Malignant tumors in the head and/or neck area always pose challenges for experts. Immunotherapy can now be used to treat a wide range of cancers, but the response rate often still leaves ws wishes. Therefore, intensive research is being conducted on prognostic models and potential biomarkers to optimize the outcome of treatment management.
Despite improvements in multimodality treatment options for patients with head and neck squamous cell carcinoma (HNSCC), survival has improved only modestly in recent decades. The frequent development of recurrences is to blame. Detection of cell-free circulating tumor DNA (ctDNA) after surgery and during clinical follow-up has the potential to identify patients with molecular residual disease (MRD) or at increased risk of relapse who could then benefit from personalized treatment strategies. To address this hypothesis, a prospective cohort study was conducted to investigate ctDNA in patients with HNSCC who received primary surgical treatment with curative intent [1]. RaDaR, a highly sensitive personalized assay that uses deep sequencing of tumor-specific variants to analyze serial pre- and postoperative plasma samples for evidence of residual molecular disease and recurrence, was used. In addition, preoperative saliva samples were collected for detection of tumor DNA in saliva.
To date, 236 longitudinal plasma samples from 35 patients have been analyzed using personalized panels targeting a median of 48 (20-60) somatic variants. Preliminary data show that 94.28% of ctDNA was detected in baseline samples collected before surgery. In samples collected after surgery, ctDNA was detected at concentrations as low as 0.0005% variant allele fraction (eVAF). Survival analysis showed a significant difference in recurrence rate between patients tested for ctDNA+ during follow-up (72.7%) and those who were negative for ctDNA (0%). In all cases with clinical recurrence, ctDNA was detected before disease progression, with lead times ranging from 56 to 265 days. Patients were followed up for clinical recurrence with a median follow-up of 9.5 months, but a longer follow-up period is required for patients at increased risk of recurrence.
Detection of residual disease using ctDNA is associated with poorer progression-free survival and much earlier detection of disease before clinical relapse. The introduction of a highly sensitive ctDNA assay such as RaDaR into clinical practice has the potential to develop personalized treatment strategies for residual molecular disease and recurrence in patients with HNSCC. In the future, ctDNA analysis followed by ctDNA-targeted treatment may reduce the morbidity of HNSCC patients.
Four prognostic factors for RM SCCHN
But what about prognostic factors in first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (RM SCCHN)? The study was based on a large data set of 403 patients from a completed randomized phase III trial of platinum-based chemotherapy with or without bevacizumab [2]. Clinical and tumor characteristics were examined using Cox proportional hazard models. Variables that were significant at a level of ≤0.10 on univariate examination were included in a multivariable model, and backward selection was performed. The final multivariable model was then applied separately to the two treatment arms. Variables for which the hazard ratio (HR) within an arm differed by more than 10% from that of the entire cohort were removed from the final cohort model.
The median OS in the entire study cohort was 11.8 months. Using the four independent prognostic factors identified in the multivariable model, a prognostic score model was constructed for OS: ECOG performance status (1 vs. 0), prior radiation, primary region (non-oropharynx vs. oropharynx), and metastatic disease to bone or liver (vs. other sites/no metastases). The prognostic score was dichotomized (0-2 and >2). Patients with 0-2 risk factors (n=249) had a median OS of 15.2 months, whereas patients with more than two risk factors (n = 154) had a median OS of 7.6 months. Accordingly, the newly proposed model includes four prognostic factors for OS (performance status, primary site, prior radiation, presence of bone/liver metastases) in first-line treatment of RM SCCHN.
New biomarkers for better outcome
Low response rates in HNSCC treated with immune checkpoint inhibitors (ICB) lead to an urgent need for robust, clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in several cancers, including HNSCC. However, its predictive value for ICB response has not yet been investigated. Preclinical studies suggest that K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling, which attracts activated CD8+ T cells to the tumor. Furthermore, knocking down K17 restores the response to ICB in an HNSCC mouse model. A retrospective analysis included 26 HNSCC patients who had received at least one cycle of pembrolizumab [3]. Prior to treatment, archived, formalin-fixed, paraffin-embedded specimens were immunohistochemically stained with a K17 monoclonal antibody. Clinical outcomes were assessed by the investigator in all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathological examination, cases were categorized as “K17 high” and “K17 low” using a cut-off value of >5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component.
