Challenging a Traditional Paradigm: 12-Year Experience with Autologous Free Flap Breast Reconstruction for Inflammatory Breast Cancer

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1 BREAST Challenging a Traditional Paradigm: 12-Year Experience with Autologous Free Flap Breast Reconstruction for Inflammatory Breast Cancer Edward I. Chang, M.D. Eric I. Chang, M.D. Ran Ito, M.D., Ph.D. Hong Zhang, Ph.D. Alexander T. Nguyen, M.D. Roman J. Skoracki, M.D. Matthew M. Hanasono, M.D. Melissa A. Crosby, M.D. Naoto T. Ueno, M.D. Kelly K. Hunt, M.D. Houston, Texas Background: Inflammatory breast cancer is a rare but aggressive breast cancer with an overall poor prognosis. Traditionally, reconstruction has not been offered, because of poor long-term survival, the need for multimodality treatment, and complex treatment sequencing. The authors examined the safety and feasibility of free flap breast reconstruction for inflammatory breast cancer. Methods: A retrospective analysis of all patients who underwent reconstruction for inflammatory breast cancer from January of 2000 to December of 2012 was conducted. Results: Of 830 inflammatory breast cancer patients, 59 (7.1 percent; median age, 48 years; range, 27 to 65 years) underwent free flap reconstruction. All patients received chemotherapy and radiation therapy. Most patients (n = 52) underwent delayed reconstruction. Five patients with a history of prior partial mastectomy and irradiation developed inflammatory breast cancer and underwent immediate reconstruction following completion mastectomy. Two others underwent immediate chest wall and breast reconstruction following resection. Thirteen patients underwent bilateral reconstruction, and seven required a bipedicled abdominal flap for the unilateral mastectomy defect. Thirty-seven patients (62.7 percent) required revision of the reconstructed breast, and 29 (49.2 percent) had a contralateral balancing procedure to optimize symmetry. Complications occurred in 21 patients (35.6 percent), with one total flap loss (1.7 percent). The median length of follow-up was 43.9 months; 49 patients (83.1 percent) were alive without evidence of recurrent disease. Conclusions: Autologous free flap breast reconstruction can be performed safely in inflammatory breast cancer patients, with acceptable complication rates and without an increased risk for flap loss. Inflammatory breast cancer should not preclude free flap breast reconstruction. (Plast. Reconstr. Surg. 135: 262e, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. Inflammatory breast cancer is an aggressive form of breast cancer that has traditionally been associated with a poor prognosis and limited long-term survival. 1,2 Inflammatory breast cancer often manifests with hallmark findings of rapidly progressing erythema, swelling, and induration From the Departments of Plastic and Reconstructive Surgery and Breast Medical Oncology, the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, and the Department of Surgical Oncology, Breast Surgery, The University of Texas M. D. Anderson Cancer Center. Received for publication May 18, 2014; accepted July 17, Presented at the 92nd Annual Meeting of the American Association of Plastic Surgery, in New Orleans, Louisiana, April 20 through 23, Copyright 2015 by the American Society of Plastic Surgeons DOI: /PRS leading to the classic peau d orange appearance of the affected breast. Unfortunately, inflammatory breast cancer also tends to afflict a younger patient population, with high recurrence rates, and treatment involves a multimodality approach that includes chemotherapy, aggressive surgical resection, and irradiation. 3 5 As such, reconstruction for these patients is often not performed or even offered. Reconstruction for a patient following surgical resection of inflammatory breast cancer Disclosure: The authors have no commercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article. No funding was received for the work presented in this article. 262e

2 Volume 135, Number 2 Inflammatory Breast Cancer can be particularly challenging for a variety of reasons. Given the diffuse skin and lymph node involvement seen with inflammatory breast cancer, it is necessary to resect a significant portion of the breast, chest wall, and skin, resulting in an extensive mastectomy defect. Furthermore, the need for radiation therapy, which has been shown to have an impact on breast reconstruction, also adds a degree of difficulty. As such, breast reconstruction in this complex cohort of patients requires replacement of skin and volume in an irradiated field, which is best achieved with autologous tissue. Given the relative low incidence of inflammatory breast cancer and poor survival, there is a relative paucity of studies examining breast reconstruction following resection for inflammatory breast cancer. 6 Significant controversy exists regarding reconstruction for these patients, and many consider inflammatory breast cancer to be a relative contraindication to reconstruction. 