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What is cancer drug resistance? Q&A with Dr Maurizio D’Incalci

One of the biggest obstacles in treating cancer is drug resistance. There are still many unanswered questions about the genomic features of this resistance, including different patient responses to therapy, the role drug resistance plays in the relapse of tumours, and how cancer treatments in the future will combat drug resistance. One doctor at the forefront of ovarian cancer research is Dr Maurizio D’Incalci, who answered some of the important questions for us about this serious issue in oncology.

What is chemotherapy drug resistance?

Antineoplastic resistance, or chemotherapy resistance, is the ability of cancer cells to survive and continue to grow despite being treated with anti-cancer therapies.

How does this drug resistance develop?

Chemotherapy kills the drug-sensitive cells within the tumour, but leaves a proportion of drug-resistant cells behind – meaning that when the tumour begins to grow again, chemotherapy may fail because the cells are now resistant.

Epithelial ovarian cancer (EOC) is one example of a cancer type which experiences drug resistance. EOC is generally sensitive to platinum-based chemotherapy, and the vast majority of patients respond to platinum-based therapy after debulking surgery, a process in which part of the malignant tumour is removed. Unfortunately, more than 80% of these patients relapse with a progressively resistant disease, and tend to die within five years of diagnosis.

Why is it important that we understand more about the genetic make-up of tumours?

The relationships between molecular characteristics of tumours, patient outcome, and patient responses to therapy are still unknown. Studies performed so far in large cohorts of patients, at both the genetic and epigenetic level, have failed to provide reliable biomarkers, or specific genes, which can help us to improve patient classification. We also cannot identify the genomic alterations which are critical for the development of a targeted approach against EOC and other types of cancer.

"Micrograph of serous carcinoma, a type of ovarian cancer, diagnosed in peritoneal fluid" by Nephron. CC BY-SA 3.0 via Wikimedia Commons.
“Micrograph of serous carcinoma, a type of ovarian cancer, diagnosed in peritoneal fluid” by Nephron. CC BY-SA 3.0 via Wikimedia Commons.

In addition, there is currently no molecular information available on tumour biology at relapse, as secondary debulking surgery for epithelial ovarian cancer is only performed in a small fraction of patients who relapse. Therefore, we do not know whether the molecular scenario connected with tumour relapse mirrors the initial tumour tissues.

What were the key findings in your study on profiling cancer gene mutations?

Our study took advantage of a unique tumour tissue collection of more than 1,700 frozen tumour biopsies collected over the last 20 years. In this biobank there were a few cases in which biopsies were taken both before any therapy or after some lines of chemotherapy when the recurrent disease was less sensitive to treatment. The study shows two key findings to be taken away. There is a less than 2% concordance between the primary tumour and the recurrent disease – demonstrating the wide variations between initial occurrence of the cancer, and the subsequent regrowth. Secondly, the genetic make-up of the relapsed disease is less diverse than the primary disease. Alterations in the initial tumours do not accurately reflect those that are present at relapse, and this has potential implications for prognosis and treatment.

How are cancer treatments going to develop in the future to combat drug resistance?

Understanding the relationship between the initial tumour and the relapsed tumour is an important step in the solution to chemotherapy drug resistance. Until now, important choices regarding treatment have been made by looking at the initial tumour, when in fact the relapsing disease, which is resistant to the chosen therapy, may have evolved in a completely different direction. This is initial proof that longitudinal biopsies – the continual observation of the same patients over a period of time – could be useful for the clinical management of epithelial ovarian cancer.

Featured image credit: ‘Granulosa Cell Tumour of the Ovary, CEA Immunostain’ by Ed Uthman. CC BY 2.0 via Flickr.

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