Skin Recurrences After Breast-Conserving Therapy for Early-Stage Breast Cancer

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1 Skin Recurrences After Breast-Conserving Therapy for Early-Stage Breast Cancer By Irene Gage, Stuart J. Schnitt, Abram Recht, Anthony Abner, Steven Come, Lawrence N. Shulman, Jedidiah M. Monson, Barbara Silver, Jay R. Harris, and James L. Connolly Purpose: To assess the frequency and prognosis of skin recurrences after breast-conserving therapy (BCT) compared with other breast recurrences. Materials and Methods: From 1968 to 1986, 1,624 patients with unilateral stage I or II breast cancer treated with BCT at the Joint Center for Radiation Therapy (Boston, MA) underwent gross tumor excision and received a dose of - 60 Gy to the tumor bed. Skin recurrences (SR) were defined as breast recurrences without associated parenchymal disease. An invasive breast recurrence with any parenchymal disease noted clinically or radiographically was scored as an other breast recurrence (OBR). Median follow-up for survivors was 137 months. Results: SR represented 8% (18 of 229) of all breast recurrences and occurred in 1.1% of all patients. The outcome after local recurrence was different for patients with SR and invasive OBR. Patients with SR more frequently had uncontrolled local failure (50%; 9 of 18) N UMEROUS randomized clinical trials have shown that breast-conserving therapy (BCT) that consists of conservative surgery (CS) and radiation therapy (RT) provides equivalent survival rates to mastectomy for patients with early-stage breast cancer. 1, 2 However, the pattern of local recurrence after either of these two treatment approaches is different. Local recurrence after mastectomy occurs in the skin of the chest wall, typically in relation to the scar, 3 whereas breast recurrences after CS and RT most frequently are noted within the breast parenchyma in the region of the primary tumor site. 4-6 Local recurrence after mastectomy also is more frequently associated with distant metastasis and lower rates of survival compared with recurrences after BCT. Local recurrence that occurs in the skin of the treated breast has been described after CS and RT, but it is rare in From the Joint Center for Radiation Therapy; Departments of Pathology and Hematology/Oncology, Beth Israel-Deaconess Medical Center; and the Department of Hematology-Oncology, Brigham and Women 's Hospital and Dona-Farber Cancer Institute, Harvard Medical School, Boston, MA. Submitted June 10, 1997; accepted September 16, Address reprint requests to Irene Gage, MD, Department of Oncology/ Division of Radiation Oncology, Johns Hopkins Oncology Center, 600 N. Wolfe St, Baltimore, MD 21287; gageir@wpmail.onc.jhu.edu by American Society of Clinical Oncology X/97/ $3.00/0 than did patients with OBR (14%; 26 of 188) (P =.0007). Forty-four percent (8 of 18) of patients with SR had distant metastasis simultaneously or within 2 months of the recurrence compared with 5% (9 of 188) of invasive OBR patients (P <.0001). For patients without distant metastasis at the time of recurrence, the 5-year actuarial rate of development of distant metastasis was 60% for SR patients compared with 39% for invasive OBR patients (P =.07), and the corresponding 5-year actuarial survival rates beyond the time of local failure were 51% and 79%, respectively (P =.06). Conclusion: In contrast to other types of invasive breast recurrence after breast-conserving therapy, skin recurrences are rare and are associated with a significantly higher rate of distant metastasis and uncontrolled local disease as well as a lower rate of survival. J Clin Oncol 16: by American Society of Clinical Oncology. most series; therefore, little has been documented in regard to its appearance, risk factors, and outcome. In this study, the time course and frequency of such skin recurrence is examined in a group of 1,624 patients treated with CS and RT and followed for a median of 11.4 years. Also, the risk factors and outcome for patients with skin recurrence are compared with those of patients with other types of invasive local recurrence. MATERIALS AND METHODS During the years 1968 to 1986, 1,865 patients with unilateral clinical stage I or II breast cancer were treated with conservative surgery and radiation therapy at the Joint Center for Radiation Therapy (Boston, MA). Two hundred forty-one patients who received a dose of less than 60 Gy to the tumor bed or who were not treated with complete gross tumor excision were excluded from the analysis. The remaining 1,624 patients constituted the study population. The length of follow-up was measured from the first day of radiation therapy. The median follow-up time for survivors was 137 months. The details of treatment technique have been previously reported. 