4,5,7 However, despite the overall prognosis, the improved treatment for inflammatory breast cancer and recent advances in therapy have had a favorable impact on survival in this complex cohort of patients A multidisciplinary approach to treatment involving breast medical oncology, radiation oncology, breast surgical oncology, and plastic surgery at our comprehensive cancer center has been successful in providing the option for breast reconstruction in this patient population. Given the need for radiation therapy and, often, the need for significant volume and skin replacement, we have used autologous free flap reconstruction for patients with inflammatory breast cancer. In this article, we present our 12-year experience with free flap reconstruction for inflammatory breast cancer and provide a comprehensive analysis of treatment and survival outcomes. PATIENTS AND METHODS We queried our inflammatory breast cancer and reconstructive surgery databases, which are maintained prospectively, to identify all patients who had a diagnosis of inflammatory breast cancer at The University of Texas M. D. Anderson Cancer Center from January of 2000 to December of After identifying all patients undergoing treatment for inflammatory breast cancer, we cross-referenced the patients who received a free flap for breast reconstruction and performed a retrospective review of those patients. All patient records were reviewed for clinical presentation, pathologic diagnosis, demographics, comorbidities, adjuvant therapies, surgical treatment, timing of reconstruction, type of flap, revisions, and complications following institutional review board approval. Postoperative outcomes, follow-up data, and survival were also reviewed. RESULTS Patients Overall, 59 patients with inflammatory breast cancer underwent autologous free flap reconstruction from January of 2000 through December of 2012, with a median age of 48.0 years (range, 27 to 65 years) and a mean body mass index of 29.5 kg/m 2 (range, 20 to 40 kg/m 2 ). Eighteen patients (30.5 percent) had a history of smoking. All patients received chemotherapy and radiation therapy. There were two patients who received radiation therapy after the free flap reconstruction. Twenty-two patients (37.3 percent) had inflammatory breast cancer in the right breast and 37 patients (62.7 percent) had inflammatory breast cancer on the left side. Two patients had bilateral breast cancer: one of them underwent bilateral mastectomies and the other had a mastectomy for the inflammatory breast cancer affected breast and a segmental mastectomy for the contralateral breast cancer. Clinicopathologic factors and patient demographics are listed in Table 1. Twelve patients (20.3 percent) had triple-receptor-negative inflammatory breast cancer. Seven patients (11.9 percent) had immediate breast reconstruction. Five patients had undergone prior partial mastectomies followed by postoperative irradiation but subsequently developed recurrent disease in the form of inflammatory breast cancer. At the time of the completion mastectomy, a free flap was performed for reconstruction. Two patients underwent immediate breast reconstruction and chest wall coverage at the time of mastectomy because of the extensive amount of soft tissue resected. The remaining 52 patients (88.1 percent) underwent reconstruction in a delayed fashion. Of the patients undergoing bilateral reconstruction, all patients underwent a delayed reconstruction for the breast affected with inflammatory breast cancer and an immediate free flap reconstruction of the prophylactic contralateral breast. Surgical Resection and Timing of Reconstruction Fifty-six patients (94.9 percent) were treated with a modified radical mastectomy and three patients had a radical mastectomy. Of the seven 263e

3 Plastic and Reconstructive Surgery February 2015 Table 1. Patient Characteristics Characteristic Value Age, yr Mean 48.0 Range Mean BMI ± SD, kg/m ± 4.3 Radiation therapy, no. of patients (%) 57 (96.6) Chemotherapy, no. of patients (%) 59 (100) Tobacco use, no. of patients (%) 18 (30.5) Receptor profile, no. of patients (%) ER+ PR+ 20 (33.9) ER+ PR 7 (11.9) ER PR+ 3 (5.1) ER PR 26 (44.1) Unknown 3 (5.1) HER2-Neu+ 19 (32.2) Triple-negative 12 (20.3) Bra size, no. of patients (%) A 2 (3.4) B 13 (22.0) C 21 (35.6) D 10 (16.9) DD 7 (11.9) DDD 2 (3.4) Unknown 4 (6.8) ER, estrogen receptor; PR, progesterone receptor. patients (11.9 percent) undergoing immediate reconstruction, five patients had a modified radical mastectomy and two had a radical mastectomy. Five of these patients had already received prior radiation therapy for breast cancer that was treated with a segmental mastectomy but developed inflammatory breast cancer. Overall, all but two patients had radiation therapy before their reconstruction. These two patients had an extensive chest wall defect that precluded primary closure