Precision Oncology: Targeted Therapy and Immunotherapy

Precision oncology means choosing cancer treatment by the genetic make-up of the tumour rather than by its organ and stage alone. The biopsy is tested, usually by next-generation sequencing, for mutations that a targeted drug can block. If such a target is found, the patient receives the targeted drug, often a daily tablet, instead of chemotherapy. Immunotherapy adds a second option by restoring the immune system's ability to attack cancer.

Dr. Nithin S.G, Consultant, Medical Oncology, Fortis Flt. Lt. Rajan Dhall Hospital, Vasant Kunj, New Delhi, India, devoted the second half of his masterclass to these newer therapies, and illustrated them with his own patients: metastatic lung and breast cancers, a rare tumour in the chest and a rare sarcoma, all treated with targeted therapy or immunotherapy. This article sets out how precision oncology, targeted therapy, immunotherapy and liquid biopsy work, and where their limits lie. The diagnostic work-up that makes them possible is covered in how cancer is diagnosed, and the full pathway in the complete guide to cancer care.

What is precision oncology?

Precision oncology identifies which genetic abnormality is driving a particular patient's cancer, and treats that. Every cancer arises from genetic abnormalities in the cells that form it.

Dr. Nithin used ten patients with lung cancer to show the difference. Around ten years ago, all ten would have received broadly the same treatment: chemotherapy, surgery and radiotherapy. Today, all ten biopsies are sent for genetic testing by next-generation sequencing (NGS) or a genomic panel, tests that read many cancer genes at once. If the patients' cancers carry different targets, they receive different drugs, even though they all have the same cancer.

The outcome of testing falls into two groups:

• A target is found and a drug exists for it. The patient receives targeted therapy instead of chemotherapy.
• No target is found. This is common: not every patient's cancer has one. These patients receive conventional treatment, meaning chemotherapy, surgery and radiotherapy.

For many of the genetic changes seen in cancer, there is now at least one class of drug that acts on that gene, inhibits it, and so controls the cancer.

Targeted therapy versus chemotherapy

The difference lies in what each treatment attacks.

Chemotherapy acts on rapidly dividing cells. Cancer cells divide rapidly, but so do the bone marrow cells that make blood, the lining of the mouth and intestine, hair cells and skin cells. Chemotherapy damages them all, which is why it causes hair loss, vomiting, mouth ulcers, diarrhoea and falling blood counts.

Targeted therapy acts only on cells that carry the targetable mutation. Because it acts on the cancer cells, its side effects are far fewer: hair loss, vomiting, ulcers, diarrhoea and low blood counts are not often seen with targeted drugs. And most targeted drugs are oral tablets that patients take at home.

One caution, which Dr. Nithin stressed during the session: a targeted drug works only if the cancer carries its target. An EGFR inhibitor will not work in a lung cancer without an EGFR mutation. That is why testing comes first.

EGFR and lung cancer: the clearest case for genetic testing

Lung cancer is the clearest example of why genetic testing matters, because a substantial share of patients carry an actionable genetic change. The most common is a mutation in EGFR (the epidermal growth factor receptor), which Dr. Nithin put at around 10 to 35% of patients, with drugs such as osimertinib producing very good responses. European (ESMO) guidelines list approved drugs for each of the main lung cancer mutations, including EGFR, ALK and ROS1, and the majority are tablets.

Case: metastatic lung cancer with brain metastases

A non-smoking woman in her fifties came to Dr. Nithin about three years before the masterclass with cough and breathlessness. A chest X-ray showed a mass in the left lung; CT and biopsy confirmed non-small cell lung cancer, an adenocarcinoma. PET-CT showed extensive metastatic disease, and MRI of the brain showed six to eight brain metastases. She had severe headache, vomiting and difficulty seeing, and was bedridden and unable to walk.

Dr. Nithin set the historical benchmark. Treated with chemotherapy and radiation, patients like her used to survive less than one year without brain metastases, and three to six months with them.

Genetic testing found an EGFR exon 19 mutation, and she was started on osimertinib tablets. Within two months her symptoms had improved markedly. A repeat MRI showed that the brain lesions had disappeared and the lung lesion had shrunk. Three years later she remained on the same tablet and was doing well.

Breast cancer: three subtypes, three treatment strategies

Breast cancer is divided into hormone receptor positive, HER2 positive and triple-negative disease, based on immunohistochemistry on the biopsy. Each subtype now has its own treatment strategy.

Hormone receptor positive metastatic breast cancer

For stage IV hormone receptor positive breast cancer, treatment begins with tablets: an aromatase inhibitor, which lowers oestrogen levels, usually combined with a CDK4/6 inhibitor. If the disease progresses, genetic testing guides the next line. A PIK3CA mutation can be treated with alpelisib, alterations in the AKT pathway with capivasertib, and an ESR1 mutation with elacestrant. All are targeted drugs, and more are arriving.

A CDK4/6 inhibitor such as palbociclib, given as a tablet with hormonal therapy, is the standard first-line partner, and the subject of Dr. Nithin's second case.

Case: metastatic hormone receptor positive breast cancer

A woman in her sixties presented with a swelling in the right breast extending between the breasts. Mammography and CT showed a mass eroding the ribs, with enlarged lymph nodes in the armpit, and PET-CT confirmed extensive nodal spread. The biopsy showed ER and PR positive breast cancer. The disease was metastatic and not operable.

In earlier years she would have received chemotherapy. Instead, she was started on palbociclib with hormonal therapy, as two tablets. After about six months the chest wall mass had shrunk and was no longer visible on CT; on PET-CT the chest wall mass and the armpit nodes had disappeared. Four years on, she remained on the tablets and was doing well, without surgery and without chemotherapy.

