Predictive Clinical Features and Molecular Markers for tumor response and treatment Outcomes in HPV negative Oral Cancers

Rationale for study

Squamous cancers of the oral cavity, account for a major proportion of cancers in the Indian population . The sheer load and morbidity associated with these cancers mandate further evaluation of the disease biology. These Oral cancers are managed by surgery followed by adjuvant therapy (radiation/chemoradiation) and radical chemoradiation when the tumor is deemed unresectable. However, many patients present in an advanced stage wherein tumor resection is rendered questionable in view of the positive resection margins. The prognosis of unresectable stage IVA or IVB tumors treated with a non-surgical approach is poor, with median survival ranging from 2 to 12 months . It’s for these locally advanced borderline operable cases where the role of neoadjuvant chemotherapy (NACT) has been postulated as an alternative to the current existing therapeutic modalities . The aim is to downstage the tumor and provide adequate margins of resection. Although NACT provides a promising scenario for managing this patient subgroup, it should be known that response rates to this modality vary from 35-40%. It means that a significant proportion of patients do not benefit from chemotherapy.

Joshi et al. analyzed T4b oral cavity cancer patients who were offered NACT and then assessed for resectability at the end of 2 cycles of chemotherapy. NACT was safe and can achieve resectability in 30.9% of patients. Patients undergoing resection have much better OS than those who underwent non-surgical local treatment  Patil et al. evaluated 721 patients with stage IV oral-cavity cancer who received NACT, of which 310 patients (43%) had a sufficient reduction in tumor size and underwent surgical resection. NACT led to successful resection and improved overall survival in a significant proportion of technically unresectable oral cancer patients . More recently, Chaukar et al., in a prospective phase-II randomized study on OSCC patients with paramandibular disease needing segmental mandibulectomy, demonstrated that NACT (docetaxel, Cisplatin, and fluorouracil) plays a potential role in mandibular preservation in oral cancers with acceptable toxicities and no compromise in survival

Although NACT has been evaluated over the last decade, its chemoresistance and the underlying molecular mechanisms are yet to be studied comprehensively. The key clinical question is differentiating between responders (achieve resectability) and non-responders. B-tubulin II, p53, GST, ERCC, HPV, and other molecular markers have been proposed as surrogate markers for NACT responsiveness in head and neck cancer . However, there is a dearth of predictive clinical, pathological, or molecular markers to suggest a response to chemotherapy that will help us in better therapeutic stratification of these patients. No study has been focused specifically on the markers to predict response in HNSCC/ OSCC, which is the aim of this study. This will prevent unnecessary chemotherapy in patients with a ’chemoresistant’ genotype, thus sparing patients from toxicities.