Ipsilateral In-Breast Tumor Relapse after Breast Conservation Therapy: True Recurrence Versus New Primary Tumor

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1 Journal of the Egyptian Nat. Cancer Inst., Vol. 18, No., September: 18-19, 6 Ipsilateral In-Breast Tumor Relapse after Breast Conservation Therapy: True Recurrence Versus New Primary Tumor HASSAN M. ABD-ALLA, M.D. 1 ; MOHAMED M. LOTAYEF, M.D. ; AMANY ABOU BAKR, M.D. and MANAR M. MONEER, M.D. The Departments of Surgical Oncology 1, Radiation Oncology, Surgical Pathology and Epidemiology & Biostatistics, National Cancer Institute, Cairo University. ABSTRACT Background and Purpose: Ipsilateral breast tumor relapse (IBTR) occurs in approximately 8-% of women 1 years after breast conservation therapy (BCT). The aim of this study is to classify ipsilateral breast tumor relapses in patients treated with conservative surgery and radiation therapy as true recurrences or new primary and to show the clinical significance of classification into these two types of recurrences. Patients and Methods: Out of 67 patients treated at National Cancer Institute, Cairo University in the period extending from 199 to, 9 patients have experienced ipsilateral tumor relapse as the first site of recurrence. These relapses were classified as true recurrence if it was located within cm of the primary tumor bed and was of the same histologic subtype. All other ipsilateral breast tumor relapses were considered as new primary. The patients were followed-up until January 5. Results: After a mean follow-up period of 7.9±.6 years following the original diagnosis, the overall ipsilateral breast tumor relapse rate was 9.6% (9/67). Relapses were classified as TR in 1 patients (7.%) and were considered as a new primary in 8 cases (7.6%). Patients diagnosed with a new primary had a longer mean time to breast relapse (6.9 years for NP Vs.9 years for TR, p<.1) and were significantly younger than true recurrence patients (8.8 years Vs 7.5 years, p=.6). Patients with a new primary had a 1- year overall survival of 87.5%; whereas, it was 61.9% for TR cases (p=.1). Conclusions: It appears that a significant portion of patients who experience ipsilateral breast tumor relapse following conservative surgery and radiation therapy have new primary tumors as opposed to true recurrences. Patients with a new primary had better survival rates than Correspondence: Dr Hassan M. Abd-Alla, Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, abdallahassan7@hotmail.com those with true recurrence. Distinguishing new primary breast carcinoma from local disease recurrence may have importance in therapeutic decisions and chemoprevention strategies. Key Words: Breast-conserving therapy Ipsilateral breast tumor relapse True recurrence New primary. INTRODUCTION Numerous prospective randomized as well as retrospective reviews have shown that conservative management is as effective as mastectomy in term of overall survival and disease free survival for both stage I and stage II breast cancer patients [1,]. Ipsilateral breast tumor relapse occurs in approximately 8-% of women 1 years after breast conservation therapy [,]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) recently reported -year findings after breast conservation therapy and found a 1.% cumulative incidence of IBTR [1]. Even though the rate is under 1% per year; the increasing number of women opting for breast conservation means that IBTR is becoming a significant clinical problem. IBTR can be defined as the reemergence of tumor in the previously treated breast. Many studies have reported that the relative risk of distant metastases with IBTR ranges from three-to five-folds [5], and the 5-year survival ranged between 59-9%, depending on the particular study [,6,7,8]. Other studies have suggested that there are subgroups of patients who have a relatively favorable prognosis after an IBTR. Older age, longer interval between initial treatment and local relapse, small tumors, noninvasive histology, low 18

