per day. Target lesions included HBs > 0.4cm long in one maximal cross-sectional diameter. Lesions were imaged by MRI at 1.5, 3, 6 months after initiation of treatment and at 6-month intervals thereafter. Solid enhancing lesions, associated cysts and peritumoral edema were recorded and quantified. Tumor sizes were evaluated by RECIST 1.1 criteria and volumetric analysis. All patients were evaluated and treated in the Hemangioblastoma Center and the VHL Clinic of the Massachusetts General Hospital Cancer Center. Results: At the time of analysis, 9 females and ten 10 male VHL patients (n=19) have been treated. Median age at treatment initiation was 36 yo (range 19-59). Median follow up is 12 months (range 1-19.5 months). Two patients were not yet evaluable for response. Of 17 evaluable patients, 8 had a PR (ORR 47%; 95% CI, 34-60), 8 had SD and 1 patient had progression (PD, 5.8%). Two patients had dose reduction to 80 mg/d because of anemia. No patient had grade 3 or greater toxicity and no patient experienced a CNS related toxicity during treatment. Volumetric analysis of solid and cystic components of the lesions, VHL germline mutations and other correlates of response to belzutifan will be presented. Conclusions: Real world data collected at a single institution confirm the high response rate of both solid and cystic components of CNS HBs to the FDA approved HIF2a inhibitor, belzutifan. Belzutifan was well tolerated. Further prospective controlled studies addressing the optimal dose, schedule and duration of treatment of HBs with belzutifan are required.

Prognostic value of TP53 mutation status in metastatic triple-negative and hormone receptor-positive breast cancer using cell-free DNA genomic profiling.

e13099 Background: TP53 is one of the most frequently mutated genes in metastatic breast cancer (MBC); however, its prognostic role remains undetermined. Plasma-based genotyping via cell-free DNA (cfDNA) is a noninvasive means of assessing the genomic landscape of MBC, accounting for heterogeneity between tumors. This study evaluated the association between TP53 alterations detected via cfDNA and clinical outcomes among patients with hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) and triple-negative breast cancer (TNBC) in a metastatic setting. Methods: cfDNA analyses were performed on plasma samples collected from patients with TNBC and HR+/HER2- BC treated at the Massachusetts General Hospital Cancer Center and Washington University in St Louis using Guardant360, a 74-gene cfDNA sequencing assay. Progression-free survival (PFS) and overall survival (OS) were compared based on TP53 alteration status in cfDNA. Multivariable Cox regression was performed adjusting for age, de novo metastases, number of prior treatments, and immunotherapy. Results: TP53 alterations were found in 187 out of 540 patients with HR+/HER2- BC (34.6%) and 87 out of 117 patients with TNBC (74.4%). The most frequent co-existing mutations with TP53 mutations in TNBC were PIK3CA (27.6%), EGFR (26.4%), and CCNE1 (20.7%). For HR+/HER2- BC, the top co-existing mutations were PIK3CA (51.3%), ESR1 (30.5%), and EGFR (21.9%). Median PFS for patients with TNBC with and without TP53 mutations was 6.8 and 6.5 months, respectively (HR = 1.1, 95% CI 0.6-2.0, p = 0.66). Median OS for patients with TNBC with TP53 mutations was 14.2 months, whereas patients without TP53 mutations did not reach median OS (HR = 2.0, 95% CI 0.9-4.1, p = 0.08). Median PFS and OS for patients with HR+/HER2- BC were stratified by the type of therapy initiated immediately after cfDNA testing. Median PFS for patients who received endocrine therapy with and without TP53 mutations was 13.1 vs. 15.9 months, respectively (HR = 1.1, 95% CI 0.7-1.6, p = 0.78). Median OS with and without TP53 mutations was 40.6 vs. 55.8 months, respectively (HR = 1.4, 95% CI 0.8-2.3, p = 0.25). For patients with HR+/HER2- BC who received non-endocrine-based therapy following cfDNA testing, median PFS was 4.2 vs 5.6 months for those with and without TP53 mutations, respectively (HR = 1.0, 95% CI 0.6-1.7, p = 0.92). Median OS for those with TP53 mutations was 9.9 months and 17.1 months for those without (HR = 1.8, 95% CI 1-3.3, p = 0.05). Conclusions: TP53 alterations were detectable via cfDNA in patients with metastatic HR+/HER2- BC and TNBC and were associated with poor survival suggesting a potential prognostic role. The analysis did not filter out potential clonal hematopoiesis, a limitation of the study. Further study is warranted to determine the association of these mutations with outcomes in the setting of specific treatment regimens.

