- Email: [email protected]
Risk Factors for Locoregional Failure in Patients With Inflammatory Breast Cancer Treated With Trimodality Therapy
Original Study
Risk Factors for Locoregional Failure in Patients With Inflammatory Breast Cancer Treated With Trimodality Therapy Kunal Saigal,1 Judith Hurley,2 Cristiane Takita,1 Isildinha M. Reis,3,4 Wei Zhao,4 Steven E. Rodgers,5 Jean L. Wright1 Abstract We describe the characteristics and locoregional outcomes of 463 patients with locally advanced breast cancer with inflammatory (14%, n = 66) and noninflammatory (86%, n = 397) presentations who completed trimodality therapy, including neoadjuvant therapy, mastectomy with axillary node dissection, and postmastectomy radiation. Patients with inflammatory disease exhibited a poorer axillary response to neoadjuvant therapy and were at elevated risk of regional recurrence, most commonly in the axilla. Future study should focus on optimizing regional nodal management in inflammatory breast cancer. Purpose: To compare patterns of local and regional failure between patients with inflammatory breast cancer (IBC) and non-IBC in patients treated with trimodality therapy. Materials and Methods: We reviewed records of 463 patients with stage II/III breast cancer, including IBC, who completed trimodality therapy from January 1999 to December 2009. Results: The median follow-up was 46.3 months (range, 4-152 months). Clinical stage was 29.4% (n = 136) II, 56.4% (n = 261) non-IBC III, 14.2% (n = 66) IBC, 30.5% (n = 141) cN0/Nx, and 69.5% (n = 322) N1-N3c. All the patients received neoadjuvant therapy and mastectomy (98%, n = 456 with axillary dissection), and all had postmastectomy radiation therapy to the chest wall with or without supraclavicular nodes (82.5%, n = 382) with or without axilla (6%, n = 28). The median chest wall dose was 60.4 Gy. Patients with IBC presented with larger tumors (P < .001) and exhibited a poorer response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 (P ¼ .003) and more had 4 positive nodes (P < .001). Four-year cumulative incidence of locoregional recurrence was 5.9%, with 25 locoregional events, 9 of which had a regional component. On multivariate analysis, triple-negative disease (hazard ratio [HR] 7.75, P < .0001) and residual pathologic nodes (HR 7.10, P < .001) were associated with an increased risk of locoregional recurrence, but IBC was not. However, on multivariate analysis, the 4-year cumulative incidence of regional recurrence specifically was significantly higher in IBC (HR 9.87, P ¼ .005). Conclusion: In this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after neoadjuvant therapy and were at greater risk of regional recurrence. Future study should focus on optimizing regional nodal management in IBC. Clinical Breast Cancer, Vol. 13, No. 5, 335-43 ª 2013 Elsevier Inc. All rights reserved. Keywords: Breast cancer, Inflammatory breast cancer, Locoregional recurrence, Neoadjuvant chemotherapy, Postmastectomy radiation
Introduction Inflammatory breast cancer (IBC) is a relatively uncommon clinical and pathologic entity that is distinct from other locally
advanced breast cancers, and presents unique therapeutic challenges. Historically, the diagnosis was considered uniformly fatal due to its propensity for rapid local progression and early distant
Presented as an oral presentation at the American Radium Society Annual Meeting, Palm Beach, FL, May 2011
Submitted: Nov 28, 2012; Revised: Apr 15, 2013; Accepted: Apr 16, 2013; Epub: Jul 10, 2013
1
Department of Radiation Oncology Division of Hematology and Oncology, Department of Medicine Division of Biostatistics, Department of Epidemiology and Public Health and Sylvester 4 Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center 5 Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 2 3
1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.04.002
Address for correspondence: Jean L. Wright, MD, Department of Radiation Oncology, University of Miami School of Medicine, 1475 NW 12 Avenue, Suite 1500, Miami, FL 33136 Fax: 305-243-4363; e-mail contact: [email protected]
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Locoregional Outcomes in Inflammatory Breast Cancer dissemination.1 The locally advanced presentation, along with the high propensity for early distant failure with initial local therapy, led to a change in the treatment paradigm toward initial systemic therapy. Trimodality therapy that consists of neoadjuvant chemotherapy (NAT), followed by definitive surgery, consolidated with postmastectomy radiation therapy (PMRT) has become the standard of care for patients with newly diagnosed nonmetastatic IBC.2 It is clear that completion of trimodality therapy is critical to locoregional control, but, even in the setting of trimodality therapy, locoregional failure remains more common among patients with IBC compared with other presentations.3 Optimizing locoregional outcome thus is paramount because these failures can ultimately lead to substantial morbidity, disease progression, and death.4-7 In the case of IBC, in which the risk of locoregional recurrence (LRR) is greater than other locally advanced breast cancers, the incremental gains of locoregional control are theoretically greater. Due to the rarity of IBC, there remains limited prospective data to determine optimal treatment algorithms, particularly in regard to PMRT; management, therefore, is based on single institution retrospective series that addressed specific treatment-related questions.3,8-10 The optimal delivery of PMRT in the post-NAT setting remains an area with limited definitive conclusions in both patients with IBC and those with non-IBC alike. Although it is clear that patients with locally advanced presentations benefit from PMRT4 and that consensus guidelines strongly recommend inclusion of the supraclavicular (SCV) nodes in PMRT fields, the selection criteria for patients to receive comprehensive nodal irradiation, including the full axilla (levels I/II/III) and/or the internal mammary chain, remains a controversial area in breast cancer radiation therapy.11 We previously reported locoregional outcomes in a large cohort of patients with breast cancer who completed trimodality therapy, including NAT, mastectomy, and PMRT.12 In this analysis, we compared patterns of locoregional failures between patients with IBC and with the non-IBC presentations. By identifying which patients are at greatest risk for local and regional failures, we aimed to determine which patients may benefit most from comprehensive irradiation of the full axilla as a component of PMRT.
