Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach Free

Tumor genomic profiling is a standard component of the diagnostic evaluation of an increasing number of cancer subtypes. Genomic analysis of DNA derived from tumors and patient-matched normal DNA can confirm tumor diagnosis and subtyping, assess for heritable cancer risk, and identify actionable genomic alterations as a guide to therapy selection (1). While retrospective and more recently prospective clinical studies have defined the genomic landscape of common solid tumors, including cancers of the lung, colon, and prostate (2–7), the frequency of actionable genomic alterations remains poorly defined for many rare cancers. In addition, despite recent tumor-agnostic drug approvals, the paucity of data demonstrating the clinical benefit of tumor genomic profiling for patients with rare cancers limits insurance coverage and access to multi-gene next generation sequencing–based tumor genomic profiling with return of results at the point-of-care (8, 9).

To overcome barriers to tumor genomic testing for patients with rare cancers, we initiated the Make-an-IMPACT program to offer free clinical tumor genomic testing worldwide to patients with select rare cancers. Patients were identified through social media outreach and additional crowdsourcing efforts such as partnerships with disease-specific advocacy groups. As opposed to prior discovery-focused crowdsourcing initiatives (10), the Make-an-IMPACT program included clinical MSK-IMPACT tumor sequencing with return of results to patients to allow genomic findings to be used by local physicians to guide treatment selection.

As initial pilot cancer types, we focused on histiocytosis and female patients with germ cell tumors (GCT). Histiocytosis, which includes Langerhans cell histiocytosis and Erdheim–Chester disease, was chosen given its rarity (4–10 cases per 1 million population), and the high likelihood that tumor genomic testing would alter clinical management. Somatic BRAF V600E mutations are present in approximately half of patients with Langerhans cell histiocytosis and Erdheim–Chester disease, and robust and durable responses have been described with BRAF inhibitors for these entities, resulting in FDA approval of vemurafenib for BRAF V600E–mutated Erdheim–Chester disease (11–15). MEK inhibitors have also been shown to confer therapeutic benefit for patients with histiocytosis whose tumors harbor mutations in several MAPK pathway genes including RAS isoforms, ARAF, RAF1, and MAP2K1/2 (16). Female GCT was chosen given the lack of prior knowledge as to the molecular drivers of this rare cancer subtype (incidence of ∼1/100,000 women/year) and the lack of treatment options for cisplatin-resistant disease (17). Patients with a diversity of pediatric and young adult tumors who were never offered tumor genomic profiling due to a lack of availability at their primary treatment site or because of gaps in insurance coverage were also eligible.

The primary goals were to (i) assess the feasibility of recruiting patients with rare cancers for tumor genomic profiling studies through direct-to-patient outreach via advocacy groups and social media platforms such as Facebook and Twitter, (ii) determine whether tumor genomic profiling could identify actionable genomic alterations for patients with treatment refractory rare cancers, and (iii) define the genomic landscape of rare tumor types such as ovarian GCTs that are difficult to study at a single institution due to their low incidence.

Beginning in 2016, patients were screened for eligibility for the Make-an-IMPACT program following a physician referral (49% of patients enrolled), referral by a disease-specific advocacy group (27%) or following collection of contact information via the program website (24%). Following an initial screen to confirm eligibility, patients were sent an enrollment packet by mail, and patients who wished to proceed were then consented by telephone to an Institutional Review Board–approved protocol (NCT01775072), which allows for clinical tumor genomic profiling with return of results to patients as well as subsequent research analyses including whole-exome sequencing (WES). Diagnostic confirmation and clinical tumor genomic profiling were performed at no cost to the patient. Beginning in 2019, Memorial Sloan Kettering Cancer Center (MSK)’s electronic platform for virtual consenting, e-consent, became an option to facilitate these processes. Consent forms were available in a variety of languages and foreign language interpreters were available, if needed, for the consent discussion. Patient demographic and treatment data were collected directly from patients and/or their parent/guardian, if applicable, and through review of outside hospital medical records.

