By Self, Michael; Dunn, Ernest; Cox, John; Brinker, Karl
Improvements in immunosuppression have increased patient and graft survival in transplant recipients. As a result, there is greater risk of neoplastic processes such as breast cancer. Treatment in this population is complicated by the necessary immunosuppression, vascular accesses, and transplant grafts. General surgeons may expect to encounter more of these complex patients in the community setting. We sought to evaluate the surgical treatment of breast cancer in patients with renal transplants. Hospital and private physician records were queried to identify patients who developed breast cancer after a renal or pancreatic/renal transplantation. These charts were reviewed for demographics, type of breast cancer and treatment, location of dialysis access, and complications. From June 1, 1994, to May 31, 2004, 14 patients were identified. Eight patients had functioning transplants. All patients underwent operative interventions. Ten patients underwent adjuvant treatment. Three had functioning transplants and chose not to risk the graft with cessation of immunotherapy. However, no patient with functioning transplants who underwent chemotherapy developed organ failure. Breast cancer after transplantation poses a unique dilemma. The threat of transplanted organ failure is a major concern to these patients and often supersedes adjuvant therapies.
As OF 2001, THERE WERE more than 7 million American adults suffering from a decline in their renal function.1 In that same year, 15,331 underwent a kidney transplant for end-stage renal disease.2 This is greatly increased from the 9,655 transplants performed in 1988. Improvements in immunosuppressive therapy continue to further the life span of these recipients. Logically, the incidence of induced and naturally occurring neoplasms will escalate as this population of patients grows. This is true for cancers such as those of the breast, as nearly 40 per cent of transplant patients are female.3
Treatment of breast cancer in the transplant population is complicated by immunosuppression, dialysis access, and transplant grafts. General surgeons can expect to encounter more of these complex patients in the community setting. However, there is limited information regarding the surgical treatment of this intricate disease process. We sought to evaluate the unique dilemma of the treatment of breast cancer in patients with renal transplants.
Patients and Methods
This study was a retrospective review of data collected on all patients who underwent a kidney or kidney/pancreas transplant at Methodist Health System, a community-based hospital in Dallas, Texas. Hospital and private physician records were queried to identify those patients with a newly diagnosed breast cancer during the period from June 1, 1994, to June 30, 2004. These charts were reviewed for demographics, type of breast cancer, medical and surgical treatment, method of dialysis and location of access, type of transplant immunosuppression, and complications.
Results
Methodist Health System began its transplant program in 1981. From its inception to June 2004, 1,944 kidney and 129 kidney/ pancreas transplants were performed. During the 10-year study period, there were 741 transplants performed with 14 patients developing breast cancer. The characteristics of this group are shown in Table 1. The average age was 54.2 years. The mean time from transplant to the diagnosis of breast cancer was 8.29 years (0.8 to 16.3 years). None of the 14 patients had breast cancer prior to the study or their transplant. The patients were followed, on average, 3.35 years (0.5 to 8.7 years) after the diagnosis.
TABLE 1. Patient Characteristics
At the time of diagnosis of their breast cancer, eight kidney transplant patients had functioning transplants. Both of the combined kidney/pancreas transplant patients had continued function of their pancreatic graft. However, one patient lost the renal component due to chronic rejection. Of the remaining patients, all were undergoing hemodialysis for chronic organ failure.
Two patients had ductal carcinoma in situ. Invasive disease was discovered in 12 individuals: five patients presented with stage I disease; five had stage II; two individuals had stage IV disease.
All patients underwent some form of operative intervention. Mostly, modified radical mastectomy (MRM) with levels I and II nodal dissection was performed. Two individuals within the MRM group initially had lumpectomies for presumed in situ disease. This was followed by a completion mastectomy and node dissection after discovering invasive carcinoma within the initial specimen. Sentinel node biopsy was not offered due to either prior axillary dissection for vascular access or surgeon preference. Additionally, many of the patients presented prior to the use of sentinel node biopsy technique. No individuals were noted to have major wound complications.
The functioning of access grafts after nodal surgery was a concern. Two patients had functioning grafts on the ipsilateral side of the node dissection. One of these individuals developed access dysfunction in the form of decreased flow. This was amenable to percutaneous dilatation. Ipsilateral graft placement was not performed after nodal surgery. No patient in the study group developed upper extremity lymphedema.
Adjuvant therapy was presented to the patients on a case-by-case basis. Five of the six who opted for breast conservation (i.e., lumpectomy) underwent radiation therapy alone. The remaining patients varied in their course of therapy. One patient with stage IV dis ease had chemotherapy alone. Four individuals had combined chemoradiation. Two were for locally advanced cancers, one for metastatic disease, and one for recurrent disease. None of the five patients who underwent chemotherapy developed transplant failure or renal insufficiency after treatment; however, one patient had preexisting graft failure at the time of treatment and eventually died from metastatic carcinoma.