Loss of IFNgR1 signaling glioblastoma drives resistance to CAR T cell binding avidity and cytotoxicity due to lower downstream expression of ICAM-1

Abstract Though CAR T cell therapy has had success treating hematologic malignancies, these treatments have shown only modest efficacy in solid tumors. Little is known about the necessary molecular components required for CAR T cell cytotoxicity, especially in the context of solid tumors. We investigated the role of IFNgR signaling on solid tumors and discovered across tumor types (including glioblastoma, pancreatic, ovarian and lung) loss of IFNgR1 signaling resulted lower CAR T cell cytotoxicity in vitro and that this was irrespective of target antigen (including endogenous EGFR, IL13Ra2, mesothelin, and exogenous CD19). We also validated this in orthotopic xenograft models of glioblastoma and pancreatic cancer in vivo. CAR T cells exposed to wildtype (WT) or IFNgR1 KO tumor had similar transcriptional profiles, but the tumor cells had different signatures in response to CAR T cell co-culture. Further investigation showed marked upregulation of cell adhesion pathways in WT cells compared to IFNgR1 KO. We utilized microscopy with acoustic force and discovered CAR T cells had lower cell binding avidity to cells lacking IFNgR1 compared to WT cells. Following CAR T cell exposure, Intercellular Adhesion Molecule 1 (ICAM-1) was strongly upregulated at both the transcriptional and protein levels in WT cells but not IFNgR1 KO cells. We overexpressed ICAM-1 on IFNgR1 KO tumor cells and observed that CAR T cell binding avidity and cytotoxicity was restored to that of WT levels. This work highlights the importance of CAR T cell binding avidity and adhesion for optimal cytotoxicity. Better understanding of CAR T cell function will inform future construct design for successful therapies against solid tumors. RCL was supported by T32 GM007306, T32 AI007529, and the Richard N. Cross Fund. ML was supported by T32 2T32CA071345-21A1. SRB was supported by T32CA009216-38. NJH was supported by the Landry Cancer Biology Fellowship. JJ is supported by a NIH F31 fellowship (1F31-MH117886). GG was partially funded by the Paul C. Zamecnik Chair in Oncology at the Massachusetts General Hospital Cancer Center and NIH R01CA 252940. MVM and this work is supported by the Damon Runyon Cancer Research Foundation, Stand Up to Cancer, NIH R01CA 252940, R01CA238268, and R01CA249062.

SABCS 2021 Insights on Breast Cancer Research: An Interview with Dr. Laura Spring.

Laura Spring, MD, a clinical investigator and breast medical oncologist at Massachusetts General Hospital Cancer Center and Harvard Medical School, shared insights on breast cancer research presented at the 2021 San Antonio Breast Cancer Symposium (SABCS).

Study protocol for a randomised trial evaluating the non-inferiority of stepped palliative care versus early integrated palliative care for patients with advanced lung cancer

IntroductionIntegrating palliative care (PC) early in the illness course for patients with serious cancers improves their outcomes and is recommended by national organisations such as the American Society of Clinical...