Following consent, a formalin-fixed, paraffin-embedded tumor block or 20 unstained slides and at least one hematoxylin and eosin (H&E) slide were requested from the patient's local physician. Patients were provided with a prepaid postage shipping container with an EDTA blood tube or a nail or saliva kit as a source of germline DNA. Centralized pathology review was performed with a pathology report transmitted to the local physician for all patients to confirm cancer subtype diagnosis and to ensure that sufficient tumor was present in the sample for next generation sequencing. Clinical tumor genomic profiling was performed using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay (18, 19). MSK-IMPACT is an FDA-authorized next-generation sequencing assay that can detect mutations, copy-number alterations, and translocations in up to 505 cancer-associated genes depending on the assay version. While analysis of germline DNA for pathogenic variants in genes associated with increased heritable cancer risk is now routinely performed for MSK patients undergoing MSK-IMPACT testing (20), clinical germline analysis was not performed on patients enrolled in the Make-an-IMPACT study. Select patients also had targeted RNA sequencing to confirm a suspected fusion identified by MSK-IMPACT or to assess for an occult fusion in samples with no identified mitogenic driver mutation (21).

For select patients (n = 59) with ovarian GCTs, leftover sequencing libraries were used to perform WES. Briefly, whole-exome recapture of the MSK-IMPACT tumor and normal sequencing libraries was performed using remaining barcoded library captured by hybridization using either the SureSelectXT Human All Exon V4 (Agilent 5190-4632) or xGen Exome Research Panel v1.0 (Integrated DNA Technologies) according to the manufacturer's protocol. PCR amplification of the postcapture libraries was carried out for eight cycles followed by sequencing as described previously (22). Indel realignment was performed using the Assembly Based ReAligner (ABRA) v.2.1240 and base quality recalibration was performed with GATK v.3.3-041. Somatic mutations were identified using MuTect v.1.1.442 and Vardict v.1.5.1 and recurrently mutated genes were identified using MutSig2CV (22, 23). Cancer cell fraction (CCF) was calculated using ABSOLUTE based on variant allele frequency, purity, and local allelic copy number (24). Mutations with a CCF of at least 0.85 were deemed clonal. Samples with an estimated tumor purity of less than 0.10 by ABSOLUTE were excluded from subsequent analyses. Using final segmentation calls from ABSOLUTE, we defined copy-number events as arm level if the event spanned at least 80% of the arm and affected at least one allele. Arm-level amplifications were defined as arm-level events with an absolute allelic copy number above 1.9 if the tumor sample was not whole-genome doubled or above 2.9 if the tumor sample was whole-genome doubled. We determined whether a tumor sample underwent whole-genome doubling or had a haploid genomic profile by manually evaluating ABSOLUTE solutions (24). We were unable to confidently determine whether any haploid tumors were whole-genome doubled, and therefore whole-genome duplication (WGD) status for these tumors was not included in the comutation plot. Summary visualization of mutational profiles integrated with clinical variables was performed with CoMut (25). The mean fraction of amplified arms with a reciprocal arm-level deletion [reciprocal loss of heterozygosity (RLOH)] was calculated as described previously (26).

All MSK-IMPACT results, including the MSK-IMPACT version used to analyze each individual tumor, and associated clinical data are available via the cBioPortal for Cancer Genomics (https://www.cbioportal.org/study/summary?id=makeanimpact_ccr_2023; ref. 27) and as part of AACR Project GENIE (28). WES BAM files are deposited in dbGAP (Accession #phs001783: Exome Recapture and Sequencing of Prospectively Characterized Clinical Specimens From Cancer Patients).

Between March 8, 2016 and October 10, 2020, 359 patients with cancer expressed interest in the Make-an-IMPACT program, and 333 met protocol eligibility and signed consent. The mean age was 31 years (range, 1–89). Tumor tissue was received for 288 (86.4%) patients, of which 250 (86.8%) had DNA of sufficient quantity and quality for MSK-IMPACT testing. A total of 63% of patients were enrolled from sites within the United States (24% from non-tertiary care facilities, Fig. 1A). A total of 124 patients (37%) from 17 countries were enrolled from sites outside the United States (Fig. 1B). A total of 27% of patients were referred by a disease advocacy group, 24% enrolled via the study website, and 49% were referred by a physician familiar with the Make-an-IMPACT program, most of whom initially were made aware of the program by an earlier patient enrolled via the study website or a diseases advocacy group. Among the patients who underwent successful tumor genomic profiling, the most common cancer types were histiocytosis (n = 84), female GCT (n = 54), male GCT (n = 54), and adenoid cystic carcinoma (n = 19; Fig. 1C).