Patients and Methods
336
-
This retrospective review was approved by the University of Miami Institutional Review Board. We reviewed the medical records of patients with breast cancer who completed trimodality therapy that consisted of NAT, followed by mastectomy and PMRT, between January 1999 and December 2009 at Jackson Memorial Hospital and at the University of Miami Sylvester Comprehensive Cancer Center. We identified 463 patients, 66 (14.2%) of whom presented with IBC, 261 (56.4%) with stage III non-IBC, and 136 (29.4%) with stage II non-IBC. We collected data on patient demographics, disease and treatment characteristics, and clinical outcome. Clinical staging at the time of diagnosis was determined by physical examination. The diagnosis of IBC was made in patients who presented with a rapid onset (typically, < 3 months) of breast edema, erythema, clinical evidence of dermal-lymphatic invasion (peau d’orange) with or without a palpable breast mass, accompanied by a pathologic diagnosis of breast cancer. Patients with
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neglected locally advanced breast tumors with the above findings were not considered to have IBC. Tumor size, if applicable, was determined by physical examination. Sentinel node biopsy was not performed before NAT. In general, a metastatic workup, including computed tomography of the chest, abdomen, and pelvis; bone scan; and appropriate laboratories was performed. For patients with clinically suspicious axillary nodes, fine needle aspiration was performed in selected cases, although this was not a standard procedure during the treatment period assessed; clinically suspicious nodes that were negative on fine needle aspiration were staged as cN0. After NAT, surgery most often consisted of a modified radical mastectomy with a level I/II axillary lymph node dissection with histologic assessment of the primary tumor, surgical margins, and axillary lymph nodes. Staging was performed per the American Joint Committee of Cancer TNM classification, 6th edition. All the patients underwent NAT, mastectomy, and PMRT. PMRT was delivered by using 2- or 3-dimensional techniques via megavoltage linear accelerators. The chest wall was treated by using standard opposed tangential fields with a tissue equivalent bolus (1 cm every other day) to ensure adequate coverage of the skin. A boost dose was delivered to the mastectomy scar in the majority (89%) of cases with a margin of 2-3 cm by using a clinical setup with an en-face electron beam of 6-9 MeV, depending on patient anatomy, prescribed to the 90% isodose line. The SCV field was treated by using a matched photon anterior or anterior-oblique field prescribed to a fixed depth, typically 3-5 cm. Most patients were treated with 2-dimensional techniques by using bony anatomy as landmarks. The lateral edge of the SCV field was typically placed at the coracoid process, and the match line between tangential chest wall fields and the SCV field was typically placed below the head of the clavicle. During the time of this study, it was not customary at our institution to specifically target the internal mammary lymph nodes with PMRT. When the axilla was specifically targeted, it was done by using deeper tangents to cover the level I/II axilla, with the lateral edge of the SCV field lateral to the humeral head, and a standard posterior axillary boost (PAB) field, which was opposed to the SCV field intended to cover the level III axilla, and prescribed with the corresponding daily dose necessary to deliver the full SCV field dose at mid-plane depth. All the fields were treated by using standard daily fractions of 1.8-2 Gy. Follow-up was determined from the date of diagnosis. The date of progression was selected as the date of the first event, including LRR, distant metastasis, or death. Local recurrence (LR) was defined as tumor recurrence in the chest wall. Regional recurrence (RR) was defined as recurrence in the axilla, internal mammary nodes, or SCV fossa. LR and RR were defined together as LRR. Progression-free survival (PFS) was defined as the elapsed time from the date of diagnosis to earliest occurrence of LRR, distant metastasis, or death from any cause. Patients alive without evidence of progression were censored at the date of last contact. Overall survival (OS) was defined as the time from diagnosis to death due to any cause, with surviving patients censored at the date of the last contact. PFS and OS were estimated by the Kaplan-Meier method. The rate of LRR with or without distant failure was estimated by the method of cumulative incidence using the “cuminc” procedure in the R statistical package “cmprsk,”13 with only death as a competing risk. The effect of potential prognostic factors was
Kunal Saigal et al examined by the Gray test, which compares cumulative incidence curves, or the test of Fine and Gray,14 based on the competing risk Cox proportional hazards regression method implemented in the “crr” procedure in the “cmprsk” package. Potential prognostic factors included in the analysis were age, race, ethnicity, menopausal status, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, clinical tumor stage, clinical nodal stage, pathologic complete response in the breast and/or axilla (defined as the absence of invasive disease), pathologic nodal stage, pathologic tumor size, surgical margin status, and IBC diagnosis. Statistical analyses were conducted by using SAS software version 9.3 (SAS Institute Inc, Cary, NC) and R software version 2.15.0.