Evaluating Complete Remission with Incomplete Hematologic Recovery (CRh) As a Response Criterion in Myelodysplastic Syndromes (MDS)

Evaluating Complete Remission with Incomplete Hematologic Recovery (CRh) As a Response Criterion in Myelodysplastic Syndromes (MDS)

Extending Dosing Intervals of Denosumab As a Maintenance Strategy in Multiple Myeloma: A Real-World Experience at a Large Academic Cancer Center

Introduction: Osteolytic bone destruction is a defining characteristic of multiple myeloma (MM) and patients with MM have an increased risk of skeletal related events (SREs) - including pathologic fractures, spinal cord compression, and the need for radiation therapy or surgery to bone - which is a significant source of impaired quality of life and mortality. Bone modifying agents (BMAs), such as bisphosphonates or denosumab, have shown to substantially decrease or delay onset of new SREs. Optimal duration or frequency of a BMA, however, is less clear. Data supporting zoledronic acid administered at an extended dosing interval of every 3 months compared to the traditional 3-4 weeks interval in patients with MM have been previously reported in the Z-MARK study (Raje N, et al. Clin Cancer Res. 2016). Denosumab, an anti-RANKL monoclonal antibody, received approval for the prevention of SREs in patients with MM in early 2018, but there is a paucity of data for extending denosumab dosing intervals as maintenance. Herein, we report real-world observations by characterizing our use, safety and efficacy, and other practical considerations of denosumab administered at extended dosing intervals. Methods: In this retrospective study, patients with MM at Massachusetts General Hospital Cancer Center who received at least two doses of denosumab at extended intervals (>3 months) as a maintenance strategy between January 1, 2018 and September 30, 2019 were identified. The corresponding electronic medical records (EMRs) were reviewed for incidences of new SREs, hypocalcemia, and disease progression including those with bone-related progression requiring change in therapy. Incidences of new SREs were captured by reviewing radiologic reports/EMRs for pathologic and compression fractures and radiation/surgery to treat bone lesions while on treatment. Evaluation of hypocalcemia included the need for intravenous calcium repletion. Results: Over the 21-month period, a total of 194 patients received denosumab at various extended dosing intervals as maintenance. All patients had received monthly BMA preceding the maintenance therapy. Extended dosing intervals were: 3 months, between 3-6 months, and ≥6 months (58.8%, 26.8%, 14.4%, respectively). Majority of the patients (171, 88.1%) had received bisphosphonates prior to denosumab and evidence of bone disease at diagnosis was seen in 169 (87.1%) patients. Time from diagnosis of MM ranged from 0.3 - 17 years; 51.5% and 16.5% were ≥4 years and ≥8 years since diagnosis, respectively. New SREs while on denosumab maintenance occurred in 6 (3.1%) patients; these consisted of vertebral compression fractures and pathologic fractures of humerus and femur requiring surgical interventions or radiation. These SRE events were associated with disease progression and average time from MM diagnosis to these events was 7.9 years (range 6.2 - 9.5 years). Hypocalcemia (≥grade 1) was seen in 29 (14.9%) patients, and among these, only 6 required intravenous calcium repletion. Disease progression requiring change in therapy occurred in 46 (23.7%) patients and 34 (17.5%) patients had bone-related progression. Conclusions: Our data support the use of denosumab extended dosing during maintenance. However, our study has several limitations including retrospective nature of analysis, heterogeneity in the patient pool, and exclusion of patients with more frequent dosing of denosumab. Our experience therefore underscores the need to study denosumab extended dosing prospectively. Disclosures Branagan: Sanofi: Other: Advisory Board; Pharmacyclics: Other: Advisory Board. Yee:GSK: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptide: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Raje:Celgene: Consultancy; Janssen: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy; Amgen: Consultancy. O'Donnell:Celgene: Consultancy.