2 18 Ipsilateral In-Breast Tumor Relapse after Breast Conservation Therapy histologic grade, negative axillary lymph nodes, and remote location from the primary tumor site have all been identified as factors of an IBTR that indicate a more favorable prognosis [6,8]. One hypothesis is that some subgroups of patients have a favorable prognosis because IBTR consists of two distinct types of disease: True local recurrence (TR) and new ipsilaterl primary tumor (NP). This distinction was first articulated by Veronesi et al. [9] who described in their report that TR were cases consistent with the re-growth of malignant cells not removed by surgery or not killed by radiotherapy. Alternatively, new primary tumors were de novo cases of malignancies arising from mammary epithelial cells of residual breast tissue. The complicated behavior of IBTR may be related to the fact that the IBTR patient population represents these two distinct entities. Theoretically, an NP IBTR is independent of the primary breast cancer and the prognosis of these patients may be more favorable than those with a TR. Another hypothesis is that the development of NP may indicate an underlying genetic predisposition for breast carcinoma and thereby is associated with higher rates of carcinoma in the contralateral breast [1]. Based on this hypothesis it appeared that NP and TR have different natural histories, different prognoses, and thus, different implications for therapeutic management. The purpose of this study was to classify IBTRs in patients treated with conservative surgery and radiation therapy as either NP or TR based on tumor location and histology and to assess whether this distinction has any prognostic value. PATIENTS AND METHODS The medical records of 67 patients treated with breast conservation surgery and adjuvant radiation therapy at National Cancer Institute, Cairo University in the period from 199 to were retrospectively reviewed. All patients had either AJCC stage, I or II breast cancer. Patients with extensive intraduct component (EIC) and lymphovascular invasion were excluded. In addition, patients presenting with distant metastases or simultaneous distant and local recurrences were excluded. Patients were treated with either wide local excision or quadrantectomy and axillary lymph node dissection. All patients received postoperative radiotherapy delivered to the entire breast using photon beams (median dose 5Gy). They also received a boost to the primary tumor bed delivered by electron beams in 1 patients (8.8%) and by photons in 6 patients (17.%), for a total median dose of 66Gy. Adjuvant chemotherapy and hormonal therapy was administered according to the prognostic variables of each case, but no standard protocol was employed for patients treated during this period. Hospital records were evaluated for operative details, pathology results, mammographic findings and radiotherapy reports. Twenty-nine of those patients (9.6%) had an IBTR as the first site of failure. An IBTR was defined as a histologically confirmed recurrence of disease within the previously treated breast. We classified each IBTR as either TR or as NP based on its location and histology. We defined a TR if it was located within cm of the primary tumor bed and had a histological subtype consistent with the primary tumor. If the IBTR failed to meet these criteria, it was designated as an NP. In addition, a change from an infilterating ductal carcinoma (IDC) to a less invasive ductal carcinoma in situ (DCIS) was considered a characteristic of NP; whereas, a change in histology from DCIS to IDC was considered as TR because this change is consistent with the natural progression of breast carcinoma. The therapeutic management of IBTR patients depended on the clinical circumstances of each patient. The decision to treat with completion mastectomy or local excision and/or systemic therapy was made by the patient and her treating physician. All patients were classified as having either NP or TR before any analysis of the outcome data. Statistical analysis: Comparison between the numerical variables was done using Mann-Whitney test. Chi-square test or Fisher Exact test was used whenever appropriate for comparison between categorical variables. For all events, follow-up times were measured from the date of IBTR diagnosis.