Results Patient and Disease Characteristics of the Whole Cohort The median follow-up for the entire cohort of 464 patients who received NAT, mastectomy, and PMRT was 46.6 months (range, 3.7-152 months); 39.4 months (range, 10.9-136.7 months) for patients with IBC, 43.2 months (range, 7.7-131.7 months) for patients with non-IBC stage III disease, and 56.4 months (range, 3.7-152 months) for patients with stage II disease. Among the 355 patients alive without evidence of disease, the median follow-up was 50.5 months (range, 3.7-152 months). Among the 355 patients alive without evidence of disease, the median follow-up was 50.5 months. Patient demographics and tumor characteristics are presented in Table 1. The median age at diagnosis was 50 years, and 55% (n = 254) were pre- or perimenopausal; 25.5% (n = 118) of patients were black, 74.5% (n = 345) were white or other, and 58.5% were Hispanic. Clinical stage at presentation among the entire cohort was as follows: stage II non-IBC, 29.4% (n = 136); stage III non-IBC, 56.4% (n = 261); and IBC, 14.2% (n = 66). Nodal staging was as follows: 30.5% (n = 141) were cN0/Nx, 43.2% (n = 200) cN1, 22% (n = 102) N2, and 4.3% (n = 20) N3. Tumor histology was ductal in 82.1% (n = 380), lobular in 7.8% (n = 36), and other in 10.1% (n = 47). Receptor status was 53.8% (n = 249) ERþ, 39.5% (n = 179) PRþ, and 24.4% (n = 112) HER2þ. The triple-negative phenotype was seen in 32% (n = 148). The mean and median clinically measured tumor sizes at presentation were 7.3 and 6.0 cm, respectively.
Patients with IBC vs. Non-IBC Sixty-six (14.2%) of patients presented with IBC, 261 (56.4%) presented with stage III non-IBC, and 136 (29.4%) presented with stage II non-IBC. Patient characteristics of IBC vs. non-IBC patients are shown in Table 1. The patients with IBC were similar to the patients with non-IBC with respect to race; ethnicity; histology; ER, PR, and HER2 status; and receptor status combinations. There were no differences in treatment regimens, surgical margin status, axillary surgery performed, or total radiation dose delivered. However, patients with IBC were older (P ¼ .009), more often postmenopausal (P ¼ .004), and had larger tumors at presentation (P < .001) when compared with patients with non-IBC presentation.
Treatment Characteristics All the patients included in this analysis completed aggressive trimodality therapy. Forty-four percent (n = 205) of patients
received platinum, anthracycline, and taxane-based chemotherapy as their primary regimen; 20% (n = 91) received anthracycline and taxane-based chemotherapy; 20% (n = 93) received a platinum, taxane, and trastuzumab-containing regimen; and 16% (n = 74) received other regimens. Of note, 86% of patients with HER2þ tumors received a trastuzumab-containing regimen. There was no significant difference in chemotherapy regimens received by patients with IBC vs. non-IBC (P ¼ .213). After NAT, all the patients underwent mastectomy, and 98% underwent axillary lymph node dissection, which yielded a median of 17 lymph nodes. After surgery, all the patients received PMRT to the chest wall, usually followed by a boost to the mastectomy scar, a median chest wall dose of 60.4 Gy (range, 46.8-74.4 Gy). The SCV field was treated to a median dose of 45 Gy (range, 45-50.4 Gy) in 82.5% (n = 382) of the patients. Six percent (28) of the patients received a standard PAB field, a mean estimated total dose at mid plane of 45 Gy (range, 45-50.4 Gy). The response to treatment is summarized in Table 2. Patients with IBC were less likely to respond to NAT, particularly in the axilla, where 52% (n = 34) of patients with IBC remained with 4 or more positive axillary lymph nodes after NAT compared with 29% (n = 76) of patients with stage III non-IBC and 20% (n = 27) of those with stage II (P < .001). Correspondingly, patients with IBC were less likely to achieve a pathologic complete response in the axilla (P ¼ .003). There was no significant difference in the rate of pathologic complete response in the breast (P ¼ .295) or in the breast and axilla (P ¼ .593) among patients with IBC and non-IBC presentations.
