Prognostic impact of copy number alterations and tumor mutational burden in carcinoma of unknown primary

Abstract

Introduction Chromosomal aberrations are known to drive metastatic spread, but their profile is still elusive in carcinoma of unknown primary (CUP). Therefore, the aim of this study was to characterize the chromosomal aberration pattern in CUP depending on histological and clinical features and to assess its prognostic impact together with chromothripsis, tumor mutational burden (TMB), microsatellite instability (MSI), and mutational profiles as potential prognostic biomarkers. Methods Chromosomal aberrations and chromothripsis were detected by methylation‐based copy number variation (CNV) analysis, whereas TMB and MSI were calculated based on large next‐generation sequencing (NGS) panels. Putative primaries were assigned by consensus between two independent oncologists. Results CNV losses varied depending on putative primaries and were more abundant in patients harboring TP53 mutations and/or deletions 17p. CNV loss was prognostically adverse in localized CUP treated with surgery and/or radiotherapy, but not in disseminated poor‐risk CUP treated with palliative chemotherapy. CNV loss also worsened the prognosis in squamous cell CUP. Chromothripsis was detected in 18/59 (30.5%) patients without prognostic effect. TMB was highest in cases with MSI, squamous cell histology, and with lung, anal or cervical putative primaries. Conclusion Overall, CNV, chromothripsis, TMB, and MSI profiles in CUP are reminiscent of biological characteristics known from other cancer entities without a unifying CUP‐specific signature. Markedly, high‐level CNV loss is an adverse predictive biomarker in localized but not disseminated chemotherapy‐treated CUP. This implies that chromosomal losses drive CUP progression, but also increase susceptibility to chemotherapy, with both effects apparently leveling out in disseminated CUP.

Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial

“…Based on clinical and immunohistochemical features patients were independently classified for their putative primary by three experienced oncologists as previously described 21 , with putative primary tumors being only registered in case of consensus between at least two of the three investigators. As a result, 16 of 31 cases were assigned to either lung (6 cases, 19.4%), upper gastrointestinal (5 cases, 16.1%), anal/cervix (3 cases, 9.7%), breast (one case, 3.2%) or colon (one case, 3.2%) cancer, while 13 cases (41.9%) were considered fully enigmatic, and two cases could not be unanimously assigned to any of these groups.…”

“…For the clinical primary site prediction, patients were independently classified for their putative primary by three experienced oncologists based on clinical and immunohistochemical features as previously described 21 , with putative primary tumors being only registered in case of consensus between at least two of the three investigators. Putative primary tumor groups comprised distinct favorable subtypes recognized in the ESMO guidelines 1 , namely colon (adenocarcinoma with CK7–, CK20 + , CDX2+ immunohistochemistry [IHC] and metastatic spread compatible with colon cancer), head and neck (squamous cell carcinomas with predominant cervical lymph node metastases), breast (adenocarcinoma with predominant axillary lymph node metastases in females) and inner genitals (serous pelvic/peritoneal adenocarcinoma in females), but also upper gastrointestinal tract (adenocarcinoma with leading peritoneal carcinosis and/or abdominal wall infiltration with compatible IHC and without colonic profile), lung (CK7+ adeno- or squamous cell carcinomas with a metastatic pattern suggestive of lung cancer, that is, mediastinal lymph nodes, predominant tumor burden within the chest and distant metastatic sites typical of lung cancers) and anal/cervix (squamous cell carcinomas with pelvic masses and or inguinal lymph node metastases), as well as fully enigmatic cases where no or no unanimous assignment could be made.…”

“…Based on the results of the KEYNOTE-158 study linking high TMB (TMB high ) to better response and survival to immune checkpoint blockade across several solid tumor types, the Food and Drug Administration (FDA) granted approval for the use of pembrolizumab in TMB high patients regardless of the cancer´s tissue of origin, thereby including CUP 17 . Several studies analyzing the genomic profile of CUP reported that about 10–20% of cases harbor high TMB levels 18 – 21 . In order to determine the value of immunotherapy in CUP, prospective data on treatment efficacy and biomarker reliability are needed.…”

Cancer of Unknown Primary: When Imaging, Pathology, and Molecular Biology Do Not Match

“…Additionally, normal albumin and absence of liver metastases are considered favorable prognostic factors while poor performance status (ECOG ≥2) and bone metastasis are identified as poor prognostic factors [ 18 , 21 ]. Molecular markers that have poor prognosis include KRAS , NRAS activation, CDKN2A deletion, chromosomal copy number losses, deleterious TP53 , deletion of Chr17p [ 4 , 22 ]. Finally, CUP patients with high PD-L1 expression and TMB have better response and survival to ICI [ 17 ].…”

“…The American Cancer Society estimated 30,620 cases of CUP in 2022, with 47,770 deaths, roughly 2% of all cancer diagnosis [ 2 ]. Their most common histology is adenocarcinoma (50%), and associated risk factors include smoking with a 1.8–4.1-fold increase in risk, high BMI, alcohol, and family history [ 3 , 4 ].…”