3 Hassan M. Abd-Alla, et al. 185 RESULTS The overall ipsilateral breast tumor relapserate for 67 patients was 9.6%; 9 patients experienced an IBTR as their primary site of failure. For this group, the follow-up period ranged from.5 to 1 years (median 8 years). The mean follow-up period was 7.9±.6 years following the original diagnosis spanning until December 5. Using the classification scheme outlined above, 1 cases (7.%) were judged as TR while, 8 cases (7.6%) were judged as NP. Table (1) displays a comparison of clinicopathologic characteristics of the primary tumor for patients with NP versus TR. Patients who developed new primary tumor relapses were significantly younger than those who developed true recurrences (NP 8.8±7.5 years Vs. TR 7.71±5.6 years, p=.6). The mean disease free interval of NP (6.9±.8 years) was statistically longer than that of TR (.9±.56 years) (p<.1). There was also a significant difference in age of NP patients when compared to TR patients at time of relapse. The mean age at recurrence of NP patients was.6±7.79 years, whilst that of TR patients was 5.8±5.8 years (p=.6). No significant difference was found between the two groups with respect to histology of the primary tumor, primary tumor size, tumor stage, axillary lymph node involvement, safety margin status and adjuvant systemic therapy received. Of the 8 patients classified as NP, 6 (75%) of their recurrences changed location from the original primary, 5 (6.5%) changed histology, and 7 (87.5%) changed both histology and location. One of the NP tumors (1.5%) was classified solely on the basis of histology as the IBTR occurred near the tumor bed. Although the histology of the original primary tumors and their IBTR did not differ significantly between the two groups; however, NP tumors had more intraduct carcinomas than TR tumors (5% Vs. 9.5%). As anticipated, the relapse location was significantly different between TR and NP patients (p=.). Tumors with TR were more often located at or near the original primary; whereas, NP were more often distant from the original primary tumor. In three patients, the location of the IBTR could not be delineated because the tumor mass encompassed the entire breast at the time of disease recurrence. These patients were classified as TR because the histology was consistent with the original primary tumor. Metastasis was observed in only one case (1.5%) in the NP group. On the other hand, about 5% of TR cases metastasized (n=11); cases recurred almost concurrently in the breast and distant organs, while 7 cases showed recurrence in the breast preceding metastases. Table () summarizes the treatment of the IBTR cases according to classification of NP versus TR. In the NP group, all cases were subjected to re-operation in the form of mastectomy. In the TR group, cases (1.5%) did not receive additional surgery because they recurred as inflammatory breast cancer and systemic therapy was administered. Four patients in the TR group (19%) underwent relumpectomy, while salvage mastectomy was undertaken in 1 cases (66.75%). Two of the latter patients, developed a second local recurrence. There was no significant difference between the two groups with respect to systemic therapy after relapse (p=.8). The overall survival (OS) rate following IBTR was 68.97% at 1-years. However; patients classified as NP had more favorable outcomes. Fig. (1) illustrates that the 1-year OS rate of NP patients was 87.5%, while it was 61.9% for TR patients (p=.16). Cum Survivial Proportion Survival Functions Group New primary True rec New primary-censored True rec-censored Years Fig. (1): The 1-year overall survival of 9 cases of IBTR classified as either true recurrence or a new primary.

4 186 Ipsilateral In-Breast Tumor Relapse after Breast Conservation Therapy Table (1): Comparison between the clinico-pathological characteristics of TR and NP tumors. Parameters TR N=1 NP N=8 p-value Mean age at diagnosis (years) Mean age at relapse (years) Mean interval to relapse (years) Histology of the primary: Infiltrating duct cancer Infiltrating lobular cancer Medullary cancer Ductal cancer in-situ Mean tumor size (cm) Stage of the primary: I II Axillary lymph node involvement Safety margin: Negative Positive Adjuvant therapy after primary treatment: No adjuvant Chemotherapy Hormonal therapy Both lines 7.71± ±5.8.9±.56 * Fisher exact test comparing infiltrating tumors versus carcinoma in-situ. ** Small number of cases. 1.6± (8.1%) ±7.5.6± ± ±.56 6 (5%) <.1.55*.579 NS** NS Table (): Clinical characteristics and management of both types of IBTR. Parameters TR N=1 NP N=8 p-value Surgery for IBTR: Mastectomy Wide local excision No surgery * Recurrence site: Same site Different site Histology of recurrence: Infiltrating duct cancer Infiltrating lobular cancer Medullary cancer Ductal cancer in-situ * Adjuvant therapy after surgery for relapse: No adjuvant Chemotherapy Hormonal therapy Both * Follow-up: No recurrence Distant metastases only Local recurrence and distant metastases NS* * Small number of cases.