The 26 patients included in this study were 85% male, a median age of 60.5 years, 74% had an ECOG performance status <2, and 80% had received prior chemotherapy. Primary localization included the oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) had high K17 expression, and 9 tumors (35%) had low K17 expression. Six patients (23%, all with low K17 expression) achieved clinical benefit, whereas 20 patients (77%, 17 with high and 2 with low K17 expression) had disease progression. High K17 expression was associated with lack of clinical benefit, shorter time to treatment failure, progression-free and overall survival. The results suggest that K17 expression can predict the clinical benefit of ICB in HNSCC patients, supporting further validation studies.
Immunotherapy (ITx) has become the standard of care for RM HNSCC. However, the response rate is limited to 13-18% of patients, highlighting the need to identify mechanisms responsible for response or resistance. One study aimed to uncover novel biomarkers for ITx outcomes in RM HNSCC using Digital Spatial Profiling(DSP) technology [4]. For this purpose, pre-treatment biopsy samples from 50 ITx-treated RM HNSCC patients were included and tissue microarray (YTMA496) was generated. Cases were subjected to DSP using the Human Immuno-Oncology Protein Panel, which includes 71 primary antibodies labeled with photocleavable oligonucleotides that were used to quantify target proteins in four different molecularly defined compartments: Tumor (CK+), Leukocyte (CD45+), Macrophage (CD68+), and Immune Troma (CD45+/CD68+). All markers were assessed for their association with progression-free (PFS) and overall survival (OS) using a univariate Cox regression model. Significant markers were validated using an alternative quantitative immunofluorescence method and in an independent validation cohort of 29 ITx-treated RM HNSCC cases (YTMA523).
Univariate DSP data analysis revealed high levels of beta2-microglobulin (B2M), LAG-3, CD25, and 4-1BB in the tumor; high B2M, CD45, and CD4 levels in the stroma; and low fibronectin levels in the macrophage compartment as markers associated with improved PFS. Increased levels of B2M and CD25 in tumor and CD11c in stroma also correlated with prolonged OS. As for B2M, cases in the top tertile of B2M expression in tumor were associated with improved PFS and OS. The results were replicated in the validation cohort for PFS and showed a similar trend for OS. B2M-high tumors also showed significant enrichment with immune cell markers (CD3, CD4, CD8, CD11c, CD68, and CD163) and increased expression of immune checkpoints (PD-L1, ICOS, TIM-3, LAG-3, IDO1, B7-H3), especially in the tumor compartment.
This study suggests that intact, high-functional antigen presentation maintained by high B2M expression in the tumor confers a survival benefit in RM HNSCC patients treated with ITx, an effect driven by increased intra-tumor immunogenicity.
Congress: ASCO Annual Meeting
Literature:
- Flach S, Howarth K, Hackinger S, et al: Liquid Biopsy for Minimal Residual Disease Detection in Head and Neck Squamous Cell Carcinoma (LIONESS): A personalized cell-free tumor DNA analysis for patients with HNSCC. J Clin Oncol 40, 2022 (suppl 16; abstr 6017).
- Agiris A, Flamand Y, Savvides P, et al: A new prognostic model in patients with recurrent or metastatic head and neck cancer treated with chemotherapy: An analysis of ECOG-ACRIN E1305. J Clin Oncol 40, 2022 (suppl 16; abstr 6026).
- Lozar T, Fitzpatrick M, Wang W, et al: Stress keratin 17 as a novel biomarker of response in immune checkpoint blockade-treated head and neck squamous cell carcinoma. J Clin Oncol 40, 2022 (suppl 16; abstr 3117).
- Gavrielatou N, Vathiotis I, Aung TN, et al: Digital spatial profiling to uncover biomarkers of immunotherapy outcomes in head and neck squamous cell carcinoma. J Clin Oncol 40, 2022 (suppl 16; abstr 6050).
InFo ONCOLOGY & HEMATOLOGY 2022; 10(3): 24-25.
