RADIOTHERAPY FOR STAGE II AND STAGE III BREAST CANCER PATIENTS WITH NEGATIVE LYMPH NODES AFTER PREOPERATIVE CHEMOTHERAPY AND MASTECTOMY

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp. e1 e7, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved /$ - see front matter CLINICAL INVESTIGATION Breast Cancer RADIOTHERAPY FOR STAGE II AND STAGE III BREAST CANCER PATIENTS WITH NEGATIVE LYMPH NODES AFTER PREOPERATIVE CHEMOTHERAPY AND MASTECTOMY ROMUALD LE SCODAN, M.D.,* JESSICA SELZ, M.D.,* DENISE STEVENS, M.D., y MARC A. BOLLET, M.D., PH.D.,* BRIGITTE DE LA LANDE, M.D.,* CAROLINE DAVEAU, M.D.,* FLORENCE LEREBOURS, M.D., PH.D., z ALAIN LABIB, M.D.,* AND SARAH BRUANT, M.D. y Departments of *Radiation Oncology, y Biostatistics, and z Medical Oncology, Institut Curie-H^opital Rene Huguenin, Saint-Cloud, France Purpose: To evaluate the effect of postmastectomy radiotherapy (PMRT) in Stage II-III breast cancer patients with negative lymph nodes (pn0) after neoadjuvant chemotherapy (NAC). Patients and Materials: Of 1,054 breast cancer patients treated with NAC at our institution between 1990 and 2004, 134 had pn0 status after NAC and mastectomy. The demographic data, tumor characteristics, metastatic sites, and treatments were prospectively recorded. The effect of PMRT on locoregional recurrence-free survival and overall survival (OS) was evaluated by multivariate analysis, including known prognostic factors. Results: Of the 134 eligible patients, 78 (58.2%) received PMRT and 56 (41.8%) did not. At a median follow-up time of 91.4 months, the 5-year locoregional recurrence-free survival and OS rate was 96.2% and 88.3% with PMRT and 92.5% and 94.3% without PMRT, respectively (p = NS). The corresponding values at 10 years were 96.2% and 77.2% with PMRT and 86.8% and 87.7% without PMRT (p = NS). On multivariate analysis, PMRT had no effect on either locoregional recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, ; p =.18) or OS (hazard ratio, 2.06; 95% confidence interval, ; p =.18). This remained true in the subgroups of patients with clinical Stage II or Stage III disease at diagnosis. A trend was seen toward poorer OS among patients who had not had a pathologic complete in-breast tumor response after NAC (hazard ratio, 6.65; 95% confidence interval, ; p =.076). Conclusions: The results from the present retrospective study showed no increase in the risk of distant metastasis, locoregional recurrence, or death when PMRT was omitted in breast cancer patients with pn0 status after NAC and mastectomy. Whether the omission of PMRT is acceptable for these patients should be addressed prospectively. Ó 2012 Elsevier Inc. Breast cancer, Neoadjuvant chemotherapy, Postmastectomy radiotherapy. INTRODUCTION Neoadjuvant chemotherapy (NAC) has become the standard of care for patients with locally advanced breast cancer (BC) and is also a valid treatment option for earlier stage operable disease (1 6). NAC generally induces significant changes in the pathologic disease extent and has been reported to eradicate nodal involvement in 20 40% of patients (7 9). This potential downstaging has challenged the standard indications for adjuvant postmastectomy radiotherapy (PMRT). PMRT significantly reduces the risk of locoregional recurrence (LRR) and improves the overall survival (OS) of selected patients undergoing initial surgery and postoperative chemotherapy (10). However, none of the prospective Phase III trials investigating PMRT have enrolled BC patients treated with NAC. Thus, the patient selection for PMRT after neoadjuvant therapy remains unclear and has been guided by retrospective analyses of small sample sizes (11 16), mostly from patients treated at the M.D. Anderson Cancer Center (11, 12, 14, 16). In 2008, a multidisciplinary expert panel organized by the National Cancer Institute published a statement concerning locoregional treatment after preoperative chemotherapy for BC (13). They reported that PMRT should be considered for patients presenting with clinical Stage III disease or with histologically positive lymph nodes after preoperative chemotherapy (13). The panel further concluded that it was unclear whether PMRT offers clinical benefit for patients with clinical Stage II disease and negative lymph nodes after preoperative chemotherapy. In the present study, we studied the effect of PMRT on LRR-free survival Reprint requests to: Romuald Le Scodan, M.D., Department of Radiation Oncology, Centre Rene Huguenin, 35 rue Dailly, Saint Cloud France. Tel: (+33) ; Fax: (+33) ; lescodan@crh1.org e1 Conflict of interest: none. Received June 9, 2010, and in revised form Dec 22, Accepted for publication Dec 31, 2010.