5 Hassan M. Abdalla, et al. 187 DISCUSSION As breast-conserving surgery and radiotherapy has become a common treatment modality for early stage breast cancer, a growing number of women will develop IBTR. Many reports have shown that IBTRs represent two distinct entities, TR and NP [1,11]. Furthermore, previous studies have suggested that the treatment may change depending on whether IBTR is TR or NP. The aim of the present study was to ascertain the difference between TR and NP and to show the clinical significance of classifying IBTR into two types of recurrence. According to our classification criteria, 9 out of 67 (9.6%) patients suffered an IBTR over a mean period of 7.9±.6 years of followup. As for the clinical outcome after IBTR, NP showed a higher overall survival rate when compared to TR. Ten year survival rates were 87.5% for NP and 61.9% for TR. The difference between the two groups was insignificant may be due to the small number of cases. The overall survival for our patients with NP were comparable to survival rates reported for women treated with BCT for a primary carcinoma without an IBTR (7-8% 1-year survival rate) [1,]. This observation makes sense because NP relapse should have a prognosis similar to patients with de novo early-stage primary breast carcinoma. The findings of the current study were in agreement with previous studies [1,11]. In the study by Smith et al. [11] an IBTR rate of 11.8% (16/115) was reported over a mean period of 1. years follow-up. They demonstrated that 51% of the IBTR were NP, based on changes in location, histology and/or DNA flow cytometry, and the 1-year overall survival for NP patients was 75% while it was 55% for TR patients. Similarly, Huang et al. [1] used the location and histology to classify IBTR as either TR or NP. After a median of 1. years of follow-up, 1.% (19/19) of their patients suffered an IBTR, of which 8% were compatible with NP. Patients with NP had a better 1- year overall survival rates (6%) when compared with the TR group (77%). Another group classified their patients with IBTR based on the location of the primary and secondary tumor, initial surgical margin and other pathologic features [1]. They reported an overall IBTR rate of 9.5% (17/191) after 5- years, with 6 (15.11%) of the cases classified as NP. The previous figure is relatively lower than that of the current study; in addition the survival rates were different. The 5 year survival rates of the latter study were 71% and 9% for TR and NP; respectively [1]. However, other studies have shown controversial data [,1,1]. Two of these studies did not report a significant difference in prognosis between TR, marginal miss recurrence and elsewhere recurrence at 5- years after IBTR [,1]. Differences of classifying criteria and duration of follow-up might explain this controversy. Many studies were based on difference in location when judging TR/NP. Kurtz et al. [15] defined NP as occurring elsewhere in the breast and reported their favorable behavior. Fowble et al. [] also distinguished IBTR mainly by the location of the primary and secondary cancers. On the other hand, another study classified IBTR according to the relation of the recurrent site and the radiation field [1]. Given the fact that the precise location and the relationship between location of the initial tumor and relapse may be difficult to ascertain, using histologic findings as another tool for classification would be appropriate. It was reported that if classification scheme was based on location change only, 7% NP rate would be recorded instead of 51% on considering histologic and DNA findings [11]. Huang et al. [1] designated a tumor as TR if it was located within cm of the primary tumor bed and if the histologic subtype was consistent with the primary tumor. Other pathologic findings suggesting NP are the presence of carcinoma in situ, and better differentiation of the second tumor. Haffty et al. [7] classified tumors according to location and DNA flow cytometry. They concluded that conversion of an aneuploid to a diploid genotype meant NP recurrence. Another reason of variation of TR and NP percentages in different series investigating IBTR is the duration of follow-up. This is best evident in the study by Kurtz et al. [15] who separated their classification scheme by time to IBTR. They found that at years following original diagnosis, 55% of the IBTR were NP, compared to an overall of 1%. As regards the risk factors that may be predictive for developing NP versus TR, two main significant factors were recorded in the present study; namely age and the disease-free interval

