Overcoming barriers to tumor genomic profiling through direct-to-patient outreach

Authors

Seyram A. Doe-Tetteh

Sabrina Y. Camp

Dalicia Reales

Jett Crowdis

Eli L. Diamond

Eliezer M. Van Allen

David B. Solit

Doi

10.1158/1078-0432.CCR-22-3247

PMID: 36862133 · DOI: 10.1158/1078-0432.CCR-22-3247 · Journal: Clinical Cancer Research (2023)

TL;DR

The Make-an-IMPACT program used direct-to-patient outreach via social media and disease-specific advocacy groups to enroll 333 patients with rare cancers (histiocytosis, female germ cell tumors, pediatric cancers) worldwide for free clinical tumor genomic profiling via MSK-IMPACT, returning results to patients and their local physicians. Matched targeted therapy produced clinical benefit in 17/18 histiocytosis patients (mean duration 21.7 months), and whole-exome sequencing of 59 female germ cell tumors uncovered a near-haploid genomic subtype in 17% of cases PMID:36862133.

Cohort & data

  • 333 consented patients enrolled between March 2016 and October 2020; 288 (86.4%) provided tumor tissue, 250 (86.8% of those) had DNA of sufficient quality for MSK-IMPACT sequencing PMID:36862133.
  • 63% enrolled from US sites; 124 patients (37%) from 17 countries outside the US.
  • Most common cancer types successfully profiled: histiocytosis (n=84; LCH, ECD), female germ cell tumor (n=54; OGCT), male germ cell tumor (n=54; MGCT), adenoid cystic carcinoma (n=19; ACYC).
  • Assay: MSK-IMPACT (up to 505 genes) with select targeted RNA sequencing; whole-exome recapture performed for 62 ovarian GCT tumor/normal pairs from 59 patients.
  • Data deposited in cBioPortal (study makeanimpact_ccr_2023) and AACR Project GENIE; WES BAMs in dbGaP phs001783.

Key findings

  • Histiocytosis (n=84 profiled): most commonly mutated actionable genes were BRAF (33%), MAP2K1 (13%), KRAS (7%), and CSF1R (2.4%); actionable fusions included MS4A6A-BRAF, DOCK8-BRAF, HLA-A-BRAF, TFG-ALK, and a PRDX1-NTRK1 fusion detected by RNA-seq PMID:36862133.
  • 47/84 (56%) histiocytosis patients had a potentially actionable alteration; 18 received matched targeted therapy; 17/18 (94%) had clinical benefit with a mean treatment duration of 21.7 months (range 6–40+) PMID:36862133.
  • Female GCT (n=83 with MSK-IMPACT; 67 ovarian primaries): oncogenic mutations in KIT, KRAS, and TP53 were seen in a minority; mean TMB was low (2.86; range 0–42.1); two ovarian GCTs with squamous transformation were TMB-H (28.1 and 42.1 mut/Mb) PMID:36862133.
  • One TMB-H ovarian GCT with squamous transformation (42.1 mut/Mb) achieved a complete response to pembrolizumab ongoing at 34 months.
  • WES of 62 female GCT pairs: whole genome doubling in ≥13 patients; 17% (n=10) of female GCTs had a near-haploid genomic profile, mutually exclusive with 12p gain — a phenotype rarely seen in other cancer types PMID:36862133.
  • 51% of arm-level deletions in female GCTs contained a reciprocal amplification (RLOH), versus 4% in TCGA-OV.
  • Central pathology review led to reclassification in several cases (e.g., yolk sac carcinoma misdiagnosed as GCT; a pediatric “rhabdomyosarcoma” reclassified as undifferentiated sarcoma with an EWSR1-PATZ1 fusion, changing the chemotherapy regimen).

Genes & alterations

  • BRAF — V600E in ~33% of histiocytosis; 8 patients treated with vemurafenib or dabrafenib. BRAF fusions (MS4A6A, DOCK8, HLA-A) also identified. One case had co-occurring KRAS G12D and BRAF D594H.
  • MAP2K1 — mutated in 13% of histiocytosis; treated with MEK inhibitors (trametinib, cobimetinib); one patient received an ERK inhibitor on trial.
  • KRAS — mutated in 7% of histiocytosis; also among oncogenic mutations in female GCT.
  • NRAS — A59_E76 mutation in one histiocytosis patient treated with MEK inhibitor; mostly subclonal in female GCT.
  • CSF1R — mutated in 2.4% of histiocytosis.
  • ALK — TFG-ALK fusion in one histiocytosis patient.
  • NTRK1 — PRDX1-NTRK1 fusion in one histiocytosis patient, detected only by targeted RNA-seq.
  • PIK3CA — one histiocytosis patient had a durable response to alpelisib; two ovarian GCT PIK3CA-mutant patients had no durable response.
  • PTPN11 — mutated in one histiocytosis patient treated with a MEK inhibitor.
  • KIT, TP53 — oncogenic mutations observed in a minority of female GCTs; mostly clonal by WES.
  • ERBB2 — amplification in one female GCT patient treated with trastuzumab (no durable response).

Clinical implications

  • Direct-to-patient outreach is feasible for rare-cancer cohort assembly and can deliver actionable genomic results returned to local physicians for treatment selection PMID:36862133.
  • MAPK-pathway matched therapy (RAF/MEK/ERK inhibitors) produced high rates of clinical benefit in histiocytosis.
  • Tumor-agnostic immunotherapy (pembrolizumab) may benefit rare TMB-H GCTs with squamous transformation.
  • Lineage context matters: PIK3CA-mutant histiocytosis responded to alpelisib while PIK3CA-mutant ovarian GCT did not, suggesting lineage-specific conditioning of targeted therapy response.
  • Central pathology review changed diagnosis/treatment in multiple cases, arguing for centralized review for rare cancers.

Limitations & open questions

  • Response assessments were made by local physicians without central radiology review; restaging intervals were not protocolized.
  • Access to matched targeted or immunotherapies was often limited by cost or local insurance, especially internationally.
  • Selection bias: a subset of histiocytosis patients were enrolled after prior local profiling was uninformative, potentially inflating the no-mutation-detected fraction.
  • The functional and therapeutic implications of the near-haploid ovarian GCT phenotype remain to be explored.
  • Germline analysis was not clinically returned in this program.

Citations from this paper used in the wiki

  • “333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing.” (Abstract)
  • “Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range 6–40+).” (Abstract)
  • “Potentially actionable genes most commonly mutated in the histiocytosis cohort were BRAF (33%), MAP2K1 (13%), KRAS (7%), and CSF-1R (2.4%)” (Results, Histiocytosis)
  • “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” (Results, Ovarian GCT)
  • “One GCT with squamous transformation and a TMB-H tumor (42.1 mut/Mb) was treated with pembrolizumab and achieved a complete response, which is ongoing at 34 months.” (Results, Ovarian GCT)

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