Association of Peer Comparison Emails With Electronic Health Record Documentation of Cancer Stage by Oncologists

Systematically capturing cancer stage is essential for any serious effort by health systems to monitor outcomes and quality of care in oncology. However, oncologists do not routinely record cancer stage in machine-readable structured fields in electronic health records (EHRs). To evaluate whether a peer comparison email intervention that communicates an oncologist's performance on documenting cancer stage relative to that of peer physicians was associated with increased likelihood that stage was documented in the EHR. This 12-month, randomized quality improvement pilot study aimed to increase oncologist staging documentation in the EHR. The pilot study was performed at Massachusetts General Hospital Cancer Center from October 1, 2018, to September 30, 2019. Participants included 56 oncologists across 3 practice sites who treated patients in the ambulatory setting and focused on diseases that use standardized staging systems. Data were analyzed from July 2, 2019, to March 5, 2020. Peer comparison intervention with as many as 3 emails to oncologists during 6 months that displayed the oncologist's staging documentation rate relative to all oncologists in the study sample. The primary outcome was patient-level documentation of cancer stage, defined as the likelihood that a patient's stage of disease was documented in the EHR after the patient's first (eg, index) ambulatory visit during the pilot period. Among the 56 oncologists participating (32 men [57%]), receipt of emails with peer comparison data was associated with increased likelihood of documentation of cancer stage using the structured field in the EHR (23.2% vs 13.0% of patient index visits). In adjusted analyses, this difference represented an increase of 9.0 (95% CI, 4.4-13.5) percentage points (P = .002) in the probability that a patient's cancer stage was documented, a relative increase of 69% compared with oncologists who did not receive peer comparison emails. The association increased with each email that was sent, ranging from a nonsignificant 4.0 (95% CI, -0.8 to 8.8) percentage points (P = .09) after the first email to a statistically significant 11.2 (95% CI, 4.9-17.4) percentage points (P = .003) after the third email . The association was concentrated among an oncologist's new patients (increase of 11.8 [95% CI, 6.2-17.4] percentage points; P = .001) compared with established patients (increase of 1.6 [95% CI, -2.9 to 6.1] percentage points; P = .44) and persisted for 7 months after the email communications stopped. In a quality improvement pilot trial, peer comparison emails were associated with a substantial increase in oncologist use of the structured field in the EHR to document stage of disease.

ESMO Virtual Congress 2020.

Sacituzumab govitecan significantly improved survival over standard chemotherapy in patients with metastatic triple-negative breast cancer (TNBC), according to the randomised, phase 3, ASCENT trial presented by Aditya Bardia (Massachusetts General Hospital Cancer Center, Boston, MA, USA). 468 patients who had relapsed on at least two chemotherapy regimens were randomly assigned (1:1) to sacituzumab govitecan (10 mg/kg intravenous on day 1 and 8, every 21 days) or single-agent chemotherapy. Median progression-free survival (PFS) in the brain metastases-negative population (primary endpoint) was 5·6 months (95% CI 4·3–6·3) in the sacituzumab govitecan group versus 1·7 months (1·5–2·6) in the chemotherapy group (hazard ratio [HR] 0·41, 95% CI 0·32–0·52; p<0·0001). The most common grade 3 or worse treatment-related adverse event was neutropenia (51% vs 33%).

SO-26 Clinical efficacy of combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients

While combinations of BRAF inhibitors with EGFR and/or MEK inhibitors have improved efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and durability is limited. Preclinical and correlative studies suggest that targeting BRAF signaling in combination with immune checkpoint inhibition could enhance activity. BRAFV600E CRC patients recruited from the Massachusetts General Hospital Cancer Center or the Dana-Farber Cancer Institute were treated with the PD-1 inhibitor spartalizumab (PDR001) 400mg IV q28d, dabrafenib 150mg PO BID, and trametinib 2mg PO daily. Single-cell RNAseq was performed on paired baseline and day 15 tumor biopsies, patient-derived organoids were established from baseline biopsies, and serial ctDNA was analyzed. To date, 21 BRAFV600E CRC patients have been enrolled (4 MSI, 17 MSS). 5 had prior therapy with BRAF inhibitors and/or immunotherapy. Median age was 64 (range 35-86) and 12 (57%) were female. Regimen was well-tolerated with rash, fever, and diarrhea as the most common AEs. Of 20 patients with at least one restaging scan, ORR was 35% (7/20) and disease control rate of 75%, which compares favorably to the historical 12% ORR of dabrafenib plus trametinib alone in BRAFV600E CRC. 45% (9/20) patients remained on therapy for >6 months, and one MSS patient remains on therapy >16 months with -100% reduction by RECIST. Among 12 MSS patients with no prior BRAF inhibitor or immunotherapy, response rate was 42% (5/12), and all 12 patients exhibited a reduction in tumor size. Response rate in MSI patients was 25% (1/4) with two remaining on therapy >6 months. Serial ctDNA analysis showed profound and sustained reduction in BRAFV600E ctDNA levels in responders and emergence of MAPK pathway alterations upon acquired resistance. Single-cell RNAseq of paired pre-treatment and day 15 on-treatment biopsies revealed increased infiltration by T-cells and other immune populations with therapy, as well as increased expression of cytotoxic genes specifically in the T-cell compartment. Single-cell RNAseq also confirmed inhibition of MAPK signature genes specifically in the tumor cell compartment, as well as induction of antigen presentation genes and other immune-modulatory programs within tumor cells. Patient-derived organoids treated with dabrafenib and trametinib exhibited gene expression changes that mirrored the changes observed in single-cell RNAseq of tumor cells in paired biopsies from the same trial patient from which they were derived. Spartalizumab, dabrafenib, and trametinib was well-tolerated and produced favorable response rates and durability relative to historical controls in BRAFV600E CRC patients. Correlative studies, including single-cell RNAseq of paired pre-treatment and on-treatment tumor biopsies and analysis of patient-derived organoids suggest potential mechanistic links that could underlie cooperativity between BRAF targeting and immune checkpoint inhibition. Updated data will be presented.

490P - Response rates and lesion-level progression patterns of solid tumor patients in an academic phase I program: implications for tumour heterogeneity

BackgroundSequencing studies have demonstrated extensive genetic heterogeneity between and within tumor lesions in treated metastatic solid tumor patients. The response of individual tumor lesions to therapy is a reflection of subclonal inhibition and growth in the face of selective pressure. Are there lesion-level progression patterns that would provide insights into the biological heterogeneity that underpins response and resistance?. MethodsRetrospective review of patients with histologically confirmed metastatic solid tumors who were treated at Massachusetts General Hospital Cancer Center’s phase 1 center from October 1, 2010 to September 30, 2015 and had at least two radiographic assessments, 30 days apart. 769 study participants were enrolled in a phase 1 trial during the study period, of which 575 had at least two radiographic evaluations. 427 participants had more than one lesion at baseline and displayed progression of at least one lesion (growth of at least 20% or a new lesion). We categorized the lesion-level progression patterns of these 427 patients. ResultsStudy participants had a mean of 2.6 prior lines of therapy in the metastatic setting with an average of 6.3 tumor lesions on their baseline scan involving an average of 3 organs. Of the 427 study patients with progressive lesions, 24% of patients had progression at a single lesion and 49% of patients had progression in a single organ when they were taken off-study or at data cut-off. 10% of patients exhibited simultaneous response (shrinkage of at least 30%) and progression in different lesions. Across our entire 575 patient cohort, liver lesions were 2.9 times as likely to progress than other lesions regardless of cancer types. ConclusionsThe significant proportion of patients with progression at a single lesion or organ demonstrates that clonal heterogeneity has important clinical implications. Liver lesions may have microenvironment-specific factors that increase the likelihood of progression relative to other organ sites. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureC. Chen: Advisory / Consultancy: Blackstone Life Sciences; Advisory / Consultancy: HotSpot Therapeutics; Advisory / Consultancy: Foundation Medicine. D. Juric: Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eisai; Advisory / Consultancy: Syros; Advisory / Consultancy: Ipsen; Research grant / Funding (self): Eisai; Research grant / Funding (self): Genentech; Research grant / Funding (self): Celgene; Research grant / Funding (self): Takeda; Research grant / Funding (self): javascript:%20create_table_line(’1’,%20new%20Array(’ent’,%20’des’,%20’tor’));Celgene; Research grant / Funding (self): Placon Therapeutics; Research grant / Funding (self): Syros; Research grant / Funding (self): EMD Serono; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Fatigue in patients on oral targeted or chemotherapy for cancer and associations with anxiety, depression, and quality of life.

