Genetic predisposition in chemotherapy‐induced cardiomyopathy in a 65‐year‐old female with metastatic breast cancer

Abstract

The prevention and management of cancer therapy‐related cardiac dysfunction (CTRCD) have become increasingly important. Recent studies have revealed the crucial role of genetics in determining the susceptibility to development of CTRCD. We present a case of a 65‐year‐old woman with breast cancer who developed recurrent CTRCD following low‐dose chemotherapy, despite lacking conventional cardiovascular risk factors. Her medical history included anthracycline‐associated cardiomyopathy, and her condition deteriorated significantly after treatment with HER2‐targeted therapies. Through the use of multimodal imaging, we detected severe left ventricular systolic dysfunction. Further investigation with genetic testing revealed a likely pathogenic variant in the TNNT2 gene, suggesting a genetic predisposition to CTRCD. This case implies the potential role of genetic screening in identifying patients at risk for CTRCD and advocates for personalized chemotherapy and cardioprotective strategies.

Introduction

Chemotherapy‐induced cardiomyopathy, now referred to as cancer therapy‐related cardiac dysfunction (CTRCD), is a critical adverse event in cancer patients. ¹ The risk of developing CTRCD is influenced by various factors, including cancer type and stage, types and doses of anticancer drugs, specific therapy combinations (drug–drug or drug–radiation), advanced age, and underlying comorbidities like previous cardiovascular disease. ¹ , ² However, while these clinical risk factors contribute, they do not fully explain why these conditions affect only a selected group, suggesting the presence of additional influencing factors.

Recent studies highlight the genetic influence on the development of cardiomyopathy. ³ Pathologic variants in genes encoding sarcomere proteins may predispose individuals to CTRCD. Here, we report a case of a 65‐year‐old woman with breast cancer admitted for severe symptomatic CTRCD, with the absence of conventional cardiovascular risk factors. Genetic testing revealed a likely pathogenic variant in the TNNT2 gene, implying its potential contribution to her susceptibility to CTRCD development.

Case Report

A 65‐year‐old woman with metastatic breast cancer was admitted to our hospital via the emergency room due to worsening dyspnea and orthopnea. She had no prior history of diabetes or hypertension, and there was no other significant family medical history. Chest radiography revealed significant cardiomegaly along with bilateral pleural effusion (Figure  1 ), with her NT‐proBNP level markedly elevated at 11 409 pg/mL. Echocardiography revealed a deterioration in left ventricular (LV) systolic function: LV ejection fraction (EF) decreased from 51.1% to 19.8%, and global longitudinal strain declined from −14.9% to −2.9% (Figure 2 , Movies S1 and S2).

Figure 1.

Chest radiograph showing bilateral pleural effusion, cardiomegaly, and a chemoport.

Figure 2.

Findings from transthoracic echocardiography. Transthoracic echocardiography, performed after stabilization from initial anthracycline‐associated cardiomyopathy, revealed mild left ventricular (LV) systolic dysfunction (LV end‐diastolic dimension 55.1 mm, LV ejection fraction 51.1%, and LV longitudinal strain value −14.9%, panel A). However, after two cycles of pertuzumab/trastuzumab/docetaxel combination chemotherapy, the patient complained of severe dyspnea. Follow‐up echocardiography revealed a dilated LV with severe LV systolic dysfunction (LV end‐diastolic dimension 63.7 mm, LV ejection fraction 19.8%, and LV longitudinal strain −2.9%, panel B).

Remarkably, 7 years ago, she had experienced anthracycline‐associated cardiomyopathy (AACM), presenting with her LVEF decreasing from 58% to 48% after four cycles of anthracycline therapy with a cumulative dose of 240 mg/m². Despite her breast cancer being identified as HER2 positive, HER2‐targeted therapy was not given. Instead, she received treatment with candesartan 4 mg and carvedilol 3.125 mg. While she had been stable without dyspnea, her LVEF showed suboptimal recovery, ranging from 50% to 53% (Figure 2 A ). However, approximately 1 month ago, she underwent two cycles of pertuzumab/trastuzumab/docetaxel combination chemotherapy due to multiple metastases. Following this treatment, her heart failure symptoms worsened significantly, with her LVEF decreasing from 51.1% to 19.8% in just 1 month (Figure 2 B ). In summary, this worsening heart failure presentation was considered a case of recurrent cardiomyopathy attributed to HER2‐targeted therapy in the context of a prior history of AACM.

