Heart Transplantation and Cancer Risk in a BRCA1 Breast Cancer Survivor

Abstract

Background

BRCA1 carriers face increased risk of cancer. Limited data exist for post-transplant immunosuppression and malignancy screening in this population.

Case Summary

A 67-year-old woman with BRCA1-positive breast cancer developed anthracycline-induced cardiomyopathy requiring heart transplantation. She received enhanced surveillance for secondary malignancies with an uncomplicated course over 13 years. However, despite reduction in immunosuppression, 14 years later she developed a rare, fatal, metastatic adnexal tumor, eccrine porocarcinoma.

Why Beyond the Guidelines?

There are no established guidelines for post-transplant immunosuppression or cancer surveillance in patients with hereditary cancer syndromes such as BRCA1-associated hereditary breast cancer.

Discussion

This case demonstrates the complexity of balancing immunosuppression and management in patients with germline mutations who require heart transplantation. Further work is required to understand the intersection of oncologic genetic risk with immunosuppression and develop best practices for screening this distinct population.

Take-Home Messages

Cancer survivorship in BRCA1 carriers adds complexity to post-transplant management. Multidisciplinary, personalized care is essential for optimizing outcomes in such high-risk patients.

Graphical Abstract

Patients with germline BRCA1 and BRCA2 mutations face markedly elevated lifetime risks for breast, ovarian, pancreatic, and other cancers. BRCA1 mutations are associated with early-onset and more aggressive tumors, including triple-negative breast cancer (BC).¹ Improved oncologic care has extended survival, creating a larger BRCA-positive population susceptible to treatment-related sequelae, such as anthracycline-induced cardiomyopathy, which may necessitate heart transplantation (HT).²

Recipients of solid organ transplantation (SOT) have a 2- to 4-fold higher cancer risk owing to long-term immunosuppression impairing immune surveillance.³ In 2018, Youn et al³ demonstrated that over 10% of adult HT recipients develop new malignancy within 5 years of transplantation, which was associated with increased mortality.

Despite growing numbers of cancer survivors (CS) undergoing HT, data on SOT recipients with hereditary cancer syndromes remain limited. Batra et al⁴ found that 5.3% of HT recipients with pretransplant malignancy developed recurrence, highlighting the need for tailored surveillance and immunosuppressive strategies. As transplant candidacy expands for patients with prior malignancy, understanding how to manage their unique post-transplant cancer risk is increasingly critical. In this case, we describe the clinical course of a patient with BRCA1-positive BC who underwent HT.

Visual Summary.

Timeline of Clinical Events

FNA = fine-needle aspiration; GDMT = guideline-directed medical therapy; HT = heart transplantation; TAH/BSO = total abdominal hysterectomy with bilateral salpingo-oophorectomy; US = ultrasound; VAD = ventricular assist device.

Case Summary

A 38-year-old woman received a diagnosis of right-sided hormone receptor–positive, HER2-negative, BRCA1-positive BC. She underwent lumpectomy, adjuvant doxorubicin/cyclophosphamide/paclitaxel chemotherapy, radiation, and hormone therapy with tamoxifen followed by anastrozole. At age 44, she developed contralateral primary BC, again treated with lumpectomy, adjuvant chemotherapy, radiation, and continued hormone therapy. She elected to undergo a prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. Within a year of her second anthracycline course, the patient developed systolic heart failure. Historical oncology records were unavailable to determine the exact cumulative anthracycline or radiation doses.

The patient’s heart failure was managed for 7 years with guideline-directed medical therapy but progressed to advanced heart failure requiring a left ventricular assist device (LVAD). She remained in remission from BC and completed all pre-HT cancer screening before undergoing uncomplicated HT at age 52.

Post-HT immunosuppression included anti-thymocyte globulin induction followed by prednisone, mycophenolate, and tacrolimus as per institutional protocol at the time. Her early post-HT course was uncomplicated with no evidence of rejection. She remained on triple therapy 1 year post-HT; by 2 years, she was weaned off prednisone; and by 8 years, she was switched to tacrolimus monotherapy (goal 4-6 ng/mL) to further reduce her malignancy risk.