6 188 Ipsilateral In-Breast Tumor Relapse after Breast Conservation Therapy from the initial diagnosis to relapse. Patients with NPs were significantly younger at initial diagnosis (8 Vs 7 years, p=.6), and at relapse ( Vs 5 years, p=.6) than those with TR. Similarly, it was reported that '' elsewhere" relapses were more common in women who were diagnosed before the age of 5 years [,1], and that patients whose tumors were classified as NP were younger than those with TR (mean age 9 Vs 55 years, p<.1) [11]. In contrast, Huang et al. [1] found no significant difference between the two groups in relation to age. The disease-free interval was significantly shorter in the TR group than the NP group (.9 versus 6.9 years, p<.1) in the current study. In agreement, it was found that the TR, marginal miss recurrence rate was substantially higher than the NP rate for the first 5 years, %/year compared to the steady increase to 1%/year at 5 years for NP tumors, but then decreased to.5% year up until 8 years [1]. In contrast, the NP rate remained steady at 1% year after 5 years. In another study [11], the average time for NP tumors to develop was 7. years following initial diagnosis as compared to.7 years for TR (p<.1). This was supported by the results of Haffty et al. [7] who found that NP developed much later than TR (5. years Vs. years). It was found that patients with earlier IBTR had a significantly poorer prognosis, regardless of cutoff time at 1,, or 5-years following initial diagnosis [5]. This observation was emphasized by other studies [1,16]. Veronesi et al. [9] assumed that TR relapses most likely develop after BCT from residual viable malignant cells. The true recurrence should develop shortly after primary treatment, with rates decreasing over time, whereas NP tumors could develop at any time independent of the initial treatment because it represents genetic predisposition and susceptibility to breast carcinoma. This adds additional evidence that the mechanisms of these two types of local recurrences are different [1]. There was no significant difference between TR and NP patients with respect to primary tumor size, stage of disease at initial diagnosis, histology of the primary tumor, axillary lymph node involvement, nuclear grade, resection margins and adjuvant systemic therapy. There was no significant difference between the histology of the NP and the TR relapses. However, the TR patients have more infilterating ductal carcinomas and NP patients have more intraduct carcinomas. These findings were consistent with our classification. This is because if a tumor went from an IDC to predominantly DCIS, it is to be considered a NP tumor as the natural history of breast cancer is not consistent with the ability of the cancer to convert from a more invasive to a less invasive carcinoma. In the current study, patients (1.%) were inoperable because of diffuse local disease or inflammatory features comparable to 6-7% reported in literature [6,17,18]. Salvage mastectomy is the standard surgical treatment for IBTR [19,], but one study have shown that the survival rates of repeat lumpectomy were equal to those of mastectomy [17]. The latter study showed excellent results of repeat lumpectomy with 85% overall survival and 81% local control rate at 5 years. However, generally the rate of secondary local relapse ranged from 19% to 6% [17,18]. Kurtz et al. [15,18], reported a 5% secondary local relapse. Two of the cases who underwent repeat lumpectomy in the current study developed secondary local failure, but no local failure occurred after salvage mastectomy. So, we recommend salvage mastectomy for IBTR based on an elevated risk of further inbreast relapse after repeat lumpectomy. Many studies including the current study demonstrated that TR and NP show a quite different behavior; which may have important implications in the clinical management of IBTR. Patients with NP generally have a favorable long-term prognosis. Therapeutic decisions concerning systemic therapy should be similar to those used for patients with de novo primary breast carcinoma of an equivalent stage. However, the risk of developing contra-lateral breast carcinoma, coupled with the possibility of a genetic predisposition, highlights the need for better chemoprevention strategies. One strategy is to recommend tamoxifen for patients with NP, as randomized trials have demonstrated its benefit in reducing contra-lateral and ipsilateral disease recurrence with minimal side effects [1,]. The NSABP P-1 trial showed that 5 years of tamoxifen reduced the 5-year risk of developing breast carcinoma by as much as 5% in all age groups []. The beneficial effects of tamoxifen in decreasing rates of NP could