Clinical Outcomes: Locoregional LRs were relatively uncommon. For the entire group, there were 25 locoregional events (Table 3). Twelve of these were isolated LRR, and 13 occurred synchronously (within 3 months), with distant failure; no LRR was detected after distant failure. The overall 4-year cumulative incidence of LRR was 5.8% (95% CI, 3.8%-8.4%). The cumulative incidence of LRR was significantly greater in patients with IBC (4-year rate: 12.1% IBC vs. 6.1% nonIBC stage III vs. 2.6% non-IBC stage II; P ¼ .033) (Table 4; Figure 1A). Other factors that led to statistically significant increased incidence of LRR among the whole cohort included ERe status (9.4% vs. 2.9%; P ¼ .006), PRe status (8.4% vs. 2.2%; P ¼ .014), triple-negative status (12.9% vs. 2.6%; P < .001), persistent positive nodal disease at the time of surgery (8.5% vs. 2.5%; P ¼ .003), and pathologic tumor size > 2 cm (8.7% vs. 3.9%; P ¼ .045). On multivariate analysis (Table 5), triple-negative status (HR [hazard ratio] 7.75; P < .0001) and residual pathologic disease in the lymph nodes (HR 7.10; P < .001) were associated with increased risk of LRR. On univariate analysis, the cumulative incidence of LRR was significantly greater in patients with IBC (P ¼ .003); however, in the multivariate model with adjustment for triple-negative status and N0 disease after NAT, IBC was no longer predictive of LRR (HR 1.34; P ¼ .540). Of the 25 LRR events, 16 were isolated LRs, 3 were LRs plus RRs, and 6 were only RRs (Table 3). These 25 LRR events included 6 patients without distant failure at the last evaluation (median follow-up from LRR of 6.4 months; range, 2.6-17.2 months), and 6 patients who developed distant failure after LRR (median time from
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Locoregional Outcomes in Inflammatory Breast Cancer Table 1 Demographics and Tumor Characteristics: Overall and by Stage Total
IBC
Non-IBC, CS III
Non-IBC, CS II
Pa
463 (100)
66 (14.2)
261 (56.4)
136 (29.4)
NA
Black
118 (25.5)
16 (24.2)
74 (28.4)
28 (20.6)
White þ other
345 (74.5)
50 (75.8)
187 (71.6)
108 (79.4)
Variable Total patients, no. (%) Race, no. (%)
.235
Ethnicity, no. (%) Hispanic
271 (58.5)
36 (54.5)
149 (57.1)
86 (63.2)
Non-Hispanic
192 (41.5)
30 (45.5)
112 (42.9)
50 (36.8)
.388
Age at diagnosis, no. (%) 50 years
239 (51.6)
26 (39.4)
129 (49.4)
84 (61.8)
> 50 years
224 (48.4)
40 (60.6)
132 (50.6)
52 (38.2)
50.5 9.9
53.4 9.7a
50.6 10.2
50.0 (25, 81)
52.5 (25.0, 75)
51.0 (27, 80)
48.0 (26, 81)
Pre-/perimenopausal
254 (54.9)
29 (43.9)
135 (51.7)
90 (66.2)
Postmenopausal
209 (45.1)
37 (56.1)
126 (48.3)
46 (33.8)
Ductal
380 (82.1)
61 (92.4)
212 (81.2)
107 (78.7)
Lobular
36 (7.8)
2 (3.0)
21 (8.0)
13 (9.6)
Metaplastic
13 (2.8)
2 (3.0)
7 (2.7)
4 (2.9)
Medullary
15 (3.2)
1 (1.5)
10 (3.8)
4 (2.9)
Other
19 (4.1)
e
11 (4.2)
8 (5.9)
Mean (SD) age, years Median (min, max) age, years
48.9 9.0a
.007 .009
Menopause status, no. (%) .004
Histology, no. (%) .380