Oral treatment (targeted or chemotherapy) for cancer is being increasingly used. While fatigue is a known side effect of intravenous chemotherapy, the rate of fatigue and the impact of fatigue on other patient-reported outcomes are not well described. At Massachusetts General Hospital Cancer Center, 180 adult patients prescribed oral targeted or chemotherapy for various malignancies enrolled in a randomized controlled trial of adherence and symptom management. Patients completed baseline self-reported measures of fatigue (Brief Fatigue Inventory; BFI), anxiety and depressive symptoms (Hospital Anxiety and Depression Scale; HADS), and quality of life, including subscales for physical, social, emotional, and functional well-being ([QOL] Functional Assessment of Cancer Therapy - General; FACT-G). We examined clinically relevant fatigue using a validated cut-off score for moderate-severe fatigue (BFI global fatigue ≥4) and tested the associations with anxiety symptoms, depressive symptoms, and QOL with independent samples t-tests. At baseline, 45 of 180 participants (25.0%) reported moderate-severe fatigue. Fatigued patients experienced more anxiety symptoms (mean diff. 3.73, P < 0.001), more depressive symptoms (mean diff. 4.14, P < 0.001), and worse QOL on the total FACT-G score (mean diff. -19.58, P < 0.001) and all subscales of the FACT-G compared to patients without moderate-severe fatigue. One in four patients on oral treatment for cancer experienced clinically relevant fatigue that is associated with greater anxiety and depressive symptoms and worse QOL.

Patient Experiences With Oral Chemotherapy: Adherence, Symptoms, and Quality of Life.

Oral therapies are increasingly common in oncology care. However, data are lacking regarding the physical and psychologic symptoms patients experience, or how these factors relate to medication adherence and quality of life (QoL). From December 2014 through August 2016, a total of 181 adult patients who were prescribed oral targeted therapy or chemotherapy enrolled in a randomized study of adherence and symptom management at Massachusetts General Hospital Cancer Center. Patients completed baseline assessments of adherence with electronic pill cap, QoL, symptom severity, mood, social support, fatigue, and satisfaction with clinicians and treatment. Relationships among these factors were examined using Pearson product-moment correlations and multivariable linear regression. At baseline, the mean electronic pill cap adherence rate showed that patients took 85.57% of their oral therapy. The most commonly reported cancer-related symptoms were fatigue (88.60%), drowsiness (76.50%), disturbed sleep (68.20%), memory problems (63.10%), and emotional distress (60.80%). Patients who reported greater cancer-related symptom severity had lower adherence (r= -0.20). In a multivariable regression, greater depressive and anxiety symptoms, worse fatigue, less social support, lower satisfaction with clinicians and treatment, and higher symptom burden were associated with worse QoL (F[10, 146]=50.53; adjusted R2=0.77). Anxiety symptoms were most strongly associated with clinically meaningful decrements in QoL (β= -7.10; SE=0.22). Patients prescribed oral therapies struggle with adherence, and cancer-related symptom burden is high and related to worse adherence and QoL. Given perceptions that oral therapies are less impairing, these data underscore the strong need to address adherence issues, symptom burden, and QoL for these patients.