Supporting this diagnosis, cardiac magnetic resonance imaging revealed severe LV systolic dysfunction (LVEF 17%) without late gadolinium enhancement. However, native T1, T2 values and extracellular volume fraction of LV were elevated (Figure  3 ). Coronary angiography exhibited no significant epicardial stenosis. To identify Mendelian genetic disorders, sequencing was performed using a TruSight One Expanded sequencing panel consisting of 6700 genes (Illumina Inc., San Diego, CA, USA) on a NextSeq 550 (Illumina, CA, USA). The test results indicated the presence of a heterozygous likely pathogenic missense variant of TNNT2, NM_001276345.2:c.452G>A (p.Arg151Gln), which was subsequently confirmed via direct sequencing (Figure  4 ). The variant was classified as a likely pathogenic variant according to the American College of Medical Genetics and Genomics guidelines and the latest Clingen recommendations. Key points supporting this classification includes (i) the variant is located in a mutational hot spot (PM1_M); (ii) the variant is very rare in gnomAD population database (0.000007997) (PM2_P); (iii) this missense amino acid change occurs at the same location as another pathogenic missense change (Arg151Trp) (PM5_M); (iv) aggregated scores from computational prediction tools indicate a deleterious effect on the gene (score: 0.893) (PP3). On the other hand, in clinical exome sequencing, no pathogenic mutations were detected in other genes related to hereditary cardiomyopathy, nor were there any variants related to CTRCD, such as truncating variants of TTN.

Figure 3.

Cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging showed dilated LV (short‐axis cine image, panel A) without definite late gadolinium enhancement (short‐axis view in panel B and horizontal long‐axis view in panel C). However, native T1, T2 values and extracellular volume (ECV) fraction of LV were elevated (elevated T1 values, mean 1440.9 ms, in panel D; elevated T2 values, mean 50.4 ms in panel E; and elevated ECV fraction, mean 42.2% in panel F).

Figure 4.

DNA sequencing chromatogram of the patient. The direct sequencing confirmed a heterozygous likely pathogenic missense variant of TNNT2, NM_000364.3:c.452G>A (p.Arg151Gln) in the patient.

The patient's hospital course progressed without complications. She received comprehensive supportive care, including pleural drainage, inotropic support, diuretics, and guideline‐directed heart failure medications. With this treatment, her symptoms gradually ameliorated, leading to her discharge after 10 days. Following stabilization, her chemotherapy regimen transitioned to Gemcitabine. Three months later, her LVEF showed improvement to 43.5%. However, she faced an unfortunate demise due to septic shock resulting from bile duct obstruction.

Discussion

The current study presents a case of recurrent CTRCD despite relatively low‐dose chemotherapy, after administering 240 mg/m² of anthracycline and recurring during the second cycle of trastuzumab therapy. AACM is typically dose‐dependent, with incidence rates of 18% and 65% observed at cumulative doses of 350 and 550 mg/m², respectively. Historically, the cumulative dosage of anthracycline was limited to 550 mg/m²; however, the recent trends have led to a reduction to 350 mg/m². ⁴ The development of AACM in our case at lower doses than the usually permissive dose raises suspicion of potential genetic susceptibility, especially in the absence of other conventional cardiovascular risk factors. Notably, the patient exhibited a heterozygous likely pathogenic variant in the TNNT2 gene, indicating a potential correlation between this genetic variant and an increased vulnerability to CTRCD.

The importance of genetics in cardiomyopathy is increasingly recognized, as recent cardiomyopathy guidelines emphasize this aspect. ⁵ Despite the growing attention on the genetics of general cardiomyopathy, the evidence regarding genetic susceptibility or predisposition to developing CTRCD is limited. As CTRCD typically manifests as a phenotype of dilated cardiomyopathy (DCMP), studies have been conducted on genetic variants associated with DCMP in patients with CTRCD. Although DCMP represents a complex and diverse genetic architecture, the most commonly reported genetic variants in DCMP are variants of TTN, LMNA, and MYH7. ⁶ In particular, reviewing studies reporting TNNT2 variants identical to our case, there were two cases that showed DCMP phenotype. ⁷ , ⁸ Previous studies described (likely) pathogenic variants in TTN and MYH7 in patients with CTRCD, suggesting genetic predisposition for DCMP might be a risk factor for CTRCD. ⁹ , ¹⁰ , ¹¹ Garcia‐Pavia et al. compared the frequency of rare genetic variants in DCMP genes among patients with CTRCD and healthy individuals. The study showed that among patients with CTRCD, truncating variants of TTN were the most commonly found, followed by MYH7, BAG3, TCAP, LMNA, and TNNT2. ⁹ Wasielewski et al. identified pathogenic variants, specifically a missense variant in the MYH7 gene, in a DCMP family with AACM. ¹¹