2 e2 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 (LRR-FS), disease-free survival (DFS), and OS in Stage II and Stage III BC patients with pathologic N0 status (pn0) after NAC. PATIENTS AND METHODS Between January 1990 and December 2004, 1,054 patients with clinical Stage II or Stage III BC (according to the 1988 American Joint Committee on Cancer Staging and End Results Reporting Guidelines) had received NAC at the Rene Huguenin Cancer Center (Saint Cloud, France). The patients who had synchronous metastases at diagnosis or who had a personal history of cancer were excluded from the present analysis. Of the 568 patients (53.9%) who had undergone total mastectomy with axillary dissection after NAC, 134 (23.6%) had pathologic N0 status (pn0) after NAC and were included in the present study. The patient characteristics, tumor characteristics, treatments, and outcomes were prospectively recorded in the hospital s MEDICOD database. All NAC was anthracycline based. The patients were either participating in randomized or nonrandomized clinical trials (nine different chemotherapy protocols were tested during this 14-year period) or received the local standard treatment. Because of the lack of consensus and the paucity of data on the effect of PMRT after NAC, no institutional recommendations were available regarding PMRT delivery in this context. The likely risks and benefits of PMRT were considered individually for each patient during multidisciplinary staff meetings in the radiation oncology department, and the final decision was made by the patient and her physicians. For patients selected for PMRT, our institutional policy was to treat the chest wall, supraclavicular lymph nodes, and internal mammary nodes to a total dose of Gy. The standard schedule consisted of daily fractions of Gy. The standard RT schedule consisted of daily fractions of Gy. PMRT typically used a photon field to treat the supraclavicular fossa/axillary apex, a mixed photon and electron field to treat the internal mammary chains, and an electron field to treat the chest wall. Our institutional review board approved the data acquisition, analysis, and reporting of the patient data. Statistical analysis The characteristics of the PMRTand no-pmrt groups were compared using the chi-square test, Fisher s exact test, or Student s t test. OS was defined as the interval from the diagnosis to the last visit or death. LRR was defined as disease recurrence on the ipsilateral chest wall or ipsilateral axillary, supraclavicular, infraclavicular, or internal mammary lymph nodes. All recurrences at other sites were recorded as distant metastases. All LRRs were considered as events, irrespective of their timing relative to the occurrence of distant metastases. The curves for LRR, DFS, and OS were constructed using the Kaplan-Meier method (17) and compared using the log rank test. The following variables were analyzed with a multivariate method (Cox regression model) for their effect on OS: age at diagnosis (#50 vs. >50 years), T (T1-T2 vs. T3-T4) and N (N0 vs. N1-N2) stage at diagnosis, histologic grade (Scarff-Bloom- Richardson score 1 vs. 2-3), inflammatory signs (yes vs. no), hormonal treatment type, hormone receptor status, NAC regimen, pathologic response of in-breast tumor to NAC (pathologic complete response [pcr] vs. no pcr), and PMRT (yes vs. no). The tests for interaction were performed as a part of the subgroup analysis by adding an interaction term to the Cox regression model. Differences with p <.05 were considered statistically significant. Statistical analyses were performed using the R software, version (available from: RESULTS Patient characteristics and treatments Of the 134 patients with pn0 status after NAC and mastectomy, 78 (58.2%) received PMRT and 56 (41.8%) did not. The patients and tumor characteristics and treatments are compared in Table 1. In brief, the mean age at diagnosis was 49.9 years (range, 28 71), and 64 patients (47.8%) were <50 years at diagnosis. All the patients in the present study were considered to have free surgical margins; however, the distance from the excision margins was not prospectively recorded in our database