Profile of Daniel A. Haber

Research oncologist Daniel Haber may not have treated patients in years, but they are never far from his mind. “When I started my MD/PhD program at Stanford I thought I could be both a physician and a researcher,” says Haber, director of the Massachusetts General Hospital (MGH) Cancer Center, where he also runs a cancer research laboratory. “But at some point the research became dominant in terms of my interest and my ability. I tried to make up for it by directing my research toward very clinically relevant questions.” Daniel A. Haber. Image courtesy of Mark Karlsberg (Studio Eleven, Newton, MA). Haber’s research focuses on using human genetics to tackle cancer through early diagnosis and targeted treatments. He was among the first to find targetable genetic mutations that cause cancer, discovering a mutation in lung cancer that helped lay the foundation for widespread testing of cancers with treatable mutations. He is also making strides in detecting rare cancer cells circulating in blood, with the goal of early detection and treatment. Haber’s Inaugural Article (1) identifies a signaling pathway that switches on dormant metastatic tumor cells that have spread through blood. This work could lead to ways to prevent cancer from spreading through blood. Haber is the Kurt J. Isselbacher Professor of Oncology at Harvard Medical School and has been a Howard Hughes Medical Institute investigator since 2008. He was elected to the National Academy of Sciences in 2018. Haber’s father taught him the importance of helping people. The elder Haber worked for an organization founded in 1881 to assist Jews fleeing pogroms and that today resettles refugees in the United States. “He had a sense of mission,” Haber says of his father. “He wanted his life to be about doing something that was larger than himself, something meaningful. That was …

Abstract PD8-06: Attitudes towards use of archived biospecimens among patients with cancer

Abstract Background: Oncology research increasingly involves biospecimen collection and data-sharing. Ethical questions have emerged when researchers seek to use archived biospecimens for purposes that were not well defined in the original informed consent document (ICD). We sought to inform ongoing debates by assessing patient views on these issues. Methods: We administered a cross-sectional self administered anonymous paper survey among patients at the Massachusetts General Hospital Cancer Center. Survey questions addressed attitudes towards cancer research and willingness to donate biospecimens, expectations regarding use of biospecimens and protections of research participants, and preferences regarding specific ethical dilemmas regarding use of archived biospecimens. Results are descriptive with comparisons among participants on the sociodemographic and clinical characteristics using chi-square and Fisher's exact tests. Results: 187 patients offered participation agreed and returned the survey (Response rate 66%). Mean age was 59 (range 2 to 91), 81% were women, 86% were white, and 81% were college educated. Among all participants, 67% had breast cancer and 33% metastatic disease. 34% had participated in a clinical trial, 27% had donated tissue for research and 93% indicated willingness to donate tissue for research. The vast majority of participants (94%) expected both that donated tissue would be used to help as many patients as possible and (92%) that privacy of a donors health information would be carefully protected. 33% expected that donated tissue would only be used for research they specifically approved and 44% that data would not be shared with other researchers. We presented 3 hypothetical scenarios in which researchers sought to use stored biospecimens from a breast cancer clinical trial for future research that was not described in the original iICD. For scenario 1, in which the ICD stated tissue would only be used for breast cancer research, 75% supported use of tissue to study other cancers as well. For scenario 2, in which the ICD specified somatic genetic research only, 89% supported use of tissue for germline research if deemed important by investigators. For scenario 3, in which the ICD stated that data would not be shared beyond the investigators, 72% supported data sharing within a national data repository. Only 28% of participants endorsed concerns that a patient could be identified from their genetic information and 12% were concerned with potential harms from donation to biobanks. However, 38% felt that they owned their tissue and should control how it is used. We did not detect significant differences in responses on the basis of sociodemographic characteristics, cancer type, disease stage, or research experience. Conclusion: Patients with cancer are highly supportive of tissue donation for research and expect that donated tissue will be used to to maximize scientific results. They also expect that interests of research participants will be protected. When there is uncertainly regarding the use of archived biospecimens based on historical ICD and inability to recontact research participants, the interest of participants in seeing productive use of their tissue for science should be considered. Citation Format: Peppercorn J, Campbell E, Rabin J, Quain K, Hlubocky F, Colyar D, Sequist L, Bardia A, Horick N, Isakoff S, Mathews D. Attitudes towards use of archived biospecimens among patients with 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 PD8-06.