The remaining four patients underwent no adjuvant treatment at all. One had a prior history of Hodgkin disease for which she had prior radiation therapy. Her breast cancer was found at stage I and she opted for a MRM. Another was a male patient with stage I papillary carcinoma treated with a simple mastectomy. One patient had a stage II cancer and underwent lumpectomy and axillary node dissection. This was followed by a completion mastectomy due to inadequate margins. One patient had a history of lupus and was not felt to be a candidate for radiation therapy. She was found, after lumpectomy for presumed in situ disease, to have a stage I cancer. She underwent a MRM and was treated with adjuvant tamoxifen.
Of the seven patients with invasive cancers who did not receive chemotherapy, four are listed above. Three patients with localized disease underwent adjuvant radiation therapy and were offered adjuvant chemotherapy but chose not to undergo treatment. These patients voiced concern over cessation or reduction of immunosuppression and the possibility of subsequent transplant dysfunction. None of these patients developed a recurrence during the follow-up period. Regarding hormonal therapy, tamoxifen was given to eight patients and letrozole to one.
Overall, there were two deaths. One patient died from sepsis- independent of the breast cancer treatment-which led to pulmonary failure. The other death occurred secondary to metastatic carcinoma. She represented the single recurrence within the group during the study period. Additionally, no patients experienced transplant insufficiency or failure.
Discussion
The diagnosis of breast cancer in a transplant patient confounds an already complex clinical picture. Many questions are raised, with little clinical data to guide management. Do transplant patients have a greater risk of breast cancer? To what degree does immunosuppression increase patients’ risk of breast cancer? What is the optimal management of immunosuppression once a diagnosis of breast cancer is made? How should systemic adjuvant therapy be incorporated in this population and what is the consequence of therapy on graft function? What is the approach to management of the axillae with respect to the need for vascular access in hemodialysis patients?
The risk of breast cancer in transplant patients is debated among authors. In a single institution study, Agraharkar et al. found that the relative risk of breast cancer in this patient population was approximately 0.7 when compared with that of the general population.4 His findings were consistent with other studies, including those from the Cincinnati Transplant Tumor Registry.5 Kasiske, in a similar article, agreed that the relative risk was not significant (0.82 in women, 1.88 in men).6 However, he went on to compare the rates of cancer post-transplant to that of non- transplant patients. This study demonstrated a nearly threefold increased rate of breast cancer during the first year in transplanted females when compared with the general public (343/ 100,000 vs 134/100,000). The incidence then decreased in years 2, 262/100,000, and year 3, 144/100,000. The male transplant population incidence mirrored that of the female with 3-year increases per 100,000 patient years from the baseline \of 1.5 to 6.8, 15.5, and 6.0, respectively. Although the risk may not be significantly increased, there is certainly a propensity toward more breast cancers as the total number of surviving transplant patients grows. In the current study, we discovered 14 breast cancers in 741 total transplants for an incidence of 1.9 per cent. However, our current 36-month patient survival is 94 per cent, thus giving the likelihood of higher prevalence in the future.
There is an established link between immunosuppressive therapies and the development of certain malignancies.7,8 These have largely been related to skin cancers and are primarily due to the effects of immunosuppression on the DNA strands and DNA repair mechanisms. Additionally, viral infections such as Epstein-Barr have been implicated in the proliferation of post-transplant lymphomas.9 These links have not been proved to be the case with breast cancers.10 Some studies suggest that the suppression of immune surveillance may contribute.11 In contrast, other authors suggest that immunosuppression may have a protective effect against breast cancers.12 Stewart contended that retrovirus-associated breast cancers were promoted by immune mechanisms and, therefore, immunosuppression during the premalignant phase reduced the transformation to cancer. He then reviewed 25,000 immunosuppressed women over 11 years and found 86 cases of de novo breast cancers. This contrasted with the expected 113 cases. In turn, the relative risk decreased to 0.49 in the first post-transplant year and then increased to 0.84 in ensuing years. However, these results could be the outcome of a strict screening program that is part of the transplant process and, therefore, excludes high-risk patients from transplantation.13 Our institution has a policy of performing screening mammograms on all female patients and a requisite 3-year waiting period after successful treatment for good prognosis, localized breast cancer. This is reflected by the relatively low number of breast cancers in our transplant population and an average diagnosis time of 8.29 years after transplant.
