Circulating Tumour DNA and the Biology of Cancer Recurrence

CAR-T cell therapy, and immunotherapy generally, works on a simple concept: our own immune cells are competent enough to fight infection and cancer, but whenever cancer is present, immunity goes down. Immunotherapy retrains the remaining immune cells to fight again, rather than killing the tumour directly. The drugs make our own immunity more competent, cells that were lying idle are retrained and made to recognise the cancer as the enemy, and then they go and fight it.

The exact mechanism is still not fully known. But one clear factor is genetic aberrations that occur over time because of environmental exposure: if a patient achieves a cure but resumes alcohol or smoking, the damage caused by tobacco or other carcinogens affects the DNA again and dormant cells can get reactivated. That is one reason recurrence happens, though most of the time the actual mechanism is not known.

For bone metastasis, use a nuclear bone scan; if that is unavailable, do a skeletal survey, plain X-rays of the spine, ribs, pelvis and limbs. For liver metastasis, a CT abdomen substitutes for PET, and an ultrasound is a fair investigation if CT is also unavailable. For the lungs, a CT chest is the alternative, and a plain chest X-ray is fair enough if CT is not available. Also check the uterus and ovaries with a pelvis ultrasound in every breast cancer patient, to rule out Krukenberg tumours. Ultrasound and X-rays are available almost everywhere in the world, and while less precise than PET-CT, this combination is enough to establish metastatic staging.

Diagnosing cancer early, at stage 1 or 2, translates into cure; stage 4 offers very minimal chances of cure for any cancer. Where facilities and education are limited, the solution has three parts: awareness, awareness, and awareness, among doctors, the public and government. Over almost 30 years of practice, running thousands of community cancer-awareness camps across India, Nepal, Bhutan and Bangladesh with NGO partners has produced a real shift: around 1997, 75-80% of patients presented in stage 3 or 4; today in metropolitan India, around 60% present at an early stage.

A non-healing mouth ulcer of 15-20 days in a smoker warrants a biopsy for oral cancer. A voice change over six weeks or dysphagia should raise suspicion. A cough not responding to 4-5 weeks of anti-tuberculosis treatment needs a chest X-ray. Early satiety, feeling full after a much smaller meal than usual, is a classic warning sign for stomach cancer. Unexplained weight loss or easy fatiguability should raise suspicion of pancreatic or liver cancer, and every jaundice patient should get at least an ultrasound rather than being assumed to have hepatitis. A change in bowel habit should prompt investigation for colorectal cancer, and around 30% of bleeding per rectum, usually assumed to be piles, is actually cancer. A painless testicular swelling should not be assumed to be a hydrocele without an ultrasound, and an enlarging soft tissue lump assumed to be a lipoma should get an FNAC to rule out sarcoma.

As a screening tool (a positive blood test prompts further investigation to locate a tumour), a treatment-response monitor (falling levels after chemotherapy or immunotherapy indicate response), and a recurrence-detection tool (reappearance of previously absent DNA years later can signal recurrence).

The exact mechanism is not fully understood, but resumed exposure to carcinogens such as tobacco or alcohol after treatment is one known contributing factor that can reactivate dormant cancer cells.