Abstract A183: Blood-based genomic profiling of cell-free tumor DNA (ctDNA) in patients with biliary tract cancer

Abstract Background: Targeted therapies are increasingly under evaluation in clinical trials for the treatment of biliary tract cancer (BTC), and cell-free tumor DNA assays are an emerging technology for the detection of actionable alterations. Methods: ctDNA analysis was performed in patients with BTC using the CLIA-certified Guardant360 liquid biopsy assay as part of routine clinical care. The assay screens up to 73 genes for single-nucleotide variants (SNVs), 23 for insertions or deletions (INDELs), 18 for copy number variations (CNVs), and 6 for fusions. Results: 855 samples were analyzed from 751 unique BTC patients. Median age was 64 years (range, 29-89), 53% were female, and 631 (84%) had at least one alteration in their first sample. In the 751 patients, the most common genes altered were TP53 (39%), KRAS (15%), PIK3CA (13%), ARID1A (13%), EGFR (11%), FGFR2 (11%), ERBB2 (11%), NF1 (10%), IDH1 (10%), APC (9%), BRAF (9%), MYC (8%), MET (7%), CCNE1 (7%), and FGFR1 (7%). Alterations in DNA damage response genes were also seen, including BRCA2 (6%), BRCA1 (5%), ATM (4%), and MLH1 (1%). The median number of alterations per sample was 3 (range, 0-40). In a clinically annotated dataset from the Massachusetts General Hospital Cancer Center, 112 samples were obtained from 61 unique patients. Among these, 52 (85%) had intrahepatic cholangiocarcinoma (ICC), 3 (5%) had extrahepatic cholangiocarcinoma, and 6 (10%) had gallbladder cancer. 20/61 (33%) patients were treated with targeted therapy. Among 20 patients with both ctDNA and tumor sequencing results, the targetable mutation was found in both ctDNA and tumor tissue in 7/20 (35%), solely in ctDNA in 1/20 (5%), and solely in tissue in 12/20 (60%) patients. The patient with the alteration detected solely in ctDNA had insufficient tissue for analysis; she was found to have an FGFR2 F276C mutation and benefited for 8.5 months from an FGFR inhibitor on a clinical trial. Of the 12 patients whose targetable mutation was not detected in plasma, 10 (83%) had an FGFR2 fusion, 1 had an INDEL in FGFR2 (Leu262_Ala266delinsAsp), and 1 had an FGFR3 splice site mutation. 15/20 (75%) patients treated with targeted therapy were followed with serial ctDNA analysis, and a potential resistance mechanism was identified in 5/15 (33%). All 5 patients had FGFR2-fusion positive ICC and developed mutations in the FGFR2 kinase domain as a potential resistance mechanism to FGFR inhibition, including the FGFR2 V564F gatekeeper mutation in 4/5 patients. Conclusions: In patients with BTC, ctDNA-based genomic profiling can detect alterations in IDH, FGFR, PIK3CA, ERBB2, BRAF, and MET. The technology is still evolving for the detection of FGFR2 fusions, which is hindered in capture-based methods in plasma by the large number of unique breakpoints and fusion partners. ctDNA analysis may also provide a noninvasive mechanism to study resistance to targeted therapy and clonal dynamics in BTC. Citation Format: Lipika Goyal, Robin Kate Kelley, Lesli Kiedrowski, Daniel Catenacci, Kabir Mody, Rachna Shroff, Aparna Parikh, Stephanie Reyes, Jordan R. Maurer, Ryan B. Corcoran, Paul Fanta, Mike Cusnir, Becky Nagy, Richard Lanman, Michael Morse, Benjamin Tan, Milind Javle, Andrew Zhu. Blood-based genomic profiling of cell-free tumor DNA (ctDNA) in patients with biliary tract cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A183.