Next-generation DNA sequencing could improve breast cancer treatment

By Will Boggs MD

NEW YORK (Reuters Health) - Next-generation DNA sequencing (NGS) could identify women with high-risk genetic mutations early enough to alter treatment decisions, researchers from the UK report.

"NGS-based BRCA testing is already available commercially and many breast cancer specialists make use of this service, particularly in well-funded healthcare settings," Dr. Simon M. Pilgrim from Addenbrooke's Hospital in Cambridge told Reuters Health by email. "What is changing is that many more genes can be sequenced as the technology becomes cheaper; the advantages and quick turnaround of NGS will increasingly be available to patients in less well funded healthcare economies in the near future."

Dr. Pilgrim and colleagues reviewed published studies relating to breast cancer genetics in an effort to demonstrate how NGS might influence breast cancer practice.

With conventional Sanger sequencing, individual exons of genes of interest are analyzed one at a time. With NGS, though, patient DNA is broken into many short segments, all of which are sequenced in parallel. Computers then reassemble the short-sequence segments into the full sequence.

Continuing advances in bioinformatics and computing power will soon make it possible to sequence the whole genome within a timeframe that will be relevant for clinical decision-making, the researchers assert.

Companies have already introduced NBS-based panels that sequence breast cancer risk genes in multicancer panels of six, 16, and 94 genes.

Use of NGS could reduce the time for BRCA1/BRCA2 testing, reporting, and communication with the patient from 10-12 weeks to four weeks, and the testing could be cheaper, according to the March 27 British Journal of Surgery online report.

For women at risk for cancer, the benefit of NGS would be not faster results, but broader panels that simultaneously test all the putative breast cancer genes.

In women already diagnosed with breast cancer, earlier availability of BRCA1/BRCA2 status could alter treatment decisions. For example, knowledge of the BRCA1/BRCA2 status may lead a woman to choose mastectomy over wide local excision or even elect to have preventive contralateral mastectomy or risk-reducing salpingo-oophorectomy during the same surgical session.

Moreover, somatic cancer gene profiling could facilitate classification of breast cancers on a molecular basis that could, in turn, allow application of the most appropriate adjuvant chemotherapy.

"In terms of challenges to breast cancer services, NGS means that services will have to be flexible in order to respond to sequencing information that arrives shortly before scheduled surgery," Dr. Pilgrim said. "Breast cancer units will have to be prepared to change treatment plans at short notice and be equipped to support their patients effectively as the new information arrives."

"In addition, NGS is likely to reveal many variations of unknown significance - that is, mutations which may or may not alter the risk of breast or other cancers," Dr. Pilgrim said. "These will present difficulties both for counseling patients and for the genetics team as they attempt to determine an individual's risk profile."

With data on so many genes and single nucleotide polymorphisms (SNPs), who will be able to sort out the implications of various combinations of mutations? "This is a particularly interesting area for the future," Dr. Pilgrim said. "Medical genetics teams will need to process complicated combinations of mutations and SNPs to counsel patients about their individual risks. I imagine that computerized algorithms will be required to determine individual risk - perhaps analogous to existing breast cancer prognosis models such as Adjuvant!Online and PREDICT."

"The main message here for breast cancer specialists is that NGS is becoming more accessible and that while it presents opportunities for improved treatment for breast cancer patients and research into breast cancer, it also presents breast cancer patients and services with challenges," Dr. Pilgrim concluded. "We hope that our paper will enable breast cancer teams to consider the impact of NGS on their services and plan any changes that might become necessary in order to maximize the benefits for their patients."

SOURCE: http://bit.ly/1lKQZ8f

Br J Surg 2014.

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