cT stage, no. (%) Tx
1 (0.2)
e
1 (0.4)
e
T1
10 (2.2)
e
9 (3.4)
1 (0.7)
T2
73 (15.8)
e
21 (8.0)
52 (38.2)
T3
245 (52.9)
e
162 (62.1)
83 (61.0)
T4a-c
68 (14.7)
e
68 (26.1)
e
T4d (IBC)
66 (14.3)
66 (100)
e
e
7.3 4.1
10.5 5.5b
7.4 3.9b
5.7 2.6b
6.0 (0.5, 32.0)
10.0 (2.0, 26.0)
7 (0.5, 32.0)
5 (1.2, 17.0)
N0, Nx
141 (30.5)
14 (21.2)
21 (8.0)
106 (77.9)
N1
200 (43.2)
24 (36.4)
147 (56.3)
29 (21.3)
N2
102 (22.0)
22 (33.3)
79 (30.3)
1 (0.7)
NA
Tumor size, cm Mean (SD) Median (min, max)
< .001
Clinical N stage, no. (%)
N3 N1-N3
< .001
20 (4.3)
6 (9.1)
14 (5.4)
e
322 (69.5)
52 (78.8)
240 (92.0)
30 (22.1)
< .001 .120
ER, no. (%) Negative
214 (46.2)
34 (51.5)
127 (48.7)
53 (39.0)
Positive
249 (53.8)
32 (48.5)
134 (51.3)
83 (61.0)
PR, no. (%) Negative
274 (60.5)
43 (65.2)
159 (62.6)
72 (54.1)
Positive
179 (39.5)
23 (34.8)
95 (37.4)
61 (45.9)
Missing
10
e
7
3
Negative
347 (75.6)
52 (78.8)
186 (72.1)
109 (80.7)
Positive
112 (24.4)
14 (21.2)
72 (27.9)
26 (19.3)
Missing
4
e
3
1
.190
HER2, no. (%)
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.134
Kunal Saigal et al Table 1 Continued Variable
Total
IBC
Non-IBC, CS III
Non-IBC, CS II
Pa
Triple negative ER-PR-HER2-
148 (32.0)
26 (39.4)
83 (31.8)
39 (28.9)
Other combinations
314 (68.0)
40 (60.6)
178 (68.2)
96 (71.1)
1
e
e
1
Missing
.323
Abbreviations: CS ¼ clinical stage; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; IBC ¼ inflammatory breast cancer (clinical T4d); max ¼ maximum; min ¼ minimum; NA ¼ not applicable; PR ¼ progesterone receptor. a P value from the c2 test, the Fisher exact test, or analysis of variance. b Significant difference (P < .005) by Tukey pairwise mean comparison.
Table 2 Response to Neoadjuvant Chemotherapy Total, no. (%)
IBC, no. (%)
Non-IBC, CS III, no. (%)
Non-IBC, CS II, no. (%)
Pa
463 (100)
66 (14.2)
261 (56.4)
136 (29.4)
NA
Neoadjuvant
247 (53.3)
28 (42.4)
134 (51.3)
85 (62.5)
Neoadjuvant and adjuvant
216 (46.7)
38 (57.6)
127 (48.7)
51 (37.5)
Variable Total patients Chemotherapy sequence
.167
Chemotherapy regimen 205 (44.3)
38 (57.6)
104 (39.8)
63 (46.3)
Anthracycline/taxane-containing
Platinum/anthracycline/taxane-containing
91 (19.7)
10 (15.2)
52 (19.9)
29 (21.3)
Trastuzumab-containing
93 (20.1)
11 (16.7)
59 (22.6)
23 (16.9)
Other
74 (16.0)
7 (10.6)
46 (17.6)
21 (15.4)
.213
No. positive lymph nodes 0
204 (44.3)
18 (27.7)
114 (43.7)
72 (53.3)
1-3
120 (26.0)
13 (20.0)
71 (27.2)
36 (26.7)
4þ
137 (29.7)
34 (52.3)
76 (29.1)
27 (20.0)
2
1
e
1
pCR
128 (27.6)
13 (19.7)
76 (29.1)
39 (28.7)
No pCR
335 (72.4)
53 (80.3)
185 (70.9)
97 (71.3)
pCR
204 (44.1)
18 (27.3)
114 (43.7)
72 (52.9)
No pCR
259 (55.9)
48 (72.7)
147 (56.3)
64 (47.1)
90 (19.4)
10 (15.2)
54 (20.7)
26 (19.1)
373 (80.6)
56 (84.8)
207 (79.3)
110 (80.9)
Missing
< .001
pCR in breast .295
pCR in axilla .003
pCR in breast and axilla pCR No pCR
.593
Abbreviations: CS ¼ clinical stage; IBC ¼ inflammatory breast cancer; NA ¼ not available; pCR ¼ pathologic complete response. a P value from the c2 test.