5 Tangential fields delivered a median whole-breast dose of 46 Gy. Bolus was not routinely used. A boost to the tumor bed was delivered in most cases, and the median dose to the tumor bed was 64.7 Gy (range, 60 to 84 Gy). Supraclavicular fields received a median dose of 46 Gy, usually prescribed to a depth of 3 cm. Supraclavicular/axillary fields received a median dose of 45 Gy, usually prescribed to a depth of 5 cm. In addition to radiation therapy, at the time of initial diagnosis, 391 patients (24%) received adjuvant chemotherapy, 31 patients (2%) received tamoxifen, and nine patients received both. Breast recurrences were defined as any carcinoma that occurred in the treated breast as the first site of recurrent disease (excluding opposite 480 Journal of Clinical Oncology, Vol 16, No 2 (February), 1998: pp

2 SKIN RECURRENCE AFTER BREAST CONSERVATION breast cancers). Twenty-three patients with purely noninvasive recurrences were excluded from the comparisons. Skin recurrences (SR) were defined as any breast recurrence without associated parenchymal disease detected clinically or radiographically. Any invasive breast recurrence with parenchymal disease noted clinically or radiographically was scored as an other breast recurrence (OBR). Because patients were censored at the time of the first event, 16 patients with distant failure or regional nodal failure who subsequently developed recurrence in the breast were not included in the analysis. In the initial analysis, patients with simultaneous discovery of a breast recurrence and distant or regional nodal failure were scored as having a breast recurrence. The data also were analyzed excluding patients with metastasis at the time of their breast recurrence. Pathology review was performed by two pathologists (S.J.S. and J.L.C.) without knowledge of the clinical outcome. All available histologic sections of the primary tumor and lymph nodes were examined. Histologic slides of the initial tumor were available for review in 17 of 18 patients (94%) with SR and in 164 of 188 patients (87%) with OBR. A proportional hazards model of time from first recurrence to distant metastasis was performed. Patients included in the analysis were those without simultaneous distant metastasis or an opposite breast cancer before first recurrence. Nine patients with SR and 172 patients with invasive OBR were analyzed. RESULTS Among the 1,624 patients treated with conservative surgery and radiation therapy and followed for a median of 11.4 years, 18 patients (1.1%) developed a recurrence in the skin of the breast without parenchymal involvement. SRs represented 8% (18 of 229) of all breast recurrences and 9% of all invasive recurrences. Invasive OBR occurred in 12% of all patients and represented 82% (188 of 229) of all breast recurrences. Noninvasive breast recurrences occurred in 1.4% of all patients and accounted for 10% of all breast recurrences. The time to SR was somewhat shorter than the time to other types of invasive OBR. The median time to recurrence for patients with a SR was 38 months compared with 60 months for patients with an OBR (P =.1). The initial clinical presentation of patients who subsequently developed an SR was compared with patients with invasive OBR. Patients with SR had a median age of 50 years compared with 44 years for patients with OBR (P =.2). The median clinical tumor size was 2.75 cm and 2 cm for SR and OBR, respectively (P =.03). Pathologic features of the primary tumor for patients with SR or invasive OBR recurrences were compared, and these data are listed in Table 1. There were no statistically significant differences between the groups in terms of histologic features of the initial tumor or pathologic nodal status. Patients with an SR were somewhat more likely to have positive lymph nodes on axillary dissection than OBR patients (53% v 28%; P =.1). The incidence of lymphatic Table 1. Initial Tumor and Nodal Features for Patients With Subsequent SR and OBR Tumor Features SR (n = 18) OBR In = 188) P 481 Median size (clinical) 2.75 cm 2 cm.03 IDC 83% 80% NS ILC or mixed IDC/ILC 17% 10% NS LVI 47% 36% NS (.6) Grade III 56% 65% NS ER+ 50% 51% NS EIC+ 27% 42% NS (.4) Nodal status Median no. of nodes sampled 8 9 NS Median