after total mastectomy. At diagnosis, compared with the patients who did not receive PMRT, those who did receive PMRT more frequently had Stage T3-T4 disease (58% vs. 38%, p =.021), more frequently had clinical Stage N1-N2 disease (58% vs. 34%, p = 0.007), and more frequently had Stage III disease (49% vs. 21%, p =.001; Table 1). The mean number of nodes dissected was 12.5 (median, 12; range, 6 30) in the no-pmrt group and 12 (median, 12; range, 1 26) in the PMRT group (p =.45). No difference was found between the PMRT and no-pmrt groups with respect to age at diagnosis, histologic grade, pcr, tumor hormone receptor status, or NAC type. All the patients received anthracycline-based combination chemotherapy, including a taxane in 13 patients (9.7%). The median number of chemotherapy cycles received was 4 (mean, 4.7; range, 2 6). The median interval between surgery and RT was 50 days (range, ). PMRT delivered a mean dose of Gy (range, 45 50), Gy (range, 45 50), and Gy (range, 30 50) to the chest wall, supraclavicular lymph nodes, and internal mammary nodes, respectively. A total of 24 patients underwent RT to the complete axillary region (mean dose, Gy; range, 45 50), using an extended anterior supraclavicular and axillary photon field, with a standard posterior axillary photon field. LRR, DFS, and OS Overall, the median follow-up was 91.4 months (range, ). At the cutoff date for the present analysis (October 2009), 23 patients (17.2%) had died (16 [21%] in the PMRT group and 7 [12%] in the no-pmrt group; p =.23), and 10 patients (7.5%) had developed locoregional relapse. Of these 10 patients, 3 (4%) were in the PMRT group (local relapse in 2 and metastatic and local relapse in 1) and 7 (12%) were in the no-pmrt group (local relapse in 2, locoregional relapse in 2, regional relapse in 2, and metastatic and local relapse in 1; p =.09). The median interval to the first event was 88.1 months overall (range, ). The 5-year DFS and OS rate for the entire population was 81.7% (95% confidence interval [CI] %) and 90.8% (95% CI, %), respectively. The 5-year LRR-FS rate for the entire population was 94.6% (95% CI, %). In the PMRT and no-pmrt groups, the 5-year LRR-FS rate was 96.2% (95% CI, %) and

3 PMRT for negative lymph node BC after NAC d R. LE SCODAN et al. e3 Table 1. Patient characteristics and treatment Variable No PMRT group (n = 56) PMRT group (n = 78) Age (y).986 Mean SD Range Age group (y).794 <50 26 (46) 38 (49) $50 30 (54) 40 (51) Clinical Stage (AJCC).001 I 0 1 (1) II 44 (79) 39 (50) III 12 (21) 38 (49) Clinical T stage.021 T1-T2 35 (62) 33 (42) T3-T4 21 (38) 45 (58) Clinical N stage.007 N0 37 (66) 33 (42) N1-N2 19 (34) 45 (58) Primary tumor response.066 to NAC (pcr) Yes 6 (11) 18 (23) No 50 (89) 60 (77) Lymph node dissection.456 Mean SD Range Histologic type.943 Ductal carcinoma 45 (80) 62 (80) Lobular carcinoma 9 (16) 11 (14) Other 2 (4) 5 (6) Inflammatory signs*.076 No 40 (71) 44 (56) Yes 16 (29) 34 (44) Histologic grade (SBR).093 SBR1 7 (14) 3 (4) SBR2-SBR3 44 (86) 67 (96) Tumor HER2 status.09 y 9 (34) 38 (49) Positive 0 8 (10) Unknown 37 (66) 32 (41) Tumor HR status.407 y 8 (32) 34 (44) Positive 35 (62) 40 (51) Unknown 3 (5) 4 (5) Tumor ER status.493 y Negative 21 (38) 37 (47) Positive 32 (57) 37 (47) Unknown 3 (5) 4 (5) Tumor PR status.212 y Negative 25 (45) 46 (59) Positive 28 (50) 28 (36) Unknown 3 (5) 4 (5) Neoadjuvant chemotherapy regimen.798 Anthracycline 51 (91) 70 (90) Taxane 5 (9) 8 (10) Hormonal treatment.09 No 24 (43) 45 (58) Yes 32 (57) 33 (42) Hormonal treatment type Tamoxifen New AI 0 4 Tamoxifen plus AI 7 5 Other 1 5 Abbreviations: PMRT = postmastectomy radiotherapy; SD = standard deviation; AJCC = American Joint Committee on Cancer (1988); pcr = pathologic complete response; SBR = Scarff- Bloom-Richardson (score); HR = hormone receptor; ER = estrogen receptor; PR = progesterone receptor; AI = aromatase inhibitor. * Inflammatory signs were recorded in our database when local or diffuse erythema was observed at breast cancer diagnosis, not only in inflammatory breast cancer. y p with known value. p 92.5% (95% CI, %), respectively (unadjusted hazard ratio [HR], 0.36; 95% CI, ; p =.12; Fig. 1). The 