LRR to distant 9 months; range, 3.4-18 months). The remaining 13 patients were considered to have simultaneous LRR and distant failure. We further analyzed locoregional outcome by analyzing local and regional outcomes separately. With respect to LR, the overall 4-year cumulative incidence was 3.7% (Table 4, Figure 1B). When LR was analyzed alone, IBC lost its statistical significance as a predictor of recurrence (1.8% IBC vs. 5.1% non-IBC stage III vs. 1.8% non-IBC stage II; P ¼ .103). Predictors of LR were triple-negative disease (7.5% vs. 1.9%; P ¼ .007) and persistent positive nodal disease at the time of surgery (5.5% vs. 1.3%; P ¼ .009), and these 2 factors retained significance on multivariate analysis. With respect to RR, the overall 4-year cumulative incidence was only 2.2% (Table 4). There were 9 RRs; 3 SCVs, 3 axillary, and 3 synchronous SCVs and/or axillary recurrences. No internal mammary
lymph node recurrences were identified. RRs occurred predominantly in women with IBC, with 1 of the 3 SCV failures and 5 of 6 axillary recurrences occurring in patients with IBC (Table 3). The 4-year cumulative incidence of RR in patients with IBC was significantly higher than in patients with non-IBC (10.3% IBC vs. 0.9% in nonIBC stage III vs. 0.8% non-IBC stage II; P < .0001) (Table 4, Figure 1C). Other factors predictive of RR included ERe status (3.7% vs. 0.9%; P ¼ .051), PRe status (3.6% vs. 0%; P ¼ .016), triple-negative status (5.3% vs. 0.7%; P ¼ .003), clinical node positivity (3.1% vs. 0%; P ¼ .043), and pathologic tumor size > 2 cm (4.6% vs. 0.5%; P ¼ .003) (Table 4). Despite the low incidence of RR overall, there was a clear association between inflammatory presentation and risk of RR that was maintained on multivariate analysis (HR 9.87; P ¼ .005). This also was true of triple-negative disease (HR 9.84; P ¼ .005) (Table 5). All axillary
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Locoregional Outcomes in Inflammatory Breast Cancer Table 3 Locoregional Recurrences: Overall and in Patients With IBC vs. Non-IBC
Recurrences
Events in 66 Patients with IBC
Events in 261 Patients with Non-IBC, CS III
16
1
13
2
3
2
1
e
Total Events
Events in 136 Patients with Non-IBC, CS II
Locoregional Local only Local þ regional Regional only
6
4
1
1
25
7
15
3
SCV
3
1
1
1
Axilla
3
2
1
e
SCV þ axilla
3
3
Total
9
6
Total Regional
e 2
1
Abbreviations: CS ¼ clinical stage; IBC ¼ inflammatory breast cancer; SCV ¼ supraclavicular field.
recurrences were in patients who had not received radiation therapy targeted to the axilla (PAB field).
Clinical Outcomes: Overall For the entire cohort, 4-year PFS was 76.5% (95% CI, 71.9%80.5%), and OS 86.3% (95% CI, 82.3%-89.5%). The 4-year PFS was 60.3% (95% CI, 46.3%-71.8%) in IBC, 74.1% (95% CI, 67.4%-79.7%) in non-IBC stage III, and 88% (95% CI, 80.5%92.7%) in stage II (P < .001). Four-year OS was 71.9% (95% CI, 57.4%-82.3%) in IBC, 85% (95% CI, 78.9%-89.5%) in non-IBC stage III, and 94.7% (95% CI, 88.5%-97.6%) in stage II (P ¼ .002). Among the 25 patients with LRR (with or without metastasis), the 4-year survival was only 17.8% (95% CI, 3.3%-41.7%) (Figure 1D).
Discussion This analysis represents a large retrospective series of patients with stage II/III and IBC who completed aggressive trimodality therapy that consists of NAT, mastectomy, and PMRT. Overall, patients with IBC were quite similar to those with non-IBC presentations in terms of demographics and receptor status. However, patients with IBC presented with larger primary tumors and more advanced nodal disease, and were accordingly less likely to exhibit a complete response to NAT, particularly in the axilla. Although locoregional failures occurred rarely for the entire cohort, patients with IBC remained at increased risk of LRR (P ¼ .033). IBC has been predictive of risk of LRR in multiple series, including a similar series to the current report by Cristofanilli et al.14 The fewer than expected failures is likely explained by the stringent inclusion criteria of only those patients who completed trimodality therapy in this analysis. This observation is supported by data from the MD Anderson Cancer Center that compared patients with IBC who received trimodality therapy with those who did not. Locoregional control was significantly greater in the group of patients who completed trimodality therapy (84% vs. 51%; P < .0001), and completing therapy was significantly related to improved survival at 5 years (51% vs. 24%; P < .0001).4 Recent publications from the Cleveland Clinic group as well as Memorial Sloan Kettering revealed 5-year locoregional control rates of 83%
340