HER2-positive metastatic breast cancer

HER2-positive breast cancer now has several families of drugs: monoclonal antibodies given as injections, tyrosine kinase inhibitors (TKIs) given as tablets, and further injectable drugs. These have raised median survival in metastatic HER2-positive breast cancer from about 20 months before HER2-targeted drugs to 56 months and beyond, so that patients now live for more than three years even with metastatic disease.

Case: HER2-positive breast cancer with brain metastases

A woman in her forties had noticed a very small breast lump and ignored it. She presented only when she suddenly developed severe headache, vomiting and weakness on one side of the body. MRI showed metastases in the cerebellum and brainstem; the breast biopsy showed HER2-positive cancer. Because of the severity of the brain disease she was started on trastuzumab deruxtecan (T-DXd). T-DXd is an antibody-drug conjugate: an anti-HER2 antibody that carries a chemotherapy payload directly to HER2-positive cells.

The repeat scan showed that both brain lesions had disappeared. About one to one and a half years later she was doing very well on the same treatment, without surgery or conventional chemotherapy.

Targeted therapy in rare tumours

A young man presented with cough and breathlessness, and lung cancer was suspected. The biopsy instead showed an inflammatory myofibroblastic tumour (IMT), a rare tumour. Genetic testing found an ALK rearrangement, and he was given crizotinib, an oral drug that acts on ALK. The large mass beside the heart, attached to the lung, disappeared on the follow-up scan.

The case makes the broader point: genetic testing can open a targeted option in rare tumours as well as common ones.

Immunotherapy for cancer: how checkpoint inhibitors work

Immune checkpoint inhibitors are the main form of cancer immunotherapy. They are given as intravenous infusions.

Cancers grow in part by evading the immune system, so that the body's white blood cells fail to recognise and attack them. Checkpoint inhibitors remove that brake and, in Dr. Nithin's description, reprogramme the white blood cells to attack and destroy the cancer. Many such drugs are now approved across different cancers.

Asked how immunotherapy compares with other cancer medicines, Dr. Nithin made two points. It is highly effective, and its side effects are far fewer than those of standard chemotherapy. But in some cancers, lung cancer among them, immunotherapy is combined with chemotherapy at first. A large initial tumour burden takes time for immunotherapy alone to control, so the two are given together until the disease is under control, after which the patient continues on immunotherapy alone to maintain the response.

Case: metastatic sarcoma

Sarcomas are usually very difficult to treat. A young woman in her twenties presented with metastatic alveolar soft part sarcoma (ASPS), a rare sarcoma arising in the pelvis, with metastases in the lungs and liver on PET-CT. She was started on an immune checkpoint inhibitor.

After six cycles the lung metastases had disappeared and the pelvic mass had shrunk, and later scans showed a complete response. She has no symptoms and no side effects, and receives an injection every three to four weeks. Whether the disease would return if treatment stopped is unknown. Because she is young and tolerating it well, treatment has continued.

Targeted therapy in patients with poor performance status

Performance status measures how much a patient's illness limits daily activity; on the widely used ECOG scale, a score of 3 means the patient is confined to bed or a chair for more than half the day. Chemotherapy, Dr. Nithin said, cannot be given to someone in a very poor state.

Targeted therapy changes that calculation, for two reasons: most targeted drugs are oral, and they lack the classic side effects of chemotherapy. Both of his brain metastasis patients were performance status 3 at presentation: the lung cancer patient was bedridden, and the breast cancer patient had lost coordination because of cerebellar metastases. Both improved markedly on targeted treatment.

His position was nuanced. Not every patient with poor performance status can be given targeted therapy. The decision depends on which target is present, which drug is available, and that drug's specific side effects. But more patients in poor condition can be treated with targeted therapy than with chemotherapy.

Liquid biopsy: cancer detection in a blood sample

A conventional biopsy requires a needle into the tumour, often under CT or ultrasound guidance. A liquid biopsy uses a blood sample instead.

It works because tumours shed material into the blood. Some cells slip away from the tumour and circulate through the body; these circulating tumour cells can settle elsewhere and, Dr. Nithin explained, are responsible for most recurrences. And when a tumour grows fast, cells in its centre outgrow their blood supply and die, releasing their DNA into the blood as cell-free DNA. A liquid biopsy detects circulating tumour cells and cell-free DNA.

Dr. Nithin described three uses:

1. Diagnosis. Detecting cancer from a blood sample.
2. Deciding on further treatment after surgery. If a patient has had surgery and would not otherwise need chemotherapy, but circulating tumour DNA is still found, chemotherapy may be given.
3. Follow-up. About six months after treatment, a negative test suggests a lower chance of recurrence.

These applications are advancing quickly, but using a blood test to decide who receives chemotherapy after surgery is still being evaluated in clinical trials and is not yet standard practice for most cancers.

Where precision oncology does not apply: uterine fibroids

Asked whether precision oncology could produce a drug for uterine fibroids, given how common they are, Dr. Nithin's answer was no. Fibroids are benign tumours, not cancers, and there is no specific targeted drug for them. Fibroids do carry recurrent genetic changes, most often in the MED12 gene, but none has yet led to a targeted treatment. The options remain hormonal therapy or surgery, such as myomectomy.

Protecting the tissue that makes precision oncology possible

Every targeted option in this article depends on one thing: enough tumour tissue left for genetic testing. Dr. Nithin's request to referring doctors was to take a proper biopsy rather than FNAC, and to order only the minimum immunohistochemistry stains needed for the diagnosis, so that the rest of the tissue block remains for NGS. The questions doctors raised on immunotherapy and on targeted therapy in frail patients are on the Live Discussion page.