TRAcking Thoracic Cancer Evolution Through Therapy (Rx) EVO

Inclusion Criteria:

* Cohort A, B and C :

  * Written Informed consent
  * Agreement to be followed up (including on-study assessments and sample collection) every 3 months in the first 2 years and then 6 monthly.
  * Agreement to be followed up at a TRACERx EVO site

Cohort A:

* Participants ≥18 years of age, with early stage I-IIIB NSCLC disease who are eligible for primary surgery
* Histopathologically confirmed NSCLC, or a strong suspicion of cancer on lung imaging necessitating surgery (e.g., diagnosis determined from frozen section in theatre)
* Primary surgery in keeping with NICE guidelines (lobectomy, either open or thoracoscopic), lung parenchymal-sparing operations (segmentectomy or wedge resection) if a complete resection can be achieved, extensive surgery (bronchoangioplastic surgery, bilobectomy, pneumonectomy) if necessary to obtain clear margins, hilar and mediastinal lymph node sampling or en bloc resection)
* For participants proceeding with upfront primary surgery (i.e. no neoadjuvant therapy), a minimum tumour diameter of at least 15mm on imaging to allow for tissue sampling of at least two tumour regions; this can either be two fresh tissue samples or one fresh tissue sample plus one representative diagnostic FFPE block (to be requested at a later date according to trial specific procedures)
* Participants undergoing neoadjuvant treatment must have at least 1 region of fresh frozen or FFPE surgical or diagnostic biopsy tissue.
* Considered sufficiently fit for upfront standard of care primary surgery or neoadjuvant therapy if indicated
* Performance status 0 to 2

Cohort B:

* Participants ≥18 years of age, with late-stage unresectable stage IIIB and above NSCLC disease (TNM 8th edition) or presenting with stage IV de novo metastatic disease.
* Sufficient tissue (at least 1 region/biopsy), either FFPE or fresh frozen
* Deemed to be fit for anti-cancer treatment
* Performance status 0 to 2 Participants who were initially consented into Cohort A who are found to have more advanced disease pre- or immediately post operatively (e.g. locally advanced/inoperable or stage IV disease) could be included in Cohort B.

Cohort C:

* Participants ≥18 years of age, with any stage SCLC or pleural mesothelioma.
* Sufficient tissue (at least 1 region/biopsy), either FFPE or fresh frozen
* Deemed to be fit for anti-cancer treatment
* Performance status 0 to 2

Exclusion Criteria:

* Cohort A, B and C:

  * Any other active or current malignancy and/or systemic treatment (excluding hormone therapy) for that malignancy in the last 12 months (i.e., participant must be cancer free for the last 12 months, and if on therapy it can only be hormone therapy).

    * Exceptions are: non-melanomatous skin cancer, stage 0 melanoma in situ, and in situ cervical cancer, or for Cohort C, cases of NSCLC that have transformed to SCLC, or for Cohort A another synchronous lung cancer.
  * Psychological condition that would preclude informed consent
  * Diagnosis other than NSCLC, SCLC or pleural mesothelioma confirmed following surgery or biopsy
  * Confirmed diagnosis of known high-risk infections (e.g., Human Immunodeficiency Virus) (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection, tuberculosis and Creutzfeldt-Jacob disease) unless participant case is of a particular scientific interest and agreed in advance with research staff, local mortuary staff and pathologist.
  * Contra-indicated severe co-morbid conditions

Cohort A:

* Positive margins, incomplete resection or insufficient nodal sampling
* Insufficient tissue, i.e., for participants having upfront surgery and not having neoadjuvant therapy, a minimum of two tumour regions unlikely to be obtained for the study based on pre-operative imaging, or for participants having neoadjuvant therapy at least one tissue biopsy unable to be obtained prior to neoadjuvant therapy (Fresh Frozen or FFPE).
* Participant found to have pre-invasive lesions rather than invasive cancer following surgery, such as adenocarcinoma in situ or minimally invasive lesions will be withdrawn. However, the surgical tissue and baseline blood already collected will be sent to the central laboratory. These participants will not be followed-up in the study or required to provide any further blood samples. If these participants subsequently develop invasive cancer, the date of diagnosis and the tumour histology will be reported on the electronic data capture system.

Cohort B/C:

• Insufficient tissue, i.e., at least one tissue biopsy unable to be obtained (Fresh Frozen or FFPE)