requiring a flap to achieve coverage of the chest wall. The flap was used to provide stable chest wall coverage and to reconstruct the breast, and these patients received radiation therapy following reconstruction. Autologous free flap breast reconstruction was performed on average 18.6 months (range, 1.3 to 90.2 months) after irradiation. Reconstruction Forty-six patients (78.0 percent) underwent reconstruction for a unilateral breast defect, whereas 13 patients (22.0 percent) underwent bilateral free flap breast reconstruction. Twelve of these patients had a contralateral prophylactic mastectomy, and one patient had bilateral breast cancer. The contralateral breast was reconstructed in an immediate fashion for all 13 patients undergoing bilateral breast reconstruction. Seven patients received a bipedicled free flap where the entire abdominal tissue was necessary to reconstruct a unilateral mastectomy defect given the extensive skin deficit from the resection (Fig. 1). The remaining flaps used for reconstruction are presented in Tables 2 and 3. The average time to reconstruction following the mastectomy was 20.9 months. Revision, Contralateral, and Secondary Surgery Of the patients undergoing unilateral breast reconstruction, 37 patients (62.7 percent) underwent revisions to the reconstructed breast and 29 patients (49.2 percent) underwent a contralateral procedure to restore symmetry with the reconstructed breast. The specific procedures included a contralateral reduction mammaplasty (n = 12), mastopexy (n = 11), augmentation (n = 4), and augmentation with mastopexy (n = 2). Of the 13 patients who underwent bilateral abdominal flap reconstruction, 10 had a revision of the contralateral prophylactic breast that was reconstructed in an immediate fashion. Three (5.1 percent) patients underwent surgical treatment for lymphedema. One patient underwent a lymphovenous bypass, and two patients had vascularized lymph node transfers. At 1-year follow-up, average volume reduction was 7.7 percent, and all patients reported subjective improvement in their symptoms. Complications following Reconstruction Overall, 21 patients (35.6 percent) developed complications after reconstruction. Age, body mass index, smoking, comorbidities, and bra/ breast size were not associated with the development of complications. Seven patients (11.9 percent) developed minor wound-healing complications with the flap inset into the irradiated field that healed secondarily with nonoperative, local wound care. The timing of reconstruction after completion of irradiation had no impact on the incidence of complications. The mean time to reconstruction following completion of irradiation was 18.6 months (range, 1.3 to 90.2 months). Five patients (8.5 percent) developed wound-healing complications at the abdominal donor site. One patient developed a hernia in the abdominal donor site requiring a secondary operation for repair. One patient was taken back to the operating room for venous congestion of a flap that was salvaged with a second venous anastomosis of the superficial inferior epigastric vein to the retrograde internal mammary vein. There was one total flap loss (1.7 percent) secondary to arterial and venous thrombosis. Overall complications are listed in Table 4. Survival Outcomes For patients undergoing reconstruction, the median follow-up was 43.9 months (range, e

4 Volume 135, Number 2 Inflammatory Breast Cancer Fig. 1. (Left) Preoperative photograph of a patient with inflammatory breast cancer recurrence following a prior partial mastectomy and irradiation. The patient also had severe lymphedema of the left arm, with swelling, recurrent infections, and pain. (Right) Postoperative photograph following an abdominal free flap reconstruction of the breast and a vascularized lymph node transfer with noticeable improvement in swelling, erythema, and symptomatic improvement of her left arm. Table 2. Unilateral Flap Reconstruction* Flap No. of Patients (%) TRAM 11 (23.9) MS-TRAM 17 (37.0) DIEP 9 (19.6) SIEA 1 (2.2) Bipedicle 7 (15.2) ALT 1 (2.2) TRAM, transverse rectus abdominis myocutaneous; MS-TRAM, muscle-sparing TRAM; DIEP, deep inferior epigastric perforator; SIEA, superficial inferior epigastric artery; ALT, anterior lateral thigh. *n = 46 patients. Table 3. Bilateral Flap Reconstruction* Left Right TRAM MS-TRAM DIEP SIEA TRAM 1 MS-TRAM 1 4 DIEP SIEA 1 TRAM, transverse rectus abdominis myocutaneous; MS-TRAM, muscle-sparing TRAM; DIEP, deep inferior epigastric perforator; SIEA, superficial inferior epigastric artery. *n = 13 patients. to 149 months), with a median survival of 44.0 months (range, 38.6 to 48.6 months). There were seven patients (11.9 percent) who died as a result of disease, one patient who died from other causes, and one patient alive with disease at the time of this report. One patient developed recurrent disease in the chest wall 7 months after reconstruction and underwent a repeated resection and coverage