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MDS Patients Fare Worse With Two Mutated Copies of TP53 Than One, Research Shows

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NEW YORK – It has long been established that mutations in TP53 — the gene most frequently altered across all cancer types — can be an important predictor of patients' survival outcomes and response to treatment.

In myeloid dysplastic syndromes, for instance, TP53 mutations are associated with shorter overall survival, resistance to standard treatments, and the transformation of MDS into acute myeloid leukemia.

Now, a group of researchers from Memorial Sloan Kettering and the International Working Group for Prognosis in MDS have found that it isn't just the presence of the TP53 mutation that confers worse outcomes for patients with MDS but rather the number of copies of the mutated allele they have. Specifically, as the researchers detailed in a paper recently published in Nature Medicine, patients with MDS who have two mutated copies of TP53 have worse outcomes, whereas patients with just one mutated copy have similar outcomes as patients with wildtype TP53.

"It's a simple paper based on a simple theory," said Fransesc Solé, who is a member of the MDS Group at the Josep Carreras Leukaemia Research Institute in Spain, and one of the researchers and authors of the paper. But in Solé's view, it's often the simple papers that end up having the most valuable implications.

Although more research is needed to establish if TP53 allelic state is predictive of whether MDS patients will benefit from specific treatments, Solé believes the association with outcomes is strong enough that next-generation sequencing labs should start detailing whether MDS patients have one or two mutated copies of TP53 in test reports.

And researchers should look at the impact of this molecular feature in other cancers. "We have only shown this [significance of TP53 allelic state] in MDS in this paper, but in the coming months I am sure that we will start to see papers coming out showing the same in other cancers, [like] AML, CML, myeloma, breast cancer, or colorectal cancer," he said.

Prognostic value of allelic state

To assess the implications of the TP53 allelic state on patient outcomes, the researchers analyzed the genetic profiles of 3,324 treatment-naïve patients with MDS or similar myeloid neoplasms. Patients' samples were profiled using tumor-only, capture-based NGS. The test panel is designed to detect common genetic mutations and copy number changes in MDS. The researchers used an in-house algorithm to generate the allele-specific copy number profiles from the NGS data, and they validated their findings using an additional 1,120 patient samples.

Out of the 3,324 patients, 378 patients had oncogenic TP53 mutations, and in one-third of those patients the mutations were monoallelic, meaning patients still had one residual wildtype copy of TP53. In the remaining two-thirds of patients with TP53-mutated MDS, the mutations were dubbed "multi-hit," meaning the patients had two TP53 abnormal copies. The abnormal copies included TP53 mutations, deletions, or copy-neutral loss of heterozygosity.

Analyzing patients' outcomes alongside their TP53 allelic state, the researchers found significant differences between the monoallelic TP53 mutation group and the multi-hit TP53 mutation group. Patients with monoallelic mutations, for instance, had a median of 4 percent of bone marrow blasts compared to multi-hit patients, who had 9 percent. The overall survival for monoallelic patients and multi-hit patients was 2.5 years versus 8.7 months, respectively, and the likelihood of MDS transforming into AML was 21 percent for the monoallelic group versus 44 percent for the multi-hit group.

Ultimately, through statistical modeling that accounted for other risk factors such as patients' age and established prognostic markers, the researchers were able to deduce that multi-hit TP53 was an independent predictor for the risk of death and AML transformation. Monoallelic TP53 state, on the other hand, was ultimately found to be no different compared to wild-type TP53 in predicting these risks.

"Now, it's no longer enough to say, 'TP53 is mutated,'" Solé said. "What is important now is to say, 'The two copies of TP53 are mutated.' To say a patient's prognosis is poor [based on TP53], it is mandatory to know if they had one or two copies affected."

Although patients with monoallelic TP53 mutations were found to have better outcomes than those with multi-hit mutations, the researchers did note in their findings that, within the monoallelic group, prognoses differed quite a bit depending on how heterogeneous patients' cancers were, and whether they harbored co-occurring driver mutations. Patients with monoallelic TP53 mutations and no other identifiable mutations had an 81 percent five-year survival rate, for instance, compared with 36 percent, 26 percent, and 8 percent for those with one or two, three or four, or more than five other driver mutations, respectively.

On the other hand, for patients with multi-hit TP53 mutations, additional co-mutations didn't make as much of a difference. Among the multi-hit patients, five-year survival rates were below 6 percent, regardless of the presence of co-mutations. "These data further showcase that monoallelic TP53 mutations are not independently predictive of adverse risk," concluded the researchers.

Treatment implications, clinical relevance

In addition to assessing patients' survival rates according to TP53 allelic state, the researchers also explored whether this biologic feature could predict treatment response. They looked at patients who received three standard MDS treatments — lenalidomide (Bristol Myers Squibb's Revlimid), hematopoietic stem cell transplantation, and various hypomethylating agents — and found that those with monoallelic TP53 mutations experienced prolonged survival compared to patients with multi-hit TP53 mutations. Of note, researchers reported "a trend for improved survival" among monoallelic patients who received stem-cell transplants, though the cohort was too small for the researchers to say for sure.

Without additional proven treatment options, these findings lack utility for patients found to have multi-hit TP53 mutations, however. "I hope in some years a company will develop a treatment against [mutated] TP53, but for now, this is bad news for patients with two [altered] copies," said Solé. "It would be difficult to know the best treatment to administer for a patient who presents with two copies of mutated TP53 at diagnosis."

To be sure, while no TP53-targeting agents have been approved for MDS, there are companies actively working on their development. In June, for instance, Aprea Therapeutics announced it had completed patient enrollment for a Phase III trial of its investigational agent eprenetapopt combined with azacitidine (Celgene's Vidaza) in TP53-mutant MDS. In earlier trials of this regimen, the company had reported that the combination enabled roughly half the patients with TP53 mutations to go on to receive a stem cell transplant, which is usually possible for only about one in every 10 patients with TP53-mutated MDS.

For the ongoing trial of Aprea's eprenetapopt, the eligibility criteria stipulate that patients have "at least one" TP53 mutation. As such, it may be possible for the investigators to evaluate patients' TP53 allelic state, contingent on the testing technology they are using to identify patients with the gene mutation for trial eligibility. Aprea Therapeutics did not respond to a request for comment on the method used to identify and enroll patients with TP53 mutations. 

While Solé did not specifically speak to Aprea's Trial, he generally stressed the importance of drugmakers' continuing to develop agents to target TP53. On the brighter side, he said, for patients with just one copy of the mutation, treatments that have historically been thought to confer worse outcomes in all patients with TP53-mutated MDS, including stem cell transplants, may now be viewed as a more promising option.

For now, more research is needed to determine exactly how these findings should be used to guide treatment decisions for MDS patients with monoallelic and multi-hit TP53 mutations. Indeed, Solé and colleagues concluded their paper by urging researchers to continue assessing TP53 allelic state — including in other cancers beyond MDS.

In the interim, Solé advised molecular testing labs to begin including information on allelic state in reports. "The technique would be the same," Solé said, explaining that labs performing NGS are already able to determine TP53 allelic state, but may not be reporting it.

"They should add that information," he insisted. "This is really something very simple that could have important implications for MDS and for other cancers."