A total of 128 patients with histiocytosis from 13 countries were consented for tumor genomic profiling, of whom 112 (87.5%) had sufficient tumor tissue for tumor genomic profiling. Patient demographic and treatment information for the histiocytosis cohort are summarized in Table 1. Central pathology review led to a change in diagnosis to inflammatory sclerosing fibrosis in 1 patient and to poorly differentiated cancer of unknown primary in a second. Of the remaining 110 patients, tumor genomic profiling was successful for 84 (76.3%). The higher-than-expected rate of technical failure (23.7%) for patients with histiocytosis likely reflects the high degree of stromal infiltration characteristic of histiocytic tumors. Potentially actionable genes most commonly mutated in the histiocytosis cohort were BRAF (33%), MAP2K1 (13%), KRAS (7%), and CSF1R (2.4%; Fig. 2; ref. 15). Actionable fusions were identified in 4 patients: 3 BRAF fusions (MS4A6A-BRAF, DOCK8-BRAF, HLA-A-BRAF) and 1 TFG-ALK fusion. A PRDX1-NTRK1 fusion was also subsequently detected by targeted RNA sequencing in a patient with histiocytosis in which no mutations were detected by DNA sequencing (Fig. 2).

Histiocytosis is managed with a variety of local and systemic therapies depending on the disease subtype and extent of organ involvement. Upon enrollment, 7 patients had received prior targeted therapies [trametinib (2), cobimetinib (2), vemurafenib (1), imatinib (1), and sirolimus (1); Table 1]. To date, 18 patients have received targeted therapies based on the MSK-IMPACT results (Supplementary Table S1), including 8 with BRAF V600E who were treated with a RAF inhibitor (vemurafenib or dabrafenib). Eight patients with BRAF V600E wildtype tumors were treated with a MEK inhibitors (trametinib, cobimetinib), including 2 with MAP2K1 mutations, 1 with co-occurrent KRAS G12D and BRAF D594H mutations, 1 with a NRAS A59_E76 mutation, 1 patient with a PTPN11 mutation, and 3 with no mutations detected. An additional patient with a MAP2K1 mutation received an ERK inhibitor on a clinical trial, and 1 patient with histiocytosis with a PIK3CA mutation was treated with alpelisib.

Of the patients with histiocytosis who received targeted therapy, 17 of 18 exhibited clinical benefit based on local physician response assessment. Two examples of efficacious therapy implemented as a result of MSK-IMPACT tumor sequencing are highlighted in Fig. 2B and C. Responses were durable with 16 patients still receiving genomically matched therapy with durations of 6 to 40 months (Fig. 2D). In sum, the results highlight the feasibility and potential clinical benefit of recruiting patients with rare cancers such as histiocytosis who lack insurance coverage or local access to clinical tumor genomic profiling via direct-to-patient outreach.

Ovarian GCT was chosen as a pilot to determine whether outreach via social media and disease advocacy groups could accelerate research for patients with rare cancers by facilitating the assembly of cohorts of sufficient size for genomic discovery. As GCTs can arise in extragonadal sites and as even less is known about the biology of such tumors, female patients with extragonadal primary GCT were also eligible (see Supplementary Table S2 for patient demographics). By combining the 54 female patients with GCT successfully sequenced via Make-an-IMPACT with female patients with GCT offered MSK-IMPACT testing through a prospective institution-wide tumor genomic profiling initiative at MSK, we were able to assemble a cohort of 83 female patients with GCT of whom 67 had ovarian primaries. Central pathology review was discordant with the local diagnosis in two cases; both had carcinomas with yolk sac differentiation (Fig. 3A). Several patients also had transformation to secondary somatic malignancies (acute myelogenous leukemia, adenocarcinoma, or squamous carcinoma; Fig. 3B; ref. 29). Additional demographic and treatment information are summarized in Table 2.