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and 87%, respectively in patients completing trimodality therapy, similar to that observed in the current series.8,15 Despite the low rates of LRR and RR overall, patients with IBC presentations were at increased risk of RR. IBC was not a significant predictor of LR or LRR on multivariate analysis. However, when RR was analyzed individually, IBC had strong statistical significance as a predictor. Among patients with IBC and with RR, axillary recurrences were most common, despite the fact that complete axillary dissections that yielded a median of 17 nodes were performed in 98% of patients. This fact, along with the greater burden of residual positive disease in the axilla ( 4 positive nodes) observed in patients with IBC after NAT, suggests that these patients could potentially benefit from comprehensive nodal irradiation therapy to the full axilla, even after axillary dissection; this is an avenue for future study. It is important to acknowledge that it is unclear if radiation therapy to the axilla would have prevented the axillary recurrences observed in this cohort. Important advances have been made in radiation planning for complete coverage of axillary nodes, and it is now clear that the traditional approach to axillary coverage by using a traditional PAB field is not optimal in many cases.16 Thus, the technique used to treat the axilla in our series does not reflect the more modern approach to axillary treatment based on computed tomographyebased lymph node contouring, which can accurately assess the radiation dose to axillary nodal basins. In addition, although the most common lateral border of the SCV field was the coracoid process, in some cases, the lateral border was placed lateral to the humeral head, thus including large portions of the axilla in the field. The majority of patients included in this series were treated at a county hospital where 2-dimensional planning was most common for breast cancer treatment during the period reviewed; thus, it is a limitation of the study that we cannot accurately assess the axillary dose received. Our data highlight the value of achieving long-term logoregional control, which is demonstrated by the poor 5-year survival in patients who experienced an LRR (17.8%) compared with that in patients without a locoregional event (90%) (P < .0001). Although this survival difference may be explained by the aggressive biology of recurrent disease in this locally advanced population, it is clear that locoregional control relates to long-term survival,4 and efforts to improve axillary control may prove of
Kunal Saigal et al Table 4 The 48-Month Cumulative Incidence of LRR (With or Without DM), LR, and RR LRR (25 events) Prognostic Factor
Rate (95% CI)
LR (16 events) P
a
Rate (95% CI)
RR (with or without LR) (9 events) P
a
Rate (95% CI)
Pa
5.9 (3.8-8.4)
e
3.7 (2.1-5.9)
e
2.2 (1.1-3.9)
e
Non-IBC, CS II
2.6 (0.7-6.9)
.033
1.8 (0.3-5.8)
.103
0.8 (0.1-4.1)
< .0001
Non-IBC, CS III
6.1 (3.5-9.7)
5.1 (2.8-8.5)
0.9 (0.2-3.0)
12.1 (5.2-22.0)
1.8 (0.1-8.5)
10.3 (4.1-19.7)
All patients Presentation
IBC ER Positive
2.9 (1.2-5.8)
Negative
9.4 (5.8-14.1)
.006
2.0 (0.6-4.7)
.057
5.8 (3.0-9.7)
0.9 (0.2-3.0)
.051
3.7 (1.6-7.1)
PR Positive
2.2 (0.6-5.9)
Negative
8.4 (5.4-12.3)
.014
2.2 (0.6-5.9)
.237
4.8 (2.6-7.9)
0.0 (NE)
.016
3.6 (1.8-6.5)
HER2 Positive
2.0 (0.4-6.5)
Negative
7.1 (4.6-10.4)
.053
1.0 (0.1-4.7)
.090
4.6 (2.6-7.4)
1.1 (0.1-5.2)
.359
2.6 (1.2-4.8)
Triple negative No TN
2.6 (1.2-5.1)
TN
< .001
12.9 (7.8-19.3)
1.9 (0.7-4.2)
.007
7.5 (3.9-13.0)
0.7 (0.1-2.4)
.003
5.3 (2.3-10.1)
Clinical nodes N0, Nx
1.8 (0.3-5.7)
N1
6.7 (3.7-11.1)
3.9 (1.7-7.5)
2.8 (1.1-6.1)
N2-N3
9.2 (4.6-15.6)
5.5 (2.2-11.1)
3.6 (1.2-8.4)
N0, Nx
1.8 (0.3-5.7)
N1-3
7.7 (4.9-11.1)
.026
.010
1.8 (0.3-5.8)
1.8 (0.3-5.8)
.216
.099
4.5 (2.5-7.4)
0.0 (NE)
0.0 (NE)
.111
.043
3.1 (1.5-5.7)
Positive lymph nodes at surgery 0 (pN0)
2.5 (0.8-6.0)
1-3
6.3 (2.8-11.8)
.005
1.3 (0.3-4.4) 5.3 (2.2-10.6)
.032
1.0 (0.1-4.8)
1.2 (0.2-4.0)
4þ
10.4 (5.8-16.5)
5.7 (2.5-10.7)
4.7 (1.9-9.4)
.053
pCR in axilla Yes
2.5 (0.8-6.0)
No
8.5 (5.3-12.5)
.003
1.3 (0.3-4.4)
.010
5.5 (3.1-9.0)
1.2 (0.2-4.0)
.182
2.9 (1.3-5.7)
pCR in breast Yes
3.1 (0.8-8.1)
No
6.9 (4.4-10.1)
.078
3.1 (0.8-8.1)
.441
3.9 (2.1-6.6)
0.0 (NE)
.065
2.8 (1.5-5.4)
pCR in breast and axilla Yes
3.2 (0.6-10.1)
No
6.5 (4.2-9.4)
.155
3.3 (0.6-10.1)
.516
3.8 (2.1-6.2)
0.0 (NA)
.147
2.7 (1.3-4.8)
Clinical and pathologic node stage cNx/cN0 / pN0 þ
1.7 (0.1-8.0)
.001
1.7 (0.1-8.0)
.014
0.0 (NE)
cNx/cN0 / pN
1.8 (0.1-8.5)
1.8 (0.1-8.5)
0.0 (NE)
cNþ / pN0
3.0 (0.8-7.8)
1.0 (0.1-4.9)
2.0 (0.4-6.4)
cNþ / pNþ
10.7 (6.7-15.8)
6.8 (3.7-11.2)
3.9 (1.7-7.5)
.125
Pathologic tumor size 2 cm
3.9 (1.9-7.0)
> 2 cm
8.7 (5.1-13.5)
.046
3.4 (1.6-6.4) 4.1 (1.8-7.8)
.826
0.5 (0.1-2.5)
.003
4.6 (2.2-8.5)
Abbreviations: CS ¼ clinical stage; DM ¼ distant metastasis; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; IBC ¼ inflammatory breast cancer; LR ¼ local recurrence; LRR: locoregional recurrence; NA ¼ not available; NE ¼ not estimable; pCR ¼ pathologic complete response; PR ¼ progesterone receptor; RR ¼ regional recurrence; TN ¼ triple negative. a P value from univariate analysis by using the Gray test, with LRR, LR, RR, isolated DM, and death as competing risk for failure.