At 9 years post-HT, the patient was found to have grade 1 cardiac allograft vasculopathy. Everolimus (goal 2–4 ng/mL) was initiated 11 years post-HT for management of cardiac allograft vasculopathy and potential antineoplastic benefit, with the tacrolimus goal reduced to 3 to 5 ng/mL.

She also underwent a bilateral radical mastectomy to reduce her BRCA1-specific malignancy risk. In addition to routine age-related cancer screening, she underwent annual dermatologic examinations, pancreatic MRI scans, and thyroid ultrasound scans. Thyroid nodules were appreciated on ultrasound 6 years post-HT. Fine-needle aspirations of both nodules were benign.

At 13 years post-transplant, a new nasal lesion was discovered. Pathology showed features of invasive metatypical basal and squamous cell carcinoma resected by Mohs micrographic surgery followed by complex reconstruction and skin grafting.

The patient developed a nodule under her left eye 14 years post-transplant. Biopsy revealed carcinoma, and fine-needle aspiration of an adjacent lymph node confirmed metastatic poorly differentiated carcinoma. She underwent a radical resection, which demonstrated eccrine porocarcinoma with positive margins and perineural invasion.

Why Beyond the Guidelines

This case exemplifies a complex clinical intersection not addressed in existing transplant or oncology guidelines: a BRCA1-positive CS undergoing HT requiring long-term immunosuppression. Although general guidance exists for post-HT malignancy screening, there are no specific recommendations for managing patients with hereditary cancer syndromes regarding immunosuppressive modulation and cancer surveillance intensity. The use of nonstandard screening modalities (eg, pancreatic MRI, thyroid ultrasound) and eventual de-escalation to tacrolimus monotherapy in this patient were guided by expert consensus rather than evidence-based protocols. The development of metastatic eccrine porocarcinoma underscores the limitations of current strategies for genetically high-risk recipients and emphasizes the need for focused research to guide future care.

Case Outcome and Follow-Up

The patient underwent repeat Mohs surgery, modified radical neck dissection, and limited lateral rhinectomy with reconstruction followed by 33 fractions of external beam radiation to the left face and neck. Combined positron emission tomography/computed tomography showed no local disease, but demonstrated avid lesions in the lungs concerning for new metastases. Right upper lobe lung biopsy confirmed metastatic poorly differentiated carcinoma consistent with prior eccrine porocarcinoma (Figure 1).

Figure 1.

Lung Pathology From Right Upper Lobe Mass Consistent Confirming Metastatic Poorly Differentiated Carcinoma Consistent With History of Eccrine Porocarcinoma

The patient tolerated 5 cycles of carboplatin and paclitaxel, with initial response followed by progression involving soft tissue, liver, lymph nodes, spleen, lung, and bone. FoundationOne (Foundation Medicine) molecular analysis demonstrated multiple significant genetic variants in addition to BRCA1 including NTRK fusion and loss of APC, TP53, and RB1.

She then presented with seizures. MRI suggested nodular dural metastases with leptomeningeal enhancement, though cerebrospinal fluid cytopathology was negative for malignant cells. She underwent brain radiation (24 Gy left, 16 Gy right over 5 fractions). Dexamethasone was tapered to prednisone in anticipation of outpatient immunotherapy.

She began cemiplimab; however, after the first cycle she developed worsening dyspnea requiring readmission. Evaluations for rejection and checkpoint inhibitor myocarditis were negative, but computed tomography scans showed further progression of disease. The patient was transitioned to hospice and passed away in the hospital during the admission, 15 years post-HT.

Discussion

This case underscores the unique and unexplored challenges in managing patients with hereditary cancer syndromes who undergo SOT. The patient with BRCA1-positive BC and anthracycline-induced cardiomyopathy underwent HT and later developed multiple post-transplant malignancies, including a rare, fatal, metastatic eccrine porocarcinoma. Her course highlights critical gaps in guidance regarding cancer surveillance, treatment, and immunosuppression management in this dual-risk population.