Standard care for ovarian GCT includes staging surgery, and in patients with stage ≥1C disease, chemotherapy. Notably, the treatment received by patients with ovarian GCT differed between MSK and a subset of non-MSK patients. Unilateral salpingo-oophorectomy is recommended if feasible for children and young women with ovarian GCTs to avoid the long-term sequelae of early-onset estrogen deprivation. None of the MSK patients ages 30 or below underwent bilateral salpingo-oophorectomy whereas bilateral salpingo-oophorectomy was performed in 3 patients in this age group who received their initial surgery at an outside institution (Table 2). Similarly, bleomycin, etoposide, and cisplatin (BEP), or etoposide and cisplatin (EP) were administered as first-line chemotherapy for all female MSK patients with GCT (16/16), whereas BEP or EP (with carboplatin substituted for cisplatin due to impaired renal function in 1 patient) was the choice of first-line chemotherapy in only 80% (48/60) of the female patients with GCT who did not receive their initial chemotherapy at MSK, with several patients receiving treatment regimens that are standard care for high-grade serous ovarian cancer such a platinum (cisplatin or carboplatin) and paclitaxel (Fig. 3D; Table 2).

Similar to testicular GCT, oncogenic mutations in KIT, KRAS, and TP53 were observed in tumors from a minority of female patients with GCT (Fig. 3C; refs. 30–32). The mean tumor mutational burden (TMB) was low at 2.86 (range, 0–42.1; Fig. 3C); however, 2 patients had high TMB (TMB-H) tumors (28.1 and 42.1 mutations/MB), both of whom had ovarian GCTs with malignant squamous transformation. A total of 39 female patients with GCT developed disease recurrence after first-line chemotherapy, of whom 13 have died of disease and 7 are alive with active disease. Sixty-three patients currently have no evidence of disease. To date, 4 female patients with GCT have received targeted therapy guided by the MSK-IMPACT sequencing results, including alpelisib for PIK3CA-mutant tumors and trastuzumab for a patient with ERBB2 amplification, none of whom had durable responses (Supplementary Table S1). One patient with an ovarian GCT with squamous transformation and a TMB-H tumor (42.1 mutations/Mb) was treated with pembrolizumab and achieved a complete response, which is ongoing at 34 months.

As MSK-IMPACT failed to identify known or likely oncogenic mutations in 69% of the female GCTs, we performed whole-exome recapture of 62 female GCT tumor/normal pairs from 59 patients using the tumor and germline sequencing libraries generated for clinical MSK-IMPACT testing. Mutational analysis of the whole-exome data largely recapitulated findings from the MSK-IMPACT targeted sequencing results for genes covered by both (Fig. 4A). Given the lack of treatment response noted in patients who received genomically matched therapy, we used the WES data to explore the clonality of known oncogenic alterations in KRAS, NRAS, KIT, PIK3CA, and TP53. Aside from alterations in NRAS, the majority of mutations detected in these genes were clonal (Fig. 4B; Supplementary Fig. S1). In contrast to the sparsity of oncogenic mutations detected in female GCTs, large-scale copy-number events were nearly ubiquitous with over a fifth (n = 13) of patients contributing at least one tumor sample demonstrating evidence of whole-genome duplication. Notably, 17% (n = 10) of female GCTs had a near-haploid genomic profile, a phenotype rarely observed in other cancer types, and this phenotype was mutually exclusive with 12p gain (Fig. 4A and C; refs. 33, 34). Prior work by our group identified chromosome arm-level amplifications with reciprocal deletions or RLOH events as a common feature of testicular GCT genomes (26, 35). Similarly, we found that 51% of arm-level deletions in female GCTs contained a compensatory reciprocal amplification after controlling for whole-genome doubling (Fig. 4D). By comparison, only 4% of the arm-level deletions had a compensatory amplification in the Tumor Cancer Genome Atlas ovarian serous cystadenocarcinoma (TCGA-OV) cohort.

Tumor genomic profiling is increasingly used by oncologists to guide the selection of FDA-approved and investigational therapies in patients with advanced cancer. While few studies have explored the clinical utility of next-generation sequencing in rare cancers, recent tumor-agnostic approvals including pembrolizumab for microsatellite instability high and TMB-H tumors and larotrectinib for tumors with NTRK fusions provide justification for clinical genomic profiling of all patients with cancer for whom curative therapies are lacking. Access to tumor genomic testing for patients with rare cancers is often limited by a lack of insurance reimbursement or local testing expertise. Here, we sought to assess the feasibility of recruiting patients with rare cancer types for a tumor genomic profiling study via direct-to-patient outreach through patient advocacy groups and social media. As tumor genomic profiling was performed in a clinical laboratory, results were reported in real time to patients and their local physicians where they could be used to guide treatment selection.

