Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells.

Our bodies are equipped with powerful immune surveillance to clear cancerous cells as they emerge. How tumor-initiating stem cells (tSCs) that form and propagate cancers equip themselves to overcome this barrier remains poorly understood. To tackle this problem, we designed a skin cancer model for squamous cell carcinoma (SCC) that can be effectively challenged by adoptive cytotoxic T cell transfer (ACT)-based immunotherapy. Using single-cell RNA sequencing (RNA-seq) and lineage tracing, we found that transforming growth factor ß (TGF-ß)-responding tSCs are superior at resisting ACT and form the root of tumor relapse. Probing mechanism, we discovered that during malignancy, tSCs selectively acquire CD80, a surface ligand previously identified on immune cells. Moreover, upon engaging cytotoxic T lymphocyte antigen-4 (CTLA4), CD80-expressing tSCs directly dampen cytotoxic T cell activity. Conversely, upon CTLA4- or TGF-ß-blocking immunotherapies or Cd80 ablation, tSCs become vulnerable, diminishing tumor relapse after ACT treatment. Our findings place tSCs at the crux of how immune checkpoint pathways are activated.

Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Outcomes and toxicities of definitive radiotherapy and reirradiation using 3-dimensional conformal or intensity-modulated (pencil beam) proton therapy for patients with nasal cavity and paranasal sinus malignancies.

BACKGROUND: Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS: Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS: The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P < .01) and independently predicted LC (hazard ratio, 0.14; P = .01). Sixteen radiation-naive patients (24%) experienced acute grade 3 toxicities; 4 (6%) experienced late grade 3 toxicities (osteoradionecrosis, vision loss, soft-tissue necrosis, and soft tissue fibrosis) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]). Slightly inferior LC was noted for patients undergoing reirradiation with higher complications: 11% experienced late grade 3 toxicities (facial pain and brain necrosis). Patients treated with reirradiation had more grade 1 to 2 radionecrosis than radiation-naive patients (brain: 33% vs 7% and osteoradionecrosis: 17% vs 3%). CONCLUSIONS: PT achieved remarkable LC for patients with nasal cavity and paranasal sinus cancers with lower grade 3 toxicities relative to historical reports. IMPT has the potential to improve the therapeutic ratio in these malignancies and is worthy of further investigation.

The 3 Bs of cancer care amid the COVID-19 pandemic crisis: "Be safe, be smart, be kind"-A multidisciplinary approach increasing the use of radiation and embracing telemedicine for head and neck cancer.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis.

Restaging [18F] fludeoxyglucose positron emission tomography/computed tomography scan in recurrent cutaneous squamous cell carcinoma: Diagnostic performance and prognostic significance.

BACKGROUND: There are no specific recommendations for [18F] fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing recurrent cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To evaluate FDG-PET/CT in recurrent cSCC. METHODS: FDG-PET/CT scans were retrospectively reviewed. Sites of abnormal uptake were noted and correlated with biopsy/histopathology studies, where available, and with follow-up imaging or clinical data in others. Comparison with available CT/magnetic resonance imaging was performed. The prognostic significance of PET/CT parameters was evaluated, and PET/CT-based change in management was recorded. RESULTS: A total of 115 FDG-PET/CT scans were analyzed in 100 consecutive patients with cSCC. Of these, 96 (84%) scans were positive for recurrence, and 25 showed distant metastases. PET/CT detected unsuspected disease sites in 39 of 115 scans (34%), locoregional disease in 14, distant metastases in 11, both locoregional disease and distant metastases in 8, additional local cutaneous disease in 5, and second malignancy in 1. Comparison of 78 PET/CT scans with available CT/magnetic resonance imaging showed 37 additional abnormalities on 23 PET/CT scans, predominantly including skin/subcutaneous lesions and nodes. PET/CT led to change in management in 28% of patients. On univariate/multivariate analysis, increased number of FDG-positive lesions and lung metastases on PET/CT was associated with increased risk of death/disease progression. LIMITATIONS: Retrospective study. CONCLUSIONS: FDG-PET/CT was sensitive in detecting recurrent disease in cSCC, led to change in management for 28% of patients, and proved to be of prognostic value.

Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase.

N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation-dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl-amide-binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2-E3 ligases.

Squamous cell carcinoma-related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission.

Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation in vitro and in vivo Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody. The Cul3 adaptor KLHL21 mediates the effects of SCCRO on abscission, as it fails to localize to the midbody in SCCRO-deficient cells during abscission, and its inactivation resulted in phenotypic changes identical to SCCRO inactivation. Ubiquitination-promoted turnover of Aurora B at the midbody was deficient in SCCRO- and KLHL21-deficient cells, suggesting that it is the target of Cul3KLHL21 at the midbody. Correction of abscission delays in SCCRO-deficient cells with addition of an Aurora B inhibitor at the midbody stage suggests that Aurora B is the target of SCCRO-promoted Cul3KLHL21 activity. The activity of other Cul3-anchored complexes, including Cul3KLHL9/KLHL13, was intact in SCCRO-deficient cells, suggesting that SCCRO selectively, rather than collectively, neddylates cullins in vivo Combined, these findings support a model in which the SCCRO, substrate, and substrate adaptors cooperatively provide tight control of neddylation and cullin-RING-ligase activity in vivo.

Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation.

SCCRO (squamous cell carcinoma-related oncogene; also known as DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO(-/-) mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led us to assess whether compensation by SCCRO paralogues rescues lethality in SCCRO(-/-) mice. Using murine and Drosophila models, we assessed the in vivo activities of SCCRO and its paralogues in cullin neddylation. We found that SCCRO family members have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO and dSCCRO3 promote neddylation and cell proliferation, whereas dSCCRO4 negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones with a net decrease in neddylation activity. We found that dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promote, and human SCCRO3 inhibits, neddylation and proliferation when expressed in flies. Our findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation.

Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

Despite improvements in functional outcomes attributable to advances in radiotherapy, chemotherapy, surgical techniques, and imaging techniques, survival in head and neck squamous cell carcinoma (HNSCC) patients has improved only marginally during the last couple of decades, and optimal therapy has yet to be devised. Genomic complexity and intratumoral genetic heterogeneity may contribute to treatment resistance and the propensity for locoregional recurrence. Countering this, it demands a significant effort from both basic and clinical scientists in the search for more effective targeted therapies. Recent genomewide studies have provided valuable insights into the genetic basis of HNSCC, uncovering potential new therapeutic opportunities. In addition, several studies have elucidated how inflammatory, immune, and stromal cells contribute to the particular properties of these neoplasms. In the present review, we introduce recent findings on genomic aberrations resulting from whole-genome sequencing of HNSCC, we discuss how the particular microenvironment affects the pathogenesis of this disease, and we describe clinical trials exploring new perspectives on the use of combined genetic and cellular targeted therapies.

The ubiquitin-associated (UBA) domain of SCCRO/DCUN1D1 protein serves as a feedback regulator of biochemical and oncogenic activity.

Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers.

Defining a Valid Age Cutoff in Staging of Well-Differentiated Thyroid Cancer.

BACKGROUND: Age 45 years is used as a cutoff in the staging of well-differentiated thyroid cancer (WDTC) as it represents the median age of most datasets. The aim of this study was to determine a statistically optimized age threshold using a large dataset of patients treated at a comprehensive cancer center. METHODS: Overall, 1807 patients with a median follow-up of 109 months were included in the study. Recursive partitioning was used to determine which American Joint Committee on Cancer (AJCC) variables were most predictive of disease-specific death, and whether a different cutoff for age would be found. From the resulting tree, a new age cutoff was picked and patients were restaged using this new cutoff. RESULTS: The 10-year disease-specific survival (DSS) by Union for International Cancer Control (AJCC/UICC) stage was 99.6, 100, 96, and 81 % for stages I-IV, respectively. Using recursive partitioning, the presence of distant metastasis was the most powerful predictor of DSS. For M0 patients, age was the next most powerful predictor, with a cutoff of 56 years. For M1 patients, a cutoff at 54 years was most predictive. Having reviewed the analysis, age 55 years was selected as a more robust age cutoff than 45 years. The 10-year DSS by new stage (using age 55 years as the cutoff) was 99.2, 98, 100, and 74 % for stages I-IV, respectively. CONCLUSION: A change in age cutoff in the AJCC/UICC staging for WDTC to 55 years would improve the accuracy of the system and appropriately prevent low-risk patients being overstaged and overtreated.

Sentinel Lymph Node Biopsy for Cutaneous Head and Neck Melanoma: Mapping the Parotid Gland.

BACKGROUND: Sentinel lymph node biopsy (SLNB) for primary cutaneous head and neck melanoma (CHNM) has been shown to be successful and is the current standard of care for intermediate-thickness melanoma. We evaluated our experience with CHNM associated with SLNB mapping to the region of the parotid gland. METHODS: Retrospective review of a prospectively collected melanoma database identified 1014 CHNMs. Two-hundred twenty-three patients underwent SLNB, and 72 (32%) had mapping in the region of the parotid gland between May 1995 and June 2003. RESULTS: The mean number of SLNs per patient was 2.5. A sentinel lymph node (SLN) was successfully identified in 94% of patients, and in 12%, the SLN was positive for metastatic disease. Biopsy of intraparotid SLNs was performed in 51.4% and of periparotid SLNs in 26.4%, and a superficial parotidectomy was performed in 22.2%. Ten patients were found to have lymph nodes in the parotid region with metastatic disease (eight identified by SLNB), and two (20%) patients developed intraparotid lymph node recurrence in the setting of a negative SLNB. Same-basin recurrence in SLN-negative patients was 3.3% with a median follow-up of 26 months. Facial nerve dysfunction was identified in seven (10%) patients. Facial nerve function returned to preoperative status in all patients. CONCLUSIONS: SLNB for patients with primary CHNM mapping to the parotid gland can be performed with a high degree of accuracy and a low morbidity consisting of temporary facial nerve paresis.

SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1).

The activity of cullin-RING type ubiquitination E3 ligases is regulated by neddylation, a process analogous to ubiquitination that culminates in covalent attachment of the ubiquitin-like protein Nedd8 to cullins. As a component of the E3 for neddylation, SCCRO/DCUN1D1 plays a key regulatory role in neddylation and, consequently, cullin-RING ligase activity. The essential contribution of SCCRO to neddylation is to promote nuclear translocation of the cullin-ROC1 complex. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. We found that although SCCRO3 binds to CAND1, cullins, and ROC1, it does not efficiently bind to Ubc12, promote cullin neddylation, or conform to the reaction processivity paradigms, suggesting that SCCRO3 does not have E3 activity. Expression of SCCRO3 inhibits SCCRO-promoted neddylation by sequestering cullins to the membrane, thereby blocking its nuclear translocation. Moreover, SCCRO3 inhibits SCCRO transforming activity. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Taken together, our findings suggest that SCCRO3 functions as a tumor suppressor by antagonizing the neddylation activity of SCCRO.

Nomograms for preoperative prediction of prognosis in patients with oral cavity squamous cell carcinoma.

BACKGROUND: This study sought to develop prognostic tools that will accurately predict overall and cancer-related mortality and risk of recurrence in individual patients with oral cancer based on host and tumor characteristics. These tools would take into account numerous prognosticators beyond those covered by the traditional TNM (tumor-node-metastasis) staging system. METHODS: Demographic, host, and tumor characteristics of 1617 patients with cancer of the oral cavity, who were treated primarily with surgery at a single-institution tertiary care cancer center between 1985 and 2009, were reviewed from a preexisting database. Recurrent disease was recorded in 509 patients (456 locoregional and 116 distant); 328 patients died of cancer-related causes, and 542 died of other causes. The median follow-up was 42 months (range, 1-300 months). The following variables were analyzed as predictors of prognosis: age, sex, race, alcohol and tobacco use, oral cavity subsite, invasion of other structures, comorbidity, tumor size, and clinical nodal status. The stepdown method was used to select the statistically most influential predictors for inclusion in the final nomogram for each outcome of interest. RESULTS: The most influential predictors of both recurrence and cancer-specific mortality probability (CSMP) were tumor size, nodal status, subsite, and bone invasion. Nomograms were generated for prediction of overall survival (OS), CSMP, and locoregional recurrence-free probability (LRRFP). The nomograms were internally validated with an overfit-corrected predictive discrimination metric (concordance index) for OS of 67%, CSMP of 66%, and LRRFP of 60%. CONCLUSIONS: Nomograms have been developed that can reasonably estimate OS, CSMP, and LRRFP based on specific tumor and host characteristics in patients with oral cancer.

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR. In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA, EGFR, protein tyrosine phosphatase receptor S (PTPRS), and RICTOR. In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Post-operative PET/CT improves the detection of early recurrence of squamous cell carcinomas of the oral cavity.

BACKGROUND: We evaluate the impact of post-operative 18-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) for radiation planning on the detection of early recurrence (ER) and treatment outcomes in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed the records of patients treated with post-operative radiation between 2005 and 2019 for OSCC at our institution. Extracapsular extension and positive surgical margins were classified as high risk features; pT3-4, node positivity, lymphovascular invasion, perineural invasion, tumor thickness >5 mm, and close surgical margins were considered intermediate risk features. Patients with ER were identified. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between baseline characteristics. RESULTS: 391 patients with OSCC were treated with post-operative radiation. 237 (60.6%) patients underwent post-operative PET/CT planning vs. 154 (39.4%) who were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER than those planned with CT only (16.5 vs. 3.3%, p < 0.0001). Among patients with ER, those with intermediate features were more likely than those high risk features to undergo major treatment intensification, including re-operation, the addition of chemotherapy, or intensification of radiation by ≥ 10 Gy (91% vs. 9%, p < 0.0001). Post-operative PET/CT was associated with improved disease-free and overall survival for patients with intermediate risk features (IPTW log-rank p = 0.026 and p = 0.047, respectively) but not high risk features (IPTW log-rank p = 0.44 and p = 0.96). CONCLUSIONS: Use of post-operative PET/CT is associated with increased detection of early recurrence. Among patients with intermediate risk features, this may translate to improved disease-free survival.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.