With improved cancer therapies and risk-reducing strategies, selected CS are increasingly considered for HT. The 2024 International Society for Heart and Lung Transplantation (ISHLT) guidelines support SOT in CS when recurrence risk is acceptably low and malignancy-related survival will not limit post-HT survival.⁵ Similarly, the 2023 ISHLT guidelines recommend BRCA testing in candidates with family history, prophylactic surgery if positive, and referral to Cancer Risk Assessment Programs. The guidelines also stress individualized post-HT screening that may exceed standard American Cancer Society or US Preventive Services Task Force recommendations.⁶ For BRCA carriers, National Comprehensive Cancer Network and European Society for Medical Oncology similarly endorse intensified surveillance and surgical risk reduction.^7,8

The patient in this case developed a fatal metastatic eccrine porocarcinoma, an exceedingly rare cutaneous malignancy originating from the intraepidermal sweat gland duct. Eccrine porocarcinoma accounts for <0.01% of all cutaneous tumors and is often misdiagnosed.⁹ The presence of perineural invasion, nodal metastasis, and subsequent distant spread in this case emphasizes its aggressive potential and underscores the increased risks in immunosuppressed patients. To our knowledge, this is the first reported case of metastatic porocarcinoma in a BRCA1-positive patient undergoing SOT.

Optimal post-transplant surveillance for BRCA-positive patients is undefined. This patient's regimen of routine dermatologic examinations, pancreatic MRI scans, and thyroid ultrasound scans reflects a highly individualized, proactive approach. However, there are no existing guidelines to determine appropriate screening intervals or modalities for such high-risk patients post-HT, creating reliance on expert opinion and extrapolation from oncology literature. In the near future, possible options such as whole-body screening and circulating tumor DNA testing may better evaluate these patients for cancer.

Immunosuppression presents parallel challenges. Anti-thymocyte globulin induction reflected institutional practice at the time. However, current strategies increasingly weigh antibody status and malignancy risk, with efforts to minimize lymphocyte-depleting agents. Ultimately, this patient transitioned from triple therapy to tacrolimus/everolimus given new findings showing mechanistic target of rapamycin inhibitors may reduce both cardiac allograft vasculopathy and post-transplant malignancies.¹⁰ ISHLT guidelines similarly suggest considering mechanistic target of rapamycin–based regimens in high-risk patients.⁶ Nonetheless, comparative data are limited, highlighting the need for further study.

Transplant candidacy also requires weighing HT vs destination LVAD in high-risk patients. This patient initially required LVAD, but ultimately pursued transplant. Importantly, this approach aligned with the patient's preference for transplantation. Her subsequent long-term survival, beyond the median survival post-HT of 12.5 years, underscores that favorable outcomes are achievable in carefully selected cancer survivors, though higher oncologic risk must always be recognized.⁵

Finally, the patient’s history of anthracycline exposure illustrates broader lessons: non-anthracycline regimens may be safer for high-risk patients, and when repeat anthracyclines are unavoidable, dexrazoxane or liposomal doxorubicin can mitigate toxicity. Guideline-directed echo surveillance post-chemotherapy is also recommended, though data were unavailable in this case.⁶

As both transplant and cancer survivorship improve and the population of patients with genetic cancer syndromes continues to grow, medical teams will increasingly face complex scenarios such as this. Dedicated research and registry development are needed to establish evidence-based screening protocols, immunosuppression frameworks, and long-term oncologic strategies for BRCA-positive transplant recipients.

Conclusions

This case highlights the urgent need for evidence-based guidance at the intersection of hereditary cancer syndromes and HT. BRCA1-positive patients remain at lifelong risk of malignancy, a risk that may be amplified by long-term immunosuppression. Tailored screening strategies, multidisciplinary management, and dynamic immunosuppressive planning are essential in navigating these complex scenarios. This case also underscores the imperative to generate prospective data through registries and develop consensus guidelines for genetically predisposed patients undergoing transplantation.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •Cancer survivors with germline mutations such as BRCA1 can have successful post-transplant outcomes, but new or rare cancers may emerge years later.
• •Immunosuppressed patients are at significantly heightened risk of developing skin cancers, including rare and aggressive types.