As an initial pilot, we focused on histiocytosis, a rare cancer type in which actionable genomic alterations are common. A total of 128 patients with histiocytosis residing in 13 countries were enrolled. A total of 47 of 84 (56%) patients for whom sufficient tumor DNA for MSK-IMPACT could be obtained had a potentially actionable genomic alteration. Notably, the fraction of patients with histiocytosis for whom no mutations were detected by MSK-IMPACT was higher in the Make-an-IMPACT cohort than in our internal MSK cohort (18). This likely reflects selection bias, as a subset of patients with histiocytosis (8% of the histiocytosis cohort) were enrolled after more limited local molecular profiling was uninformative. Clinical benefit from matched therapy, as assessed by the local treating physician, was high with a mean time on therapy of 21.7 months, with 16 of 18 patients remaining on matched targeted therapy at last response assessment. Patients with histiocytosis often have slowly progressive disease and our expectation is that additional patients in the Make-an-IMPACT cohort will receive molecularly guided therapy upon progression to a symptomatic disease state. However, feedback from several international patients with histiocytosis and their local providers indicated that access to matched therapies has been either delayed or to date prevented by limited local insurance coverage.

Ovarian GCT was chosen as a pilot as limited prior knowledge was available as to the frequency of actionable genomic alterations in this rare cancer. By combining patients enrolled via the Make-an-IMPACT program with female patients with GCT offered MSK-IMPACT testing through a prospective institution-wide tumor genomic profiling initiative, we were able to assemble a cohort of 67 patients with ovarian GCT and 16 female patients with extragonadal GCT primaries for whom we have successfully generated MSK-IMPACT sequencing results. While potentially actionable genomic alterations were rare, two patients with ovarian GCTs (both with squamous transformation) had TMB-H tumors, one of whom had a complete and durable response to pembrolizumab. Three additional patients received genomically matched therapy to date, 2 for hotspot oncogenic mutations in PIK3CA, neither of whom had a durable response. As the 1 patient with histiocytosis and an oncogenic PIK3CA mutation achieved a durable response to the PI3K inhibitor alpelisib, the lack of clinical benefit with alpelisib in patients with PIK3CA-mutant GCT suggests that lineage specific differences may condition targeted therapy response in these two cancer types. Because over half of the female patients with GCT had no oncogenic alterations identified by MSK-IMPACT, we also performed WES of 62 GCTs from 59 female patients to further characterize the genomic landscape of this rare cancer type. Similar to testicular GCTs, whole-genome duplication and RLOH were common (26). A notable difference with testicular cancer was that 17% of the female GCTs had a fully haploid genomic profile, a rarity in common solid tumors, and a potential vulnerability that could be explored in future functional studies.

A formal histologic review was a component of the Make-an-IMPACT workflow to confirm the local tumor subtype classification and to select the optimal tumor region for DNA extraction. This central pathologic review revealed that several patients were misdiagnosed, including 2 patients diagnosed locally with GCT who in fact had carcinomas with yolk sac differentiation, entities that can be difficult to distinguish from GCTs with somatic malignant transformation. As neither of these patients responded to BEP, the lack of an accurate cancer subtype diagnosis may have negatively impacted their care. An additional pediatric patient diagnosed with rhabdomyosarcoma was reclassified on central review as an undifferentiated sarcoma. Genomic profiling identified an EWSR1-PATZ1 fusion, a fusion only recently described in cohorts of undifferentiated sarcomas and neuroepithelial tumors (36, 37). A change in cancer subtype diagnosis led to a change in the recommended chemotherapy regimen for this child, highlighting the important role of tumor genomic profiling in sarcoma subtype classification and determination of the optimal therapeutic approach (38).

A notable observation from the female GCT cohort was that a substantial minority of patients (21%) did not receive the most commonly employed standard chemotherapy regimens for this disease but rather chemotherapy regimens commonly used for high-grade serous ovarian cancer. Several pediatric and young adult patients with ovarian GCT also underwent bilateral salpingo-oophorectomy, a procedure generally avoided in patients with ovarian GCT given their often exquisite sensitivity to chemotherapy and the long-term adverse impact of early-onset estrogen deprivation. Taken together, our experience highlights that treatment at a specialized cancer center with expertise in rare cancers along with central pathologic review could improve outcomes by ensuring that patients receive the optimal standard care therapies for rare but potentially curative tumor types. While a centralized approach to the treatment of rare cancers has historically been viewed as logistically challenging, the rapid adoption of telehealth as a response to the COVID-19 pandemic suggests that centralized treatment of patients with rare cancer by oncologists and pathologists with disease-specific expertise is now feasible. Such efforts could be further facilitated by the adoption of digital pathology platforms that would facilitate central pathology review. In fact, the infrastructure created for the Make-an-IMPACT program including phone and eConsents was adopted broadly at MSK as a response to the COVID-19 pandemic allowing our oncologists to continue to offer tumor genomic profiling to patients being evaluated and monitored largely via telehealth.

