A World-Wide Survey on Kidney Transplantation Practices in Breast Cancer Survivors

The Need for New Management Guidelines

Keith S. Hansen; Hila Ghersin; Merisa Piper; Mehdi Tavakol; Brian Lee; Laura J. Esserman; John P. Roberts; Chris Freise; Nancy L. Ascher; Rita A. Mukhtar

Disclosures

American Journal of Transplantation. 2021;21(9):3014-3020. 

In This Article

Discussion

The current guidelines for kidney transplantation have wide implications for those ESRD patients with a history of breast cancer.[17] Most transplant professionals queried consider current guidelines to be inadequate, and consequently, utilization is low. Additionally, we found that access to organs for patients with a history of breast cancer varied by geographic region and surgeons' beliefs. Considering the magnitude of the population affected, since approximately 5% of the world's two million patients with ESRD also have a diagnosis of breast cancer, these findings support the need for new approaches to kidney transplantation decisions in this setting.[12] Reassuringly, the vast majority of respondents (90.4%) indicated a willingness to change the approach to waiting periods for kidney transplantation in patients with prior breast cancer if new prognostic tools are available.

Historically, wait times ranging from a minimum of 2–5 years to observe tumor biology have been recommended, in the hopes that those without early recurrences will also be spared later recurrences. Retrospective studies published by the Israel Penn International Transplant Tumor Registry (formerly the Cincinnati Transplant Tumor Registry) between 1981 and 1997 serve as the basis for these guidelines. These studies found that patients with a history of treated breast cancer had a high rate of cancer recurrence ranging from 23% to 25% posttransplant.[18] While an analysis of 377 patients in Norway with pre-kidney transplant cancers found an increased risk of cancer-related death in recipients with a prior history of breast, kidney, prostate, lung or plasma cell cancers compared to those without a cancer history, a recent population-based analysis found no increased risk of recurrence in transplant recipients with a pre-transplant history of malignancy.[19,20] Concern about potential breast cancer recurrence is important however, as breast cancer recurrence in transplant recipients is associated with significantly increased risk of mortality.[2] Since tools now exist to better predict recurrence risk in breast cancer, the approach to transplantation in this population no longer needs to largely depend on a time interval since diagnosis.

Previously, breast cancer prognosis was determined by pathologic stage, which was based on anatomic features including tumor size and number and location of involved lymph nodes (Tumor, Node, Metastasis or TNM system).[24] The development of molecular markers that reflect the heterogeneity of breast cancer has resulted in a new staging system termed prognostic staging, described in the American Joint Committee on Cancer 8th edition cancer staging manual.[25] By incorporating biomarkers (ER, progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2], grade, and multigene assays), overall stage is modified to better match prognosis, and is termed Clinical Prognostic Stage. An analysis of over 50 000 patients in the California Cancer Registry found that incorporation of tumor specific biomarkers resulted in change of staging (anatomic versus prognostic) in over half of cases, with examples of changes and resulting 5-year disease-specific survival estimates shown in Table 2.[26] With many potential permutations, the Clinical Prognostic Staging system results in 170 prognostic groups.

Additionally, new approaches such as neoadjuvant therapy allow for calculating endpoints like the Residual Cancer Burden, which correlate with recurrence risk, and the development of gene expression assays like MammaPrint and Oncotype Dx both provide prognostic and predictive information.[22,23]

These emerging data and the large number of prognostic groups illustrate the broad range of recurrence risk based on tumor biology, but also highlight the complexity of incorporating personalized medicine into clinical decision-making. We feel that the best approach currently is to develop a multidisciplinary team including both the transplant committee and breast oncology specialists to make case by case recommendations for transplant candidates with breast cancer, with special attention to identifying breast cancer patients with very low likelihood of cancer recurrence for whom waiting periods prior to transplantation are unlikely to be helpful. This is especially true because most low-risk breast cancers are ER-positive; these tumors have a higher risk for late recurrence rather than early recurrence, making a 2–5 years waiting period less biologically relevant.[21] Guidelines based on waiting periods and stage alone fail to account for wide variation in recurrence risk, which can be determined more accurately with tailored, personalized approaches.[27]

While many questions remain unanswered, recent data on the use of checkpoint inhibitors give new insights into the role of the immune system in breast cancer. Several studies show an association between more aggressive breast cancers and the presence of immune infiltrates surrounding tumors, particularly in those of the so called triple-negative subtype (ER-negative, PR-negative, HER2-negative).[15,17] Our study found that 84% of respondents believe immunosuppression increases the risk of breast cancer recurrence or worsens breast cancer-related survival. This belief was strongly associated with decreased willingness to perform immediate transplant. Data suggest that the relationship between immunosuppression and breast cancer recurrence is complex and likely dependent on breast cancer subtype. Molecularly low-risk tumors without tumor-associated immune infiltrates have a limited response to checkpoint inhibition. In contrast, more aggressive tumors with high immune infiltrates have an improved response to reversal of immunosuppression, suggesting that understanding the specific tumor biology is essential in quantifying the impact of immunosuppression on cancer outcomes.[28] Triple-negative cancers, which are more responsive to immune activation, comprise less than 15% of breast cancers in the US.[20]

Patients with ESRD who wait for kidney transplantation rely on dialysis which has a 5-year survival rate of 35%, whereas patients with low-risk regional breast disease have 5-year survival rates exceeding 90%.[12,29] The risks of a mandatory years-long waiting period must be weighed against the risk of breast cancer recurrence, particularly for patients with a potential living donor. We have previously reported that molecular phenotyping can be successfully applied to transplant candidates to stratify their risk of recurrence and allowed two patients' mandatory inactive status to be eliminated prior to successful kidney transplantation.[16] This was further reflected in the latest 2020 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for transplantation which recommended a 2-year waiting period for low-risk breast cancers with an acknowledgement that there exists a role for molecular phenotyping in the stratification of recurrence risk.[4]

As currently written, the variation in guidelines leads to individual and geographically based decisions that can contribute to outcome disparities in receipt of kidney transplantation.[16,30] We found that 27% of respondents would wait at least 5 years before transplanting a patient with a history of breast cancer. There is a significant opportunity to potentially decrease morbidity and mortality resulting from prolonged dialysis for low-risk breast cancer patients. Encouragingly, most providers surveyed would consider eliminating wait-times for women with a low risk of cancer recurrence based on the accurate prediction of molecular assays, but 31% had not heard of their existence. These data reveal that there is overwhelming support for revising current practices and a need to disseminate information about breast cancer subtyping.

Our study has limitations that may affect interpretation of the data. Although the response rate in the current study was modest, it was comparable to the expected average response rate of external group surveys. To optimize participation, we designed a survey that was brief and, consequently, did not capture the full range of research being done in the field. Furthermore, it is the first survey on this topic in the literature. We did not record respondent transplant center, and there may be clustering of opinions regarding renal transplantation for breast cancer patients by centers, potentially adding bias. Another limitation is the potential for response bias, for example, those who completed the survey had stronger opinions about the topic and they may not represent the larger population of transplant surgeons and nephrologists. Furthermore, many decisions on transplantation are made via committees that include more than transplant surgeons and nephrologists. Data obtained from this survey were self-reported and reflect personal opinions of the respondents.

Importantly, this study has revealed that region of practice and beliefs about immunosuppression lead to variable access to organs for a vulnerable patient population. While the field of breast cancer has changed dramatically and our ability to predict outcome and recurrence has greatly improved, the integration of this information into transplantation guidelines has lagged. These findings should prompt revision and dissemination of guidelines and afford more opportunities for receiving kidney transplants in many women with breast cancer.

processing....