Expert Commentary – Unanticipated consequences of personalised medicine in cancer medicine

  • Levit LA & al.
  • J Oncol Pract
  • 25 Feb 2019

  • curated by Ben Gallarda
  • Univadis Clinical Summaries
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Dr Pauline Leonard is a consultant medical oncologist at Whittington Hospital NHS Trust, where she manages patients with lung and gastrointestinal malignancies, and is part of both the upper GI and lower GI multidisciplinary teams. In addition to patient care, Dr Leonard is also involved in promoting excellent communication skills in clinical consultations via several courses and programmes.

The ultimate goal for any patient who is diagnosed with cancer is to be offered the most effective treatment with the least toxicity to ensure extended survival and an optimum quality of life. That is the promise of personalised or precision medicine. By tailoring specific treatments to the molecular characteristics of the cancer, response rates can be improved, and toxicity can be minimised. Examples of personalised medicine include imatinib mesylate for chronic myeloid leukaemia where BCR-ABL oncogene is overexpressed or gastrointestinal stromal tumours which harbour the c-kit oncogene. The use of this treatment has transformed the care and survival of those who have these diseases. It also means those who do not harbour the actionable mutation or carry a mutation that confers resistance can be spared a treatment that is unlikely to work, for example, cetuximab in KRAS mutant colorectal cancer.

The enormous interest, as well as significant financial investment in further developing precision medicine for a whole host of cancer sub-types means there are an increasing number of new drugs available.

The ability to perform Next Generation whole exome sequencing (NGS) has brought further challenges as not all testing platforms perform equally. Many NGS reports include a large number of variants of uncertain significance or fail to distinguish somatic from germline mutations.The genomic reports include a wealth of information which is not always easy to understand. The rapidity in which new targeted medicines are reaching the bedside from the bench means many clinicians do not feel sufficiently trained to guide their patients to the best treatment as some detected variants will not have a therapeutic target.

There are on-going clinical trials such as the NCI-MATCH trial or the UK Lung Matrix trial which are attempting to match subsequent treatments to the molecular profile of their cancer.

Despite this exponential rise in available targeted treatments for patients with incurable or metastatic cancer, sadly, most patients will have a cancer that does not harbour an actionable mutation, so they will have an unmet need as the only viable alternative will be a cytotoxic combination with no perceived precision of care. Currently, less than 20% of all metastatic cancers will harbour any actionable mutation. Even with the enthusiasm for immunotherapy as a personalised and better tolerated systemic treatment for many cancers, for those expressing the biomarker Programmed Cell Death Ligand 1 (PD-L1) at greater than 50% in the tumour sample, the response rates are modest and there is not a targeted solution for all who receive them.

Hope enables any person with a diagnosis of cancer to adapt and face the challenges of the proposed treatment schedules. Hope however has to be appropriate and tailored to the individual and their circumstances. The communications put out by some institutions and private companies are driving some patients and their families to organise their own molecular analyses and chemotherapy sensitivity assays. Such a promise to guide systemic treatment based on individual cancer characteristics is very seductive, so many are spending thousands of pounds on having such detailed but essentially unvalidated reports.

Personalised communication lies at the heart of great care, so it is incumbent on the clinician to provide honest and balanced information when it comes to precision medicine. The art is balancing between ensuring that those who are fit for systemic treatment do have their cancers tested for all possible actionable mutations, i.e. mutations for which a drug is available to treat, against not falsely raising expectations in those whose fitness or projected prognosis may never benefit.