There were several limitations to the current study, many of which are limitations of real-world datasets more generally. For example, the timing of restaging studies was not prescribed and was thus variable and clinical benefit from matched therapy was quantified via local physician assessment and not by central radiology review. While all tumor sequencing was performed free of charge, obtaining often expensive matched targeted or immunotherapies was difficult and, in some cases, impossible, especially in countries with more limited health care resources. Despite these limitations, we found that social media outreach could facilitate the assembly of large cohorts of patients with rare cancer which could then be used for discovery science, such as the finding of fully haploid genomes in a minority of female patients with GCT. Inclusion of clinical tumor profiling with return of results also allowed us to identify genomically guided therapies that proved effective in a minority of patients especially for patients in low resource settings. Future research initiatives linked to the Make-an-IMPACT cohort will seek to leverage social media and disease specific advocacy group outreach to explore survivorship questions such as fertility postchemotherapy, which have been difficult to study for rare cancers such as ovarian GCTs.

N.D. Socci reports grants from NIH during the conduct of the study. Y.L. Liu reports grants from AstraZeneca, GlaxoSmithKline, and Repare Therapeutics outside the submitted work. C. Aghajanian reports grants from AstraZeneca and personal fees from Eisai/Merck, Roche/Genentech, AbbVie, AstraZeneca/Merck, and Repare outside the submitted work. M.X. He reports grants from NIH and NSF during the conduct of the study as well as personal fees from Genentech, Amplify Medicines, Ikena Oncology, and Janssen outside the submitted work. J.A. Riancho reports grants from Kyowa Kirin and personal fees from Gedeon Richter and Amgen-UCB outside the submitted work. M. Wilson reports grants from NIH during the conduct of the study. A.E. Webber reports grants from NIH during the conduct of the study. M. Yabe reports personal fees from Janssen Research and Development outside the submitted work. K. Petrova-Drus reports grants from MSKCC during the conduct of the study. O. Abdel-Wahab reports consultancy for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen and is on the scientific advisory board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; in addition, O. Abdel-Wahab has received prior research funding from H3B Biomedicine, Nurix Therapeutics, Minovia Therapeutics, and Loxo Oncology outside the submitted work. M.F. Berger reports personal fees from Eli Lilly and AstraZeneca outside the submitted work. A.L. Kung reports other support from Isabl and personal fees and other support from Emendo, Imago, Karyopharm, and Darwin Health outside the submitted work. J. Glade Bender reports grants from NIH/NCI during the conduct of the study as well as personal fees from Jazz Pharmaceuticals outside the submitted work; in addition, J. Glade Bender has served as an uncompensated consultant on data safety monitoring boards for Springworks, Merck, and Pfizer and on pediatric advisory boards for BMS and Eisai and receives institutional research support (but no salary support) for clinical trials from Roche, Merck, Amgen, Lilly, BMS, Eisai, Novartis, Loxo Oncology, Cellectar, and Bayer. S.A. Funt reports other support from AstraZeneca, Genetech/Roche, Decibel Therapeutics, Allogene Therapeutics, Urogen, Kronos Bio, and Doximity and personal fees from Merck and BioNTech outside the submitted work. A. Dogan reports grants from Roche and Takeda and personal fees from Incyte, Loxo, and EUSA Pharma outside the submitted work. H. Al-Ahmadie reports personal fees from AstraZeneca and Paige.AI outside the submitted work. D.R. Feldman reports grants from NCI during the conduct of the study as well as other support from Telix, Astellas, UpToDate, and Decibel and personal fees and other support from BioNTech outside the submitted work. E.M. Van Allen reports personal fees from Tango Therapeutics, Genome Medical, Genomic Life, Monte Rosa Therapeutics, Manifold Bio, Illumina, Enara Bio, Foley Hoag, Riva Therapeutics, and Serinus Bio; grants and personal fees from Novartis; and grants from BMS, Janssen, and Sanofi outside the submitted work. In addition, E.M. Van Allen has a patent for chromatin mutations and immunotherapy response and methods for clinical interpretation pending and issued. E.L. Diamond reports other support from Springworks Therapeutics, Day One Biopharmaceuticals, and Opna Bio and nonfinancial support from Pfizer, Inc outside the submitted work; in addition, E.L. Diamond serves on the board of trustees of the Histiocytosis Association. D.B. Solit reports personal fees from Pfizer, Vividion Therapeutics, Scorpion Therapeutics, Fore Therapeutics, Fog Pharma, Elsie Biotechnologies, BridgeBio, and Loxo/Lilly Oncology outside the submitted work. No disclosures were reported by the other authors.