5-year DFS rate in the PMRT and no-pmrt groups was 79.2% (95% CI, %) and 85.2% (95% CI, %), respectively (unadjusted HR, 1.46; 95% CI, ; p =.30). The corresponding 5-year OS rates were 88.3% (95% CI, %) and 94.3% (95% CI, %; unadjusted HR, 2.22; 95% CI, ; p =.08; Fig. 2). In the PMRT and no-pmrt groups, the 10-year LRR-FS rate was 96.2% (95% CI, %) and 86.8% (95% CI, %), respectively (unadjusted HR, 0.40; 95% CI, ; p =.18). The 10-year DFS and OS rates in the PMRT and no-pmrt group were 70.9% (95% CI, %) and 79.8% (95% CI, %; unadjusted HR, 1.56; 95% CI, ; p =.25) and 77.2% (95% CI, %) and 87.7% (95% CI, %; unadjusted HR, 2.00; 95% CI, ; p =.15), respectively. For the 83 clinical Stage II patients, the 5-year LRR-FS, DFS, and OS rate was 97.4% (95% CI, %), 82.0% (95% CI, %), and 89.7% (95% CI, %) for the PMRT group (n = 39) and 92.9% (95% CI, %), 83.6% (95% CI, %), and 92.9% (95% CI, %) for the no-pmrt group (n = 44), respectively (p >.4 for all comparisons). Of the 50 clinical Stage III patients, the 5-year LRR-FS, DFS, and OS rate was 94.7% (95% CI, %), 76.0% (95% CI, %), and 86.7% (95% CI, %) for the PMRT group (n = 38 patients) and 90.9% (95% CI, %), 90.9% (95% CI, %), and 100% (95% CI, %) for the no-pmrt group (n = 12), respectively (p >.2 for all comparisons). LRR-FS 10-year Kaplan Meier estimates of 10-year LRR-FS Group no PMRT PMRT 10-year LRR-FS, 96.2% (PMRT) vs 86.8% (no PMRT) p= Time (years) No. at Risk No PMRT PMRT Fig. 1. Locoregional recurrence-free survival (LRR-FS) according to receipt of postmastectomy radiotherapy (PMRT).

4 e4 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 OS 10-year Kaplan Meier estimates of 10-year OS Group no PMRT PMRT 10-year OS, 77.2% (PMRT) vs 87.7% (no PMRT), p= Time (years) No. at Risk No PMRT PMRT Fig. 2. Overall survival (OS) according to receipt of postmastectomy radiotherapy (PMRT). In the subgroup of patients without pcr after NAC, the 5-year LRR-FS, DFS, and OS rates did not differ significantly between the 60 patients in the PMRT group and 50 patients in the no-pmrt group (83.3%, 95% CI, %; 73.2%, 95% CI, %; and 84.9%, 95% CI, %; vs. 87.4%, 95% CI, %; 83.3%, 95% CI, %; and 93.6%, 95% CI, %, respectively; p >.13forall comparisons). On multivariate analysis, delivery of PMRT had no effect on LRR-FS (HR, 0.37; 95% CI, ; p =.185), DFS(HR, 1.51; 95% CI, ; p =.32), or OS (HR, 2.06; 95% CI, ; p =.18; Tables 2 through 4). No significant interaction was found between the delivery of PMRT and the known prognostic factors, suggesting that no subgroups of patients with negative lymph nodes after NAC seemed to benefit from PMRT (Table 5). A trend was seen toward poorer OS among patients who had not had a pcr after NAC (HR, 6.65; 95% CI, ; p =.076;Table 4). DFS was negatively affected by nonachievement of a pcr (HR, 8.95; 95% CI, ; p =.037). DISCUSSION The results of the present retrospective study suggest that BC patients with pathologically negative lymph nodes after NAC and mastectomy have a favorable outcome and a low risk of locoregional relapse. Also, PMRT does not appear to affect survival. NAC has been used more frequently for Stage II and III BC, raising issues with respect to subsequent locoregional treatment. The indications for adjuvant RT, in particular, the need for PMRT, have traditionally been determined by the initial pathologic disease extent. NAC has been shown to sterilize the primary tumor and involved axillary Table 2. Multivariate analysis of locoregional recurrencefree survival, Cox model (n = 116) Variable HR 95% CI p PMRT Yes 0.37 Age at diagnosis (y) <50 1 $ Clinical T stage T1-T2 1 T3-T Clinical N stage N0 1 N1-N Histologic grade (SBR) SBR1 1 SBR2-SBR ER status Positive 0.40 PR status Positive 3.16 NAC regimen Anthracycline 1 Taxane 1.19 Response to NAC 0.00 Infinity.999 pcr 1 No pcr 3.03 Inflammatory signs Yes 1.34 Hormonal treatment Yes 0.35 Abbreviations: HR = hazard ratio; CI = confidence interval; other abbreviations as in Table 1. nodes in about 20 40% of patients (4, 7, 9). Newer chemotherapy regimens have increased the percentage of patients with a pcr (18). This potential downstaging has challenged the standard indications for adjuvant PMRT. Because