The Unholy Pairing of Cancer and Peripartum Cardiomyopathy

Patrice Wendling

January 07, 2020

New research bolsters a connection between the risk for cancer before and after peripartum cardiomyopathy (PPCM) and identifies genetic variants underlying PPCM and a variety of cancers.

"This study is the first to describe a markedly increased risk for malignancies both before and after the diagnosis of PPCM," Tobias J. Pfeffer, MD, Hannover Medical School, Germany, and colleagues observe.

PPCM develops in about one in 1500 previously healthy women worldwide and is a leading cause of peripartum maternal death. Some studies have identified truncating mutations in the gene TTN in a subset of women, whereas others have shown that blocking prolactin release with bromocriptine may remove a key driver of the disease by preventing the generation of a toxic 16-kDa prolactin fragment from the nursing hormone prolactin.

"We have made a lot of progress on treating PPCM, but we still have large gaps in knowing why this disease happens to young women," senior study author Denise Hilfiker-Kleiner, PhD, also from the Hannover Medical School, told | Medscape Cardiology.

She noted that although cardiotoxic cancer therapies have been linked to a higher risk for PPCM, the team was also seeing an increase in early-onset cancer in women after PPCM at their institution.

At the same time, a large Swedish population study reported that elevated cardiac and inflammatory biomarkers in healthy individuals predicted new-onset cancer, independent of age, smoking status, and body mass index.

To examine the prevalence of cancer and a possible genetic overlap between the two diseases, the researchers compared data from 236 German and Swedish PPCM patients with age-matched patients from a German cancer registry. Median follow-up was 33 months (range, 5 months to 19 years).

The prevalence of cancer was 16-fold higher in women with a history of PPCM than in their age-matched peers without PPCM (8.9% vs 0.59%; odds ratio [OR], 16.4; 95% confidence interval, 10.5 - 25.7), the authors reported December 17 in JACC: CardioOncology.

Among the 12 patients diagnosed with cancer before PPCM, 11 had received chemotherapy and/or radiation in childhood or adolescence, but none showed signs of heart failure after cancer treatment or prior to pregnancy.

During follow-up, however, only 17% of patients with a cancer diagnosis before PPCM fully recovered — defined as a left ventricular ejection fraction (LVEF) of at least 50% — compared with 55% of PPCM patients without cancer.

Among the 10 PPCM patients with a cancer diagnosis after PPCM, seven displayed normal LV function after cancer therapy. Compared with the age-matched women without PPCM, the risk for cancer was still eightfold higher after PPCM (OR, 8.5; 95% CI, 4.5 - 16.1).

To examine what might be driving PPCM and cancer in these patients, researchers analyzed whole-exome-sequencing data available for a subset of 14 PPCM patients, 10 of whom developed cancer before and three after the onset of PPCM.

The results showed that 43% of patients carried gene variants likely pathogenic or pathogenic (LP/P) for dilated or hypertrophic cardiomyopathy (DCM/HCM) and/or cancer predisposition syndrome (CPS).

In 11 patients, variants of unknown significance (VUS) and likely pathogenic/pathogenic variants associated with cardiomyopathy were detected in eight genes: CPT2, DSG2, DSP, MYBPC3, MYH7, RYR1, TTN, and TXNRD2.

In seven of the 14 patients, VUS and likely pathogenic/pathogenic variants were found in eight other genes — ATM, BRCA1, ERCC5, FANCA, NBN, POLD1, RECQL4, and SLX4 — all of which are involved in DNA-damage repair (DDR).

"We are far away from having this complete because exome sequencing in larger cohorts is not financially an easy task, but it is interesting that from 30 additional PPCM patients without cancer, we did not find a CPS mutation in a single one," Hilfiker-Kleiner said. "So I think this cancer predisposition pathway is a really interesting aspect of the results."

"It is striking that they all map in a single pathway…: the DNA repair pathway," she said. "It's quite a crucial pathway and if mutated can lead to all sorts of cancers."

Indeed, cancers in the 21 PPCM patients varied widely, from osteosarcoma to acute myeloid leukemia, with one patient developing Hodgkin's lymphoma before PPCM and breast cancer after PPCM, noted Hilfiker-Kleiner.

Although the patient numbers are small, the absence of DDR variants in PPCM patients without cancer "may still be an interesting lead" because variants in ATM and BRCA1 may promote heart failure, including from anthracycline cardiotoxicity, through an impaired stress response, Jean-Luc Balligand, MD, PhD, UCLouvain and Cliniques Universitaires Saint-Luc, Brussels, said in a related editorial.

"For PPCM patients with a cancer history, the observation of LP/P or variants of unknown significance for CPS/DDR genes in one-half of them is intriguing and novel, and it deserves confirmatory longitudinal studies in childhood/adolescent cancer survivors to verify if they predispose to PPCM with or without cancer recurrence," he said.

With regard to PPCM possibly promoting cancer, Balligand also highlighted the link between cardiac and inflammatory biomarkers and new-onset cancer, and noted that in the context of the present study, it is plausible that women with CPS/DDR variants, and thus a genetic background for neoplastic disease, developed cancer in the wake of PPCM and heart failure.

"These observations may well have far-reaching implications, not only for the understanding of the pathogenic mechanisms of PPCM and cancer development in patients with heart failure, but also for the clinical care of women with a history of PPCM or cancer who become pregnant," he said.

Both the editorialist and the researchers say the data support close monitoring of LV function in women with a history of cancer who become pregnant, and cancer screening at least for the next 5 or 10 years in women who develop PPCM.

"The mechanistic connection of these two diseases should trigger that both fields, cardiology and oncology, are aware that this exists and counsel their patients and sensitize them for the disease of the other discipline," Hilfiker-Kleiner said.

Although PPCM cannot be prevented, current guidelines give a class IIb recommendation to add bromocriptine to standard heart failure therapies, she noted. This was done in three-fourths of PPCM patients in the study, with only one patient, who did not receive bromocriptine, requiring transplant.

Limitations of the study are the observational design, which prevents determining causality, and the small number of genetic results, Hilfiker-Kleiner said.

"We are a translational lab and what we are doing is breeding mice that have mutations in this DNA damage pathway to see if they will develop PPCM, which would support the idea that the cancer predisposition variants we found in our patients are also responsible for the PPCM the patients have," she said. "We also developed a model where we can induce heart failure in mice to see if the heart failure will lead to an early onset of cancer in individuals that carry these cancer predisposition mutations."

"Even though it was only 14 patients, the observation that all these mutations mapped in this DNA damage repair pathway, we believe, is not by chance," she added.

The study was supported by grants from the Deutsche Forschungsgesellschaft, the Bundesministerium für Bildung und Forschung, and DGK-Oskar-Lapp. The authors and Balligand report having no relevant conflicts of interest.

JACC: CardioOncology. 2019;1:196-205 and 206-207. Full text, Editorial

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