no. of nodes positive* 2 2 NS Any LN+ 53% 28% NS (.1) 1-3 LN+ 35% 22% NS >4 LN+ 18% 7% NS (.4) Extracapsular extension 38% 15% NS (.3) Abbreviations: IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma; LVI, lymphatic vessel invasion; ER, estrogen receptor; EIC, extensive intraductal component; NS, not significant; LN+, lymph node positive. *For patients with positive lymph nodes. vessel invasion (LVI+) for patients with an SR was 47% compared with 36% in OBR patients (P =.6). Initial treatment characteristics were examined for patients with SR and compared with patients with invasive OBR. Ninety-four percent (17 of 18) of patients with SR were treated to three fields compared with 63% of patients (118 of 188) with invasive OBR (P =.008). There were no significant differences in the photon energy or use of bolus. The two groups received similar total doses (66.4 v 65.4 Gy, respectively) and boost doses (20.1 v 19.2 Gy, respectively) (P = NS). At the time of initial diagnosis, chemotherapy was administered to nine of 18 patients who subsequently developed SR and 38 of 188 patients (20%) who subsequently developed an invasive OBR (P =.02). None of the patients with an SR had received tamoxifen and only one patient with an invasive OBR had received tamoxifen. Information on the clinical appearance of the SR was available in 15 of the 18 patients. Of these, seven had multiple erythematous skin nodules without inflammatory features and six patients had inflammatory features clinically or skin edema radiographically. One patient had a single cutaneous nodule and one patient had an isolated scar nodule. None of the patients had a mass clinically or radiographically. At the time of their skin recurrence, eight of 18 patients had documented evidence of distant disease. Of these, seven did not undergo mastectomy and were treated systemically. The remaining patient with distant metastasis underwent mastectomy and had a subsequent chest-wall failure within 6 months. Three of the eight patients with simultaneous distant disease were among the six patients whose skin recurrences had inflammatory features. Seven patients had inoperable disease without distant

3 482 metastasis and were treated systemically. Of these, three had inflammatory features and the others had multiple skin nodules. Three patients underwent a mastectomy for operable recurrences without distant metastasis. Of these, one had subsequent chest-wall and distant failures and the other two patients had locally controlled disease and are free of distant metastasis with follow-up times of 20 and 80 months after mastectomy. The mastectomy specimens of these three patients showed no parenchymal disease and only pathologically confirmed skin nodules of recurrent breast carcinoma. The outcome after local recurrence was considerably different for the SR and invasive OBR groups. Patients with an SR more frequently had uncontrolled local failure immediately or after salvage mastectomy (50%) than did patients with OBR (14%) (P =.007). Forty-four percent of patients (8 of 18) with an SR had distant metastasis simultaneously or within 2 months of the recurrence compared with 5% (9 of 188) of OBR patients (P <.0001). Figure 1 shows the freedom from distant failure by the initial type of local recurrence for all patients. Five-year actuarial rates of freedom from distant failure were 22% and 58% for SR and OBR patients, respectively (P =.001). The overall survival for both groups from the time of recurrence is shown in Figure 2. Five-year actuarial survival rates were 34% and 77% for SR and OBR patients, respectively (P =.001). In Figures 3 and 4, the patients analyzed were only those without simultaneous distant metastasis at the time of breast recurrence. Figure 3 shows the freedom from subsequent distant failure by the initial type of local recurrence. The GAGE ET AL 5-year actuarial rates of freedom from subsequent distant metastasis were 40% and 61% for SR and OBR patients, respectively (P =.07). The overall survival for both groups from the time of recurrence is shown in Figure 4. Five-year actuarial survival rates were 51% and 79% for SR and OBR patients, respectively (P =.06). A proportional hazards model of time from first recurrence to distant metastasis was performed. Only those patients without simultaneous distant metastasis (or an opposite breast cancer) before first recurrence were included in the analysis. Table 2 lists that skin recurrence was significantly associated with a shorter time from first