Management of immunosuppression, once a diagnosis of cancer has been made, is also an area of concern as there is little data available to guide decisions. Decreased or cessation of immunosuppression has been reported to be associated with remissions of the lymphoproliferative processes and Kaposi sarcoma; however, data involving therapeutic benefit of reducing immunosuppression in patients with solid tumors is anecdotal. Within our series, the management of immunosuppression was tailored to each patient’s circumstances. In all patients who had systemic chemotherapy, immunosuppression was altered or decreased to try to limit hematosuppression and drug toxicities. Some patients resisted these recommendations, wishing to preserve the transplant organ function over all other goals. These patients chose not to consider any therapy for their breast cancer that would require any adjustment of their immunosuppression. Largely, immunosuppression was not an issue in choosing appropriate management for our patients with breast cancer. Some authors do not recommend ceasing immunosuppression during the treatment of solid tumors.14 Some practitioners would rather decrease or temporarily suspend the immunosuppression.15
There are relatively few studies outlining the safety or efficacy of chemotherapeutic regimens in transplant populations. As described in the aforementioned studies, cessation of immunotherapy was initially thought to result in regression of neoplasms. This strategy has been suggested in treatment of transplant patients with malignant lymphoproliferative disease. In our study, the use of chemotherapy in three of the four patients with functioning grafts did not result in rejection or dysfunction possibly due to the fact that immunosuppression was continued during the treatment period. No recurrences were noted in the follow-up period of these patients. Interestingly, this group had very similar outcomes to the two patients who refused chemotherapy over concerns of a reduction in immunosuppression. However, this study’s limited group size precludes statistically significant conclusions on this matter. It is suggested that immunosuppressed patients be treated as non- immunosuppressed patients in cases of tumors such as those of the breast. Further studies have suggested that specific therapy-this includes chemotherapy, surgery, or radiation-be used in the treatment of solid organ cancers.16
It appears that, in our restricted study, functioning dialysis access grafts need not be replaced after nodal surgery. The relevant patients in our study had minor complications that cannot be directly attributed to the levels I and II axillary node dissection. Therefore, it appears that surgeons should continue to approach dialysis accesses as in those patients without axillary surgery. The role of sentinel node biopsy also requires further evaluation in this patient population as it was not used throughout our study period. The major concern in this procedure was the accuracy due to postaccess alterations in the axillae. This could be from either collaterals formation or inflammatory response in the axillae.
In conclusion, this unique problem creates a significant dilemma. There is a relatively small amount of information from which to gain counsel, and the majority of work in this area has come from the renal aspect. Zeier and Morath, in respective articles, define the prevalence and pathogenesis of post-transplant malignancies.17,18 However, discussion of the surgical management is mostly overlooked. In evaluating the results of our study, it appears that surgical approaches to breast cancer in the transplant population need not be altered. These patients provide a challenge in counseling of their treatment options. This population often places a high value on the maintenance of the transplant’s function, even to the point of altering standard recommendations for the treatment of their malignancy as the threat of graft loss often supercedes adjuvant therapy. The best approach is a combined effort among the disciplines of surgery, nephrology, and oncology. We recommend that surgeons continue to approach the primary cancer as one would in the normal population patient. Some consideration should be given to the approach of sentinel node evaluation. There is certainly a need for further study of the management of breast cancer in this population.
REFERENCES
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12. Stewart T, Tsai SC, Grayson H, et al. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 1995;346:796-8.
13. Weiss NS. Risk of breast cancer after renal or cardiac transplantation. Lancet 1995;346:1422.
14. Ondrus D, Pribylincova V, Breza J, et al. The incidence of tumors in renal transplant recipients with long-term immunosuppressive therapy. Int Urol Nephrol 1999;31:417-22.
15. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993; 12:8328-36.
16. Zeier M, Hartschuh W, Wiesel M, et al. Malignancy after renal transplantation. Am J Kidney Dis 2002;39:E5.
17. Morath C, Mueller M, Goldschmidt H, et al. Malignancy in renal transplantation. J Am Soc Nephrol 2004;15:1582-8.
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MICHAEL SELF, M.D., ERNEST DUNN, M.D.,* JOHN COX, D.O.,[dagger] KARL BRINKER, ..[double dagger]
From the Departments of *Surgery, [dagger]Oncology, and [double dagger]Nephrology, Methodist Hospitals of Dallas, Dallas, Texas
Presented at the North Texas Chapter of the American College of Surgeons Annual Meeting, Dallas, Texas, February 26, 2005.
Address correspondence and reprint requests to Ernest Dunn, M.D., P.O. Box 655999, Dallas, TX 75265.
Copyright The Southeastern Surgical Congress Feb 2006
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