Oesophageal Squamous Cell Carcinoma (OSCC) is a cancer of the food pipe that affects around 2000 patients in the UK every year. It is often detected at an advanced stage, resulting in poor survival (5-year survival less than 20%). Early detection can improve survival (5-year survival >70%). Therefore, early detection is vital to improving survival.

There are no national screening guidelines, and an endoscopy (A camera test to look at the food pipe) is the only available test to detect OSCC.

Early detection of OSCC is challenging for many reasons. Firstly, early disease symptoms are non-specific, which patients often overlook. Secondly, 'Alarm' symptoms such as weight loss, difficulty swallowing or vomiting blood are signs of advanced stage. Lastly, endoscopy is an invasive test with associated risks and significant discomfort.

The investigators propose to develop a breath test for patients with non-specific symptoms. Breath testing has the ideal characteristics for a triage test because it is non-invasive, simple to perform, cost-effective and highly acceptable to patients. The test is based on identifying volatile organic compounds (VOCs, small molecules) that are produced by the cancer and released in breath.

The breath test will be offered by General Practitioners (GPs) to patients with non-specific symptoms. Those who test positive will be referred for an urgent camera test, and those who test negative can be reassured.

In this prospective multicentre case-control study, the investigators will recruit a total of 518 patients. These will be divided into the following groups:

1. Cancer group (n=259): Patients with treatment naive, histopathology confirmed OSCC.
2. Control group (n=259): Patients who have undergone or are undergoing an upper gastrointestinal (GI) endoscopy as part of their investigation for upper GI symptoms and are found to have either - (i) A normal upper GI tract or (ii) Benign upper GI disease.

Eligible and willing participants will be asked to provide two breath samples by exhaling into single-use breath collection bags. Using a custom designed gas sampling pump, the breath VOCs will be transferred onto thermal desorption (TD) tubes at a controlled flow rate. When the participants' breath sampling is complete, room air (Blank) samples will be taken onto additional TD tubes using the same process.

Once collected, the TD tubes will be transported to Imperial College London (The Hanna lab), where they will be analysed.

Inclusion Criteria: Participants with all the following characteristics will be eligible for inclusion in the study:

1. Cancer cohort (n=259): Patients with treatment naïve, histopathology confirmed OSCC.

2. Control cohort (n=259): Patients who have undergone or are undergoing an endoscopy (OGD) as part of their investigation for upper GI symptoms and are found to have either:

   • A normal upper gastrointestinal tract
   • Benign upper gastrointestinal disease

Exclusion Criteria: Participants with the following characteristics will not be eligible for inclusion in the study:

1. Received some form of treatment (chemotherapy, radiotherapy, immunotherapy, endoscopic resection, or surgery) for OSCC
2. History of another cancer in the last five years
3. Non-squamous cell oesophageal cancer
4. Barrett's oesophagus (with or without dysplasia)
5. Previous oesophageal or gastric resection
6. Unable to provide written consent or lack capacity.
7. Pregnant women

Patients with treatment naïve OSCC will be identified via the weekly multidisciplinary team (MDT) meetings (OSCC group). Patients undergoing an OGD for upper GI symptoms will be identified using the National Health Services (NHS) trust booking systems (Control group).