recurrence to distant failure (compared with other breast recurrence). Marked mitoses, grade III tumors, the presence of lymphatic vessel invasion, and lobular histology also were associated with a shorter time to distant failure; however, these factors pertain to any type of recurrence, not only skin recurrence. This also applies to the one factor associated with a longer time to distant failure, ie, a time interval from primary diagnosis to first failure of greater than 5 years. DISCUSSION Recurrence in the skin of the breast after BCT is rare. In this series of 1,624 patients, only 18 patients (1.1%) developed an SR compared with 188 patients (12%) who developed OBRs. Patients who developed an SR were more likely to have had larger primary tumors and were somewhat more likely to have had positive axillary lymph nodes at initial presentation than patients with other types of breast recurrence. Skin failures tended to occur early (median time, '^" I C, oe S S Fig 1. Freedom from distant metastasis after breast recurrence for all patients. P =0O1,(3) patients) evasive recurrence tients) 15

4 SKIN RECURRENCE AFTER BREAST CONSERVATION % (88) Fig 2. Survival after breast recurrence by recurrence type for all patients. a to e.001 patients) vasive ecurrence tients) months), and most patients presented with multiple nodules or inflammatory features (12 of 14 assessable patients). Uncontrolled local failure was common and, in approximately one half of patients, distant metastasis was diagnosed simultaneously or developed within a few months. The pattern, time course, and salvage of breast recurrence after BCT has been previously well-documented. 5-9 Breast recurrences usually are parenchymal and in the region of the primary site, at least in the first 6 to 7 years after therapy. 4-6 Most patients are free of distant metastasis at the time of recurrence, have operable disease, and long-term diseasefree survival of 30% to 50%.5,6,8,10 This series shows that the presentation and outcome for the subset of patients with recurrence in the skin of the breast after BCT are quite dissimilar from those of patients with other types of invasive breast recurrence. In fact, the pattern of recurrence is more.5 a E 2 1, E 0t Fig 3. Freedom from subsequent distant metastasis after breast recurrence by recurrence type for patients without simultaneous distant metastasis. o skin (10 patients) 0 other invasive breast recurrences (179 patients)

5 484 GAGE ET AL % (87) 60 ae 40 (19) Fig4. Survival after breast recurrence by recurrence type for patients without simultaneous distant metastasis. 20 o skin (10 patients) * other invasive breast recurrences (179 patients) 15 similar to local recurrences after mastectomy than it is to other types of breast recurrences after BCT. Similarities to postmastectomy recurrence include the frequent association with multiple positive lymph nodes, larger primary tumors, and the shorter time course to development of local recurrence.3, 1 1 Also, the high rate of distant metastatic disease that occurrs simultaneously (or within a few months) is more similar to recurrence patterns after mastectomy.11,1 2 Furthermore, local recurrence after mastectomy and SR both have an approximate 30% to 40% rate of 5-year survival ' Few other series have described this rare type of breast recurrence after BCT. At the Institut Curie (Paris, France), there were no recurrences with acute presentations, defined as clinical inflammatory signs, in 518 patients treated with Table 2. Proportional Hazards Model of Time From First Recurrence to Distant Metastasis Characteristic Hazard Ratio P Skin (v nonskin local) Marked mitoses 0.2 <.001 Nuclear grade Lymphatic vessel invasion (Histology missing) (2.1) (.33) Ductal histology (2.5) (.15) Lobular histology Time to breast failure >5 years NOTE. Parenthetically enclosed numbers indicate those with missing values. BCT. 15 The National Surgical Adjuvant Breast Project (NSABP B-06) reported recurrences limited to the skin or nipple in only six of 1,108 assessable patients (0.5%). In a series of 1,593 patients treated with BCT, Kurtz et a1 9 described 12 patients with inoperable breast recurrence, most of whom had extensive skin involvement. In the University of Pennsylvania (Philadelphia, PA) series of 1,030 patients treated with BCT, there were two patients with inflammatory recurrences, three patients with diffuse involvement, and two patients with skin nodules. 