none of the patients enrolled on the randomized trials of PMRT were treated with NAC, the patient selection for PMRT after neoadjuvant therapy has been less obvious and has been guided by the results from retrospective analyses (11 14, 16). We report, to our knowledge, the largest cohort of Stage II and Stage III BC patients with negative lymph nodes after NAC and mastectomy. Several retrospective studies have evaluated the risk of LRR after NAC and total mastectomy, as well as the benefits of postmastectomy RT (11 14, 16). The results suggested that chest wall and regional node RT should be considered for patients who have clinical Stage III disease or pathologic lymph node involvement after NAC. However, few studies have addressed how a pcr should affect locoregional treatment decisions (16). Whether PMRT offers a clinical benefit to patients with negative lymph nodes after preoperative chemotherapy is therefore less clear (13).

5 PMRT for negative lymph node BC after NAC d R. LE SCODAN et al. e5 Table 3. Multivariate analysis of disease-free survival, Cox model (n = 116) Variable HR 95% CI p PMRT Yes 1.51 Age at diagnosis (y) <50 1 $ Clinical T stage T1-T2 1 T3-T Clinical N stage N0 1 N1-N Histologic grade (SBR) SBR1 1 SBR2-SBR ER status Positive 0.88 PR status Positive 0.73 NAC regimen Anthracycline 1 Taxane 1.21 Response to NAC pcr 1 No pcr 8.95 Inflammatory signs Yes 0.97 Hormonal treatment Yes 0.80 Abbreviations as in Tables 1 and 2. Huang et al. (14) compared the outcomes of 542 patients treated with NAC, mastectomy, and PMRT with those of a control group of 134 patients not treated with PMRT. At 10 years, the LRR rates were significantly lower for the irradiated patients at 11% than for the nonirradiated patients at 22% (p =.0001). On univariate analysis, PMRT was shown to reduce LRR for patients with clinical T3 or T4 tumors, Stage IIB or greater disease (American Joint Committee on Cancer 1988), pathologic tumor size >2 cm, or four or more positive nodes (p #.002 for all comparisons). PMRT was also shown to improve cause-specific survival in the following subsets: Stage IIIB or greater disease, clinical Stage T4 tumor, and four or more positive nodes (p #.007 for all comparisons). The small subset of patients who presented with clinical Stage III disease and who subsequently achieved a pcr to systemic therapy also had a significantly reduced LRR rate compared with patients who had not undergone PMRT. At 10 years, these patients had a 3% LRR rate (1 event among 35 patients) compared with 33% (3 events among 11 patients) in the non-pmrt patients (p =.006). However, no difference in LRR rates was observed in the patients presenting with initial Stage I-II disease with a pcr nor in those with one to three positive lymph Table 4. Multivariate analysis of overall survival, Cox model (n = 116) Variable HR 95% CI p PMRT Yes 2.06 Age at diagnosis (y) <50 1 $ Clinical T stage T1-T2 1 T3-T Clinical N stage N0 1 N1-N Histologic grade (SBR) 0.00 Infinity.998 SBR1 1 SBR2-SBR e 7 ER status Positive 0.52 PR status Positive 0.67 NAC regimen Anthracycline 1 Taxane 1.26 Response to NAC pcr 1 No pcr 6.65 Inflammatory signs Yes 0.72 Hormonal treatment Yes 1.43 Abbreviations as in Tables 1 and 2. nodes after NAC. Their updated institutional experience, reporting the outcome of 106 patients with a pcr in the breast and axillary lymph nodes to NAC, showed that the 10-year LRR rates did not differ significantly between the irradiated (5%) and nonirradiated (10%) patients (p =.4) (16). None of the 32 patients who had clinical Stage I or II disease at presentation and who had achieved a pcr developed LRR (10- year LRR rate 0% for both RT patients [n = 12] and no-rt patients [n = 20]). However, for those who initially presented with Stage III disease (n = 74), the use of RT was associated with a significantly lower 10-year rate of LRR (7.3% for RT Table 5. Interaction between PMRT delivery and known prognostic factors Variable OS p Value for interaction LRR-FS Clinical T stage Clinical N stage pcr Age at diagnosis Abbreviations: OS = overall survival; LRR-FS = locoregional recurrence-free survival; other abbreviations as in Table 1.