7 Hassan M. Abdalla, et al. 189 not be studied adequately in this study due to its infrequent use. In contrast, patients with TR have a poor prognosis in terms of both survival rates and development of other local or systemic metastases. These data highlight the need for intensive systemic chemotherapy for TR patients. The main limitation of this study is that the IBTR were classified using clinical and pathologic criteria without molecular confirmation. In the future, more precise molecular studies will likely be able to identify the clonal relation of the IBTR to the primary tumor. However, the current methodology has greater clinical applicability than molecular techniques that require sophisticated analyses. The criteria used in this study are based on readily available information and can identify subgroups of patients with significantly different outcomes after IBTR. In conclusion, based on differences in location and histology between the primary tumor and that of IBTR, a significant portion of patients who experience IBTR after BCT may have NP tumors as opposed to TR. True recurrence and new primary tumor ipsilateral breast tumor relapses appear to have a different natural history, different prognosis, and in turn, different implications for therapeutic management. Establishment of more exact classifying criteria like DNA finger printing will likely be able to identify the clonality of the IBTR and the primary tumor and should be the focus of further research in this area. REFERENCES 1- Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med., 7: Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med., 7: Fowble B, Solin LJ, Schultz DJ, Rubenstein J, Goodman RL. Breast recurrence following conservative surgery and radiotherapy: Patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment. Int J Radiat oncol Biol Phys. 199, 19: Van Dongen J, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, et al. Long-term results of a randomized trail comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 181 trial. J Natl Cancer Inst., 9: Fisher B, Anderson S, Fisher ER, Redmond C, Wickerham DL, Wolmark N, et al. Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet. 1991, 8: Kurtz JM, Amalric R, Brandone H, Ayme Y, Jacquemier J, Pietra JC, et al. Local recurrence after breastconserving surgery and radiotherapy. Frequency, time course, and prognosis. Cancer. 1989, 6: Haffty BG, Fischer D, Beinfield M, McKhann C. Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys. 1991, 1: Touboul E, Buffat L, Belkacemi Y. Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer. Int J Radiat Oncol Biol Phys. 199, : Veronesi U, Marubini E, Del Vecchio M, Manzari A, Andreola S, Greco M, et al. Local recurrences and distant metastases after conservative breast cancer treatment: Partly independent events. J Natl Cancer Inst. 1995, 87: Huang E, Buchholz TA, Meric F, Krishnamurthy S, Mirza NQ, Ames FC, et al. Classifying local disease recurrences after breast conservation therapy based on location and histology: New primary tumors have more favorable outcomes than true local disease recurrences. Cancer., 95: Smith TE, Lee D, Turner BC, Carter D, Haffty BG. True recurrence Vs. new primary ipsilateral breast tumor relapse: An analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys., 8: Komoike Y, Akiyama F, Iino Y, Ikeda T, Tanaka- Akashi S, Ohsumi S, et al. Analysis of ipsilateral breast tumor recurrences after breast-conserving treatment based on the classification of true recurrences and new primary tumors. Breast Cancer. 5, 1: Krauss DJ, Kestin LL, Mitchell C, Martinez AA, Vicini FA. Changes in temporal pattern of local failure after breast-conserving therapy and their prognostic implications. Int J Radiat Oncol Biol Phys., 6: Recht A, Silen W, Schnitt SJ, Connolly JL, Gelman RS, Rose MA, et al. Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer. Int J Radiat Oncol Biol Phys. 1988, 15: Kurtz JM, Spitalier JM, Amalric R, Brandone H, Ayme Y, Jacquemier J. The prognostic significance of late

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