TNNT2 gene encodes the cardiac isoform of troponin T, which is critical for sarcomere integrity and contractile function. ¹² Variants in the TNNT2 gene have been reported in about 5.5% of DCMP and have shown a severe disease phenotype with higher mortality and morbidity in various cardiomyopathies. ¹³ , ¹⁴ , ¹⁵ While TNNT2 variants in DCMP have been documented, only a single case report has described a TNNT2 gene variant in CTRCD to date. In the case reported by Moghadasi et al., a 46‐year‐old female breast cancer patient developed CTRCD 8 months after receiving a cumulative anthracycline dose of 240 mg/m². Furthermore, she received the insertion of Implantable Cardioverter Defibrillator (ICD). The patient was found to have a maternally inherited pathogenic variant of the TNNT2 gene, specifically identified as NM_001276347.1:c.556G>A, p.(Gly186Ser). Additionally, family history revealed that her mother had also been diagnosed with DCMP and had undergone ICD insertion. ¹⁰ In our case, similar to Moghadasi's, the patient had no comorbidities and developed severe symptomatic CTRCD following low‐dose anthracycline treatment and also had a missense variant in the TNNT2 gene, but there was no family history. Both cases exhibited severe disease phenotypes akin to those seen in DCMP associated with TNNT2 variants, manifesting as a decrease in LVEF to as low as 10%, followed by recovery to about 40% within a few months. These case reports lend support to the notion that genetic factors associated with DCMP may increase the risk of developing CTRCD.

However, our case cannot directly establish causal inferences regarding genetics and CTRCD. There is a possibility that other risk single nucleotide polymorphisms (SNPs) may influence the results. Additionally, drug metabolism‐related genotypes could impact the course of CTRCD development. Unfortunately, we lack this information as we did not conduct SNP arrays or whole‐genome sequencing. Despite these limitations, our case has the potential to advance the understanding of genetic susceptibility or predisposition to CTRCD, an area with limited available data. Regarding the reported TNNT2 variant, there is currently only one case report in CTRCD. While our case is singular and anecdotal, gathering similar cases will help bolster the evidence base. Given the limited evidence to date, there are no guideline‐based recommendations supporting genetic testing for evaluating the risk of cardiac dysfunction prior to starting chemotherapy. Nevertheless, as more evidence supports the role of genetic variation in CTRCD, conducting further investigations to identify cancer patients at high risk for CTRCD through genetic testing can help reduce CTRCD incidence while ensuring effective cancer therapy. ⁹

In conclusion, our case revealed a rare genetic variant in the TNNT2 gene of a CTRCD patient, suggesting that genetic testing could serve as a valuable screening tool to identify patients at high risk of CTRCD. This could lead to more tailored chemotherapy and cardioprotective strategies, potentially improving clinical outcomes for patients with cancer.

Supporting information

Movie S1. Transthoracic echocardiography performed after stabilization from initial anthracycline‐associated cardiomyopathy. Echocardiography showed mild LV systolic dysfunction.

Movie S2. Follow‐up echocardiography after two cycles of pertuzumab/trastuzumab/docetaxel combination chemotherapy. Echocardiography revealed a dilated LV with severe LV systolic dysfunction.

Lee, S.‐Y. , Kim, H. S. , Jung, M.‐H. , Chang, S. , Kim, M. , Youn, J.‐C. , Chung, W.‐B. , and Jung, H. O. (2024) Genetic predisposition in chemotherapy‐induced cardiomyopathy in a 65‐year‐old female with metastatic breast cancer. ESC Heart Failure, 11: 2410–2414. 10.1002/ehf2.14803.