with advancement of the abdominal free Table 4. Complications of Patients Undergoing Free Flap Breast Reconstruction Complications No. (%) Delayed healing/cellulitis of donor site 5 (8.5) Delayed healing/cellulitis of flap 7 (11.9) Fat necrosis 4 (6.8) Abdominal bulge/hernia 1 (1.7) Medical complication 2 (3.4) Pedicle thrombosis 4 (6.8) Total flap loss 1 (1.7) flap used to reconstruct the original mastectomy defect. She is currently alive without evidence of disease. The overall survival is shown for all patients in Figure 2 and for patients with metastatic disease in Figure 3. Patients undergoing reconstruction were found to have significantly improved survival compared with inflammatory breast cancer patients who did not undergo reconstruction (p = 0.04) (Fig. 4). DISCUSSION In the current study, we demonstrate that free flap breast reconstruction in selected patients with inflammatory breast cancer is feasible, with excellent outcomes. All patients underwent a stable reconstruction, and nearly half of the patients also proceeded with a contralateral procedure to reestablish symmetry with the reconstructed breast. The majority of patients (62.7 percent) also had a revision to the reconstructed breast to optimize their reconstructive outcomes, which was comparable to 64.4 percent of our e

5 Plastic and Reconstructive Surgery February 2015 Fig. 2. Kaplan-Meier curve demonstrating survival of inflammatory breast cancer patients undergoing free flap breast reconstruction. Fig. 3. Kaplan-Meier curve demonstrating survival of patients with metastases compared with those patients without metastatic disease. patients undergoing unilateral free flap breast reconstruction from 2000 to 2010 (data not published). To date, there are few studies examining free flap breast reconstruction for inflammatory breast cancer patients and no recent studies examining the success rates, complications, and 266e

6 Volume 135, Number 2 Inflammatory Breast Cancer Fig. 4. Kaplan-Meier curve demonstrating survival of all patients with inflammatory breast cancer compared with inflammatory breast cancer patients undergoing autologous free flap breast reconstruction. potential risks with free flap reconstruction in these patients. This has an impact on our ability to counsel patients with regard to breast reconstruction, which has been well documented to have a significant impact on patients quality of life. To our knowledge, only one prior study has specifically examined breast reconstruction for inflammatory breast cancer patients and demonstrated promising results; however, the study was limited by small numbers and poor overall survival. 6 The survival outcomes in our study are likely a reflection of the advances in multimodality treatment strategies that have improved, resulting in prolonged survival and allowing patients to pursue additional operations to achieve restoration of their physical appearance and psychological well-being. 7 9 Our series not only confirms that autologous free flap reconstruction for inflammatory breast cancer is safe, but also presents a comprehensive synopsis of reconstruction in this complex cohort of patients. We demonstrate that free flap reconstruction in inflammatory breast cancer patients has complication rates comparable to those in non inflammatory breast cancer patients, and can be optimized with contralateral symmetry procedures and revisions if necessary. Our data suggest that patients with inflammatory breast cancer should be considered candidates for reconstruction using autologous free flaps, and inflammatory breast cancer alone is not a contraindication for reconstruction. However, as virtually all patients will undergo irradiation as part of the treatment for inflammatory breast cancer and given the aggressive nature of inflammatory breast cancer, the timing of reconstruction needs to be coordinated with the delivery of adjuvant therapies, and we typically recommend waiting a minimum of 6 months after completion of radiation therapy before proceeding with free flap reconstruction. 11 On average, we performed reconstruction 18.6 months after irradiation. However, there are circumstances when a flap may be necessary before radiation therapy. For example, the need for aggressive resection in two of our patients mandated a flap to achieve stable coverage of the chest wall and was able to achieve both objectives, chest wall resurfacing and breast reconstruction. Therefore, in certain circumstances, immediate reconstruction may be indicated for these patients, and coordination to optimize the timing of adjuvant treatment with surgical and radiation oncology is critical. In general, we prefer proceeding with autologous free flap reconstruction because of the extensive skin defect that is created following resection that would surpass the amount of 267e

