New Clue as to Why Only Some Breast Cancers Relapse

Zosia Chustecka

September 25, 2015

UPDATED September 26, 2015 // VIENNA — A new clue as to why only some breast cancers recur comes from the largest study of genetic sequencing of breast cancer tissue to date.

While most breast cancer is cured after treatment, about 20% of cases recur. The new study shows that the cases that recur have a different genetic profile, and suggests that some of the genetic drivers of relapse are targetable with drugs.

"We demonstrate that there are clear differences within the driver landscapes of relapsed cancers. This probably reflects a combination of predisposition to relapse and of differences in the mutations acquired during the relapse and metastasis phase," say the researchers, led by Lucy Yates, MD, a clinical research oncologist from the Wellcome Trust Sanger Institute in Cambridge, United Kingdom.

The finding raises the hope that breast cancer patients who are most at risk for relapse can be identified when they are first diagnosed, they suggest.

In addition, as the newly identified genetic drivers of relapse are targetable with drugs, there is also hope that eventually women who are identified as being at high risk for relapse could be treated with such drugs to prevent recurrence, they suggest.

The study is due to be presented European Cancer Congress (ECC) 2015, but details were released early by the ECC press office.

The finding comes from a study that compared the genetic make-up of breast cancer from 836 tissue samples taken from women on primary diagnosis with 161 samples of tissue taken from recurrences or metastases.

The study is the largest and most comprehensive carried out to date, say the researchers, both in terms of the number of samples from relapsed breast cancers and in terms of the wide-ranging genetic sequencing carried out, which looked at 365 genes involved in cancer-related pathways.

The researchers performed de novo driver mutation discovery, and individual mutations were annotated with likely driver status based upon recurrence and known driver status in previously published, well-curated datasets and databases. The incidence of each driver mutation in the primary and relapse datasets was compared using Fisher's exact test and using the Benjamini–Hochberg correction for multiple testing.

The team found 11 genes that were significantly enriched in the relapsed cohort compared with the primary tumor cohort. The most heavily enriched were TP53 and ARID1B. Multiple samples were available for 66 patients, including local or distant relapse samples in all cases and a sample from the primary tumor in 21 cases. This multisample analysis allowed the team to trace the evolution of mutations.

"We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis," Dr Yates said in a statement.

"We believe that the differences we have seen reflect genetic differences that can predispose a cancer to return, combined with mutations acquired throughout the period from first diagnosis to the subsequent relapse," she added.

However, in a discussion of this paper, Fabrice André, MD, PhD, from the Gustave Roussy Institute, in Villejuif, France, questioned whether all the genes that were found to be enriched in the relapsed samples were driving the relapse and whether any could be identified as recurrent markers. He noted that although Dr Yates and colleagues found 11 genes that were highly enriched in the relapsed tissue samples, another study (which analyzed 183 samples) found only one of these genes to be highly enriched.

Dr Andre also wondered whether the late mutations that were identified are clinically relevant ― could they explain the development of resistance to therapy? This has been seen in other cancers, he noted.

Extreme Heterogeneity ― Need for Multiple Biopsies

"Our data reveal extreme heterogeneity and indicate that genomic analysis of primary, relapsed, and matched normal tissue are needed," Dr Yates concluded.

"We need to do biopsies again and again and again," said Anne-Lise Borresen-Dale, MD, from the Institute for Cancer Research, Oslo University Hospital, Norway, who chaired the session. But Dr Andre wondered whether circulating tumor cells, the so-called "liquid biopsy," could be used.

Multiple samples were available for 66 subjects, including local or distant relapse samples in all cases and a sample from the primary tumor in 21 cases. This multisample analysis permitted relative temporal ordering of driver mutation accumulation to be determined, the researchers explain.

"We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis," Dr Yates said in a statement.

"This study highlights the differences between genetic alterations that drive relapsed and metastatic disease as opposed to primary breast cancers, and underlines the importance of analyzing the genetic features of metastases when making treatment decisions," said Jorge Reis-Filho, MD, from the Memorial Sloan Kettering Cancer Center in New York City, who was acting as a spokesperson for the European Society of Medical Oncology, which is cohosting the meeting. He was not involved with this work.

However, Dr Reis-Filho also cautioned that "the extent of the differences in the repertoire of mutations among different metastatic sites within individual patients remains to be determined, however, as does the best way to obtain tumor-derived genetic material in patients with metastatic disease. We also need to know more about whether single or multiple metastatic sites should be analyzed in this context."

Also commenting on the study, Peter Naredi, MD, PhD, professor of surgery at Sahlgrenska University Hospital in Gothenburg, Sweden, who is the European CanCer Organization scientific cochair of the congress, said: "Information such as that which Dr Yates will present is very important in the era of precision medicine."

"This study also underlines the fact that we should consider a recurrence of a cancer as a new event, and carefully select the right treatment for the recurrent tumor as opposed to just relying on information from the first occurrence," Dr Naredi said in a statement.

JAK Inhibitors in Breast Cancer

Some of the genetic changes that were found in the relapsed/metastatic breast cancer samples appeared at a late stage when the cancer recurred, and were not seen in samples taken at primary diagnosis. Among these later-stage mutations, the researchers say they found "compelling evidence" for the tumor suppression activity of two related genes, called JAK2 and STAT3, that operate within the same signaling pathway.

"Within some breast cancers, a disruption in this signaling pathway seems to be advantageous for survival of the cancer," Dr Yates said in a statement.

"Interestingly, this is in contrast to the role of JAK2 in some other cancers, where overactivity of the gene drives malignancy rather than suppresses it," she added.

The JAK (Janus-associated kinase) enzymes JAK1 and JAK2 are involved in regulating blood and immunologic functioning, and a dysregulation of these enzymes is thought to be a driver in the development of myelofibrosis. The first JAK inhibitor, ruxolitinib (Jakafi, Incyte Corp), was approved for the treatment of myelofibrosis in 2011.

Dr Yates and colleagues note that enhanced JAK-STAT signaling is known to play an important role in breast cancer stem cell development and cancerous cell line survival, and preclinical evidence seems to suggest that inhibiting the gene would be therapeutically advantageous. These findings have led to the development of clinical trials for breast cancer using JAK inhibitors in the hope that they will slow cancer progression.

"However, our findings suggest that, in a subset of cancers, inhibiting this pathway may have the opposite effect, and this requires further investigation. In general, the observation highlights the importance of understanding the diverse nature of breast cancers in the era of precision medicine," Dr Yates said.

The work was funded by the Wellcome Trust. Dr Yates has disclosed no relevant financial relationships.

European Cancer Congress (ECC) 2015: Abstract 1804. To be presented September 26, 2015.

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