8 In a series of 1,026 patients treated at the Netherlands Cancer Institute (Amsterdam, the Netherlands), there were 45 breast recurrences; none were isolated SRs, although 16 recurrences were described as diffuse. 16 Because SRs occur at such low frequency, there is limited information regarding the initial pathologic and clinical presentation and the clinical outcome in these patients. Kurtz et a1 17 described 13 inoperable recurrences that occurred after BCT. Although these inoperable recurrences were not limited to SRs (some patients had regional nodal failures), eight patients had clinical signs consistent with inflammatory disease, and the skin or parenchyma of the breast was involved in 11 of 13 patients. Compared with patients who did not have such a failure, the inoperable recurrences were associated with the presence of unfavorable prognostic features, including positive lymph nodes, histologic grade 3, negative estrogen receptor, vascular

6 SKIN RECURRENCE AFTER BREAST CONSERVATION invasion, and lymphocytic stromal reaction.' 7 The importance of LVI also has been shown in the pathologic findings of the NSABP B-06. Fisher et a1' 8 described diffuse breast recurrences in three patients (7% of recurrences) as an occult inflammatory process with a pathologic association of intralymphatic extension of the primary tumor. In our experience, patients with SRs also were more likely to have LVI and positive lymph nodes at the time of their initial presentation than were patients with OBRs; however, these differences were not statistically significant, perhaps related to the small number of events. LVI also was associated with a shorter interval to the development of distant metastasis after breast recurrence in this study. The interval from initial treatment to recurrence for patients with SR is short, and these recurrences frequently are associated with distant metastasis. The median time to skin recurrence in this series was 38 months, and almost half of the patients presented with distant metastasis. An association between early breast recurrence after BCT and distant metastasis with lower survival rates has been described. 9,15,19-23 Some of these early breast failures may be SRs. For example, the series of Haffty et all 9 described some of these early events as diffuse recurrences (>3 cm and/or with dermal involvement) that were associated with a worse prognosis. Kurtz et a1 9 showed similar findings. The outcome of patients with SR after BCT is poor. The appearance of an early breast recurrence manifest as a SR seems to be associated with biologically aggressive disease. In this series, patients commonly presented with simultaneous distant metastasis, and even patients free of metastasis 485 at the time of SR had a poor overall survival rate (34% at 5 years). Stotter et a124 noted a similar rate of 5-year survival in patients with advanced recurrences, which included patients with SR (as well as nodal or chest-wall disease). 24 In a series from the Institut Gustave-Roussy (Villejvif, France), 11 patients with local-regional relapses with dermal involvement (and/or positive lymph nodes) had a disease-free survival of only 18% at 5 years. 7 SR after BCT is a very infrequent event. On the other hand, the initial pathologic features often seen with SR are fairly common; lymphatic vessel invasion, nodal positivity, and larger tumor sizes frequently are seen in patients who do not have SR. Therefore, it is not possible to predict accurately which patients are at risk for such a recurrence. However, once an SR is manifest, it does seem to predict a poor outcome. There is a high risk of developing distant metastastic disease and uncontrolled local disease. This would suggest that the clinical approach for patients with SR should be similar to that for patients with local recurrence after mastectomy and radiation therapy. Patients may be best treated with systemic therapy, perhaps including enrollment in high-dose protocols. The role of mastectomy in this setting is limited given the high frequency of presentation with distant metastasis, multiple nodules, or inflammatory features. Mastectomy might be considered in a patient without metastasis with very limited skin involvement (the two patients with local control after mastectomy in this series each had a single skin nodule) or more extensive involvement with a good response to initial systemic therapy. 1. Fisher B, Redmond C, and others for the NSABP: Lumpectomy for breast cancer: An update of the NSABP experience. 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