6 e6 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 group vs. 33.3% for no-rt group; p =.040). Our results have shown that the risk of locoregional relapse was low in patients with pn0 status after NAC and mastectomy and confirmed that delivery of PMRT was not associated with better outcomes in BC patients with Stage II disease at diagnosis and no lymph node involvement after NAC. However, in contrast to the experience from the M.D. Anderson Cancer Center, we did not observe an association between the delivery of PMRT and better outcomes in our subgroup of patients (n = 50) with Stage III disease at diagnosis. The most important predictor of the long-term outcomes in BC patients is the absence of residual tumor in the breast and axillary lymph nodes after NAC. The 5-year DFS and OS rates have approached 85 90% for BC patients with a pcr after NAC; however, those with residual invasive disease have had 5-year DFS and OS rates of about 60% (3, 9, 19 21). We confirmed on multivariate analysis that residual tumor in the breast after NAC was associated with poor DFS (HR, 8.95; 95% CI, ; p =.037) and was associated with a trend toward poorer OS (HR, 6.65; 95% CI, ; p =.076). This factor might designate a subgroup of high-risk patients in whom the benefit of aggressive or investigational adjuvant therapy could be evaluated. The potential survival advantage provided by multimodality therapies in patients with Stage II-III BC has been sometimes undermined by long-term complications. Although recent technical advances have reduced the risk of post-rt complications, irradiation of the chest wall and regional lymphatics should still be reserved for patient subgroups for whom it has been shown to be consistently beneficial. Supraclavicular lymph node irradiation has been historically linked to an increased risk of arm edema (22 24), brachial plexopathy (25 27), pneumonitis (28 30), and esthetic sequelae (31 33). Meric et al. (33), in a series of 294 prospectively monitored patients undergoing breast RT in 1991 and 1992, found that about 1 in 10 patients developed Grade 2 or greater complications, such as arm edema, breast skin fibrosis, and limited arm motion after breast-conserving surgery with or without axillary lymph node dissection. Arm edema was also more frequent in patients who had undergone lymph node RT (18% vs. 10%). Similarly, the risk of radiation pneumonitis after tangential breast RT appears to be slightly increased by regional lymph node RT (4.1% vs. 0.9%, p =.02) (29), and RT to the internal mammary nodes has been linked to increased cardiac morbidity (34). Our results suggest that the omission of PMRT was not detrimental in this subset of Stage II and Stage III BC patients with negative lymph nodes after NAC and mastectomy. This provides the possibility of sparing these patients potential long-term complications. Given the retrospective nature of the studies, it is important to interpret these data with caution. The lack of benefit associated with PMRT could have resulted, in part, from the limited number of patients and the significant differences in the known prognostic factors (e.g., clinical T or N stage at diagnosis) between the PMRT and no-pmrt groups, favoring the no-pmrt cohort. The trend in poorer OS in the PMRT group, although not statistically significant on univariate analysis, probably also reflected, owing to the precocity of its occurrence, the imbalance in disease stage, rather than a deleterious effect of PMRT. Given the significant differences in the T and N stages at diagnosis, PMRT could also have equalized the outcomes between the lower and higher risk groups, as suggested by the trend toward a greater locoregional control rate in the PMRT group. Some investigators have recommended sentinel lymph node biopsy before NAC to determine axillary status without the potential confounding effects of systemic treatment, to avoid axillary dissection in sentinel node-negative patients, and to guide locoregional adjuvant treatment. The reliability of this procedure, the recent data and limits, in particular, the use of sentinel lymph node biopsy, especially in patients with large tumors, has been extensively discussed in a recent review (35). The search for new biologic markers to predict locoregional control after mastectomy could also potentially help the determination of patients who would not benefit from PMRT (36). CONCLUSIONS The results from the present retrospective study showed no increase in the risk of distant metastasis, LRR, or death when PMRT was omitted in BC patients with negative lymph nodes after NAC and total mastectomy. Whether the omission of PMRT is acceptable for these patients should be addressed prospectively. 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