7 Plastic and Reconstructive Surgery February 2015 skin that can be harvested with a pedicled latissimus dorsi myocutaneous flap. Although a pedicled transverse rectus abdominis myocutaneous (TRAM) flap is also a viable option, the donor-site morbidity following a traditional pedicled or free TRAM flap has been shown to be worse than following a muscle-sparing TRAM or deep inferior epigastric perforator flap. 12 As all patients require irradiation, we would recommend performing delayed reconstruction a minimum of 6 months after irradiation to minimize complications and radiation damage to the flap. 11,13,14 Given the need for radiation and axillary lymphadenectomies in this cohort of patients, inflammatory breast cancer patients may suffer from lymphedema. Our early preliminary results demonstrate that surgical treatment for lymphedema can be beneficial as part of the comprehensive approach to inflammatory breast cancer reconstruction. At present, the small numbers, short follow-up, and ongoing maturation of the field of lymphedema surgery limit the assessment of the true value of these interventions, and further research is certainly warranted In addition, nearly half of the patients (49.2 percent) underwent a contralateral procedure for symmetry, which is comparable to patients without inflammatory breast cancer at our institution (49.8 percent). 19 Regarding revision surgery to optimize the reconstruction, preliminary data also demonstrate comparable rates of revision between inflammatory breast cancer and non inflammatory breast cancer patients, suggesting that inflammatory breast cancer patients can undergo not only free flap breast reconstruction but also secondary operations to create a satisfactory, balanced result. Some would argue that the aggressive nature of the disease, poor long-term survival, and high rates of recurrence in inflammatory breast cancer patients are contraindications for a long operation, hospital stay, and risk of complications and donor-site morbidity. Over one-third of the patients in our series developed a complication; however, most were managed successfully with conservative measures and only a limited number required operative intervention. Only one patient (1.7 percent) developed a postoperative hernia that required operative repair, which is comparable to rates of hernia or bulges documented in the literature in non inflammatory breast cancer patients. 12 Finally, there was only one flap loss (1.7 percent) in our series, which is also comparable to success rates for free flap reconstruction in non inflammatory breast cancer patients. Other studies have also demonstrated successful breast reconstruction in patients with advanced disease that potentially can be extrapolated to inflammatory breast cancer; however, inflammatory breast cancer does represent a unique subset of breast cancer, and further studies are needed to optimize treatment for these patients Unfortunately, one patient in our series developed recurrent disease and required a repeated resection, but the excess volume of the free flap was mobilized to provide stable, well-vascularized coverage of the defect and to maintain an aesthetic breast reconstruction. At a median follow-up time of 43.9 months, the majority of patients are alive without evidence of disease, which speaks to the tremendous advancements made in the treatment of inflammatory breast cancer. 24,25 We demonstrate that patients undergoing free flap reconstruction have superior survival compared with those who did not undergo reconstruction. Certainly, the improved survival does not represent causality between reconstruction and survival, and we are actively investigating which patient factors and tumor profiles are associated with improved prognosis and survival to delineate which subset of patients are expected to have a better response to therapy and improved survival. Overall, the results presented reflect a multidisciplinary approach, including increased awareness and early detection; thorough diagnostic work-up and imaging; and a treatment approach involving medical oncology, radiation oncology, surgical oncology, and plastic and reconstructive surgery. By using this approach, we can optimize the care, survival, and quality of life for these patients. CONCLUSIONS Given improvements in survival for patients with inflammatory breast cancer, free flap breast reconstruction is a reasonable approach for optimizing the care and quality of life for patients with inflammatory breast cancer. Contrary to historical beliefs and practice, autologous free flap reconstruction can be performed safely and should be offered to this cohort of patients. Edward I. Chang, M.D. Department of Plastic and Reconstructive Surgery M. D. Anderson Cancer Center 1400 Pressler Street eichang@mdanderson.org acknowledgments The authors thank the Morgan Welch Inflammatory Breast Cancer Research Program and a State of Texas Rare and Aggressive Breast Cancer Research Program Grant for their support with this study. 268e

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