S.A. Doe-Tetteh: Conceptualization, resources, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. S.Y. Camp: Resources, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. D. Reales: Conceptualization, resources, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. J. Crowdis: Resources, data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–review and editing. A.M. Noronha: Data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–review and editing. B. Wolff: Conceptualization, resources, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–review and editing. T. Alano: Resources, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. This author is the consenting profile for Make-an-Impact. J. Galle: Conceptualization, resources, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology. S.D. Selcuklu: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration. A. Viale: Resources, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration. N.D. Socci: Data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology. Y.L. Liu: Data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–review and editing. W.P. Tew: Resources, data curation, supervision, validation, investigation, visualization, methodology. C. Aghajanian: Resources, data curation, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–review and editing. M. Ladanyi: Resources, supervision, validation, investigation, visualization, methodology. M.X. He: Resources, data curation, software, formal analysis, validation, investigation, visualization, methodology. S.H. AlDubayan: Resources, data curation, software, formal analysis, validation, investigation, visualization, methodology. R.D. Mazor: Resources, supervision, validation, investigation, visualization, methodology. O. Shpilberg: Resources, validation, investigation, visualization, methodology. O. Hershkovitz-Rokah: Resources, validation, investigation, visualization, methodology. J.A. Riancho: Resources, data curation, validation, investigation, visualization, methodology, writing–original draft. J.L. Hernandez: Resources, data curation, validation, investigation, visualization. M.C. Gonzalez-Vela: Resources, data curation, validation, investigation, visualization. J.J. Buthorn: Data curation, validation, investigation, visualization, methodology. M. Wilson: Resources, data curation, software, formal analysis, validation, investigation, visualization, methodology. A.E. Webber: Data curation, software, formal analysis, validation, investigation, visualization. M. Yabe: Resources, data curation, formal analysis, validation, investigation, visualization, methodology. K. Petrova-Drus: Resources, data curation, formal analysis, validation, investigation, visualization, methodology. M. Rosenblum: Resources, supervision, funding acquisition, validation, investigation, visualization, methodology. B.H. Durham: Resources, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology. O. Abdel-Wahab: Resources, data curation, supervision, validation, investigation, visualization, methodology, project administration, writing–review and editing. M.F. Berger: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing. M.T.A. Donoghue: Resources, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, project administration. A.L. Kung: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing. J. Glade Bender: Resources, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–review and editing. N.N. Shukla: Resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing. S.A. Funt: Conceptualization, resources, data curation, software, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing. A. Dogan: Resources, data curation, software, formal analysis, validation, investigation, visualization, methodology, project administration, writing–review and editing. R.A. Soslow: Resources, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, project administration, writing–review and editing. H. Al-Ahmadie: Resources, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, project administration, writing–review and editing. D.R. Feldman: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. E.M. Van Allen: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. E.L. Diamond: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. D.B. Solit: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing; started the Make-an-Impact initiative and is also the principal investigator and corresponding author.

The authors thank Barbara Solit, Amy Heller, and other members of the rare cancer advocacy community for assistance in patient recruitment. We also thank members of the Kravis Center for Molecular Oncology, the Integrated Genomics Organization, and Diagnostic Molecular Pathology. This work was supported by Cycle for Survival, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, NIH R37-CA259260, NIH R37-CA222574, NIH R01-CA229624, and NIH/NCI Cancer Center Support Grant P30-CA008748.

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