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Locoregional Outcomes in Inflammatory Breast Cancer Figure 1 Comparison of Cumulative Incidence of Locoregional Failure (A), Local Failure (B), and Regional Failure (C) Between Patients With Inflammatory and Those With Noninflammatory Breast Cancer. (D) Comparison of OS for Patients With and Those Without Locoregional Failure
Abbreviations: IBC ¼ inflammatory breast cancer; LR ¼ local failure; LRR ¼ locoregional failure; OS ¼ overall survival: RR¼ regional failure.
Table 5 Multivariate Analysis of Predictors of Local Regional Recurrence (n [ 462)a LRR (with or without DM) Variable, Multivariate Analysis Non-IBC CS III vs. non-IBC CS II IBC vs. non-IBC TN vs. not TN No pCR vs. pCR axilla
HR (95% CI) 2.17 1.34 7.75 7.10
(0.65-7.22) (0.54-3.33) (3.27-18.39) (2.47-20.44)
P .210 .540 < .0001 < .001
LR HR (95% CI) 2.72 0.19 6.52 10.11
(0.55-11.22) (0.03-1.38) (2.31-18.39) (2.19-46.58)
RR (with or without LR) P .170 .100 < .001 .003
HR (95% CI) 0.85 9.87 9.84 3.55
(0.08-8.81) (2.03-48.09) (2.02-47.92) (0.87-14.52)
P .890 .005 .005 .078
Abbreviations: CS ¼ clinical stage; DM ¼ distant metastasis; HR ¼ hazard ratio; IBC ¼ inflammatory breast cancer; LR ¼ local recurrence; LRR ¼ locoregional recurrence; pCR ¼ pathologic complete response; RR ¼ regional recurrence; TN ¼ triple negative. a The Fine and Gray Cox regression analysis, with LRR, LR, RR, isolated DM, and death as a competing risk for failure.
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benefit in this population. Nonetheless, the potential benefit of full axillary radiation must be weighed against its morbidity, primarily a higher risk of developing lymphedema. It is notable that, in our series, the rate of triple-negative and HER2þ tumors was similar between the IBC and non-IBC groups, whereas other series have documented markedly elevated rates of HER2þ and higher incidences of triple-negative phenotype in IBC tumors.17,18 In our series, only 20% of the IBC tumors were HER2þand 36% were triple negative. One possible explanation for this disparity may be the unique racial and ethnic makeup of our cohort, which is largely composed of Hispanic patients. Our study is limited by its retrospective nature and relatively small number of failure events. Although we can make inferences from the pattern of failures noted, it is difficult to draw firm conclusions on optimal PMRT delivery.
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Conclusion In this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after NAT and were at greater risk of axillary RR. We suggest that future studies should focus on optimal management of the axilla, including the potential for radiation to the full axilla in patients with IBC who exhibit a poor nodal response to NAT. Our results also demonstrate the importance of locoregional control as it relates to survival outcomes and highlight the significance of optimizing outcomes with local and regional adjuvant therapies.
Clinical Practice Points We described the characteristics and locoregional outcomes of
463 patients with locally advanced breast cancer with inflammatory (IBC) and noninflammatory presentations who
Kunal Saigal et al completed trimodality therapy, including neoadjuvant therapy, mastectomy with axillary node dissection, and postmastectomy radiation. Patients with IBC exhibited a poorer nodal response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 and more had 4 positive nodes (P < .001). On multivariate analysis, triple-negative disease and residual pathologic nodes after chemotherapy were associated with an increased risk of locoregional recurrence, but IBC was not. However the 4-year cumulative incidence of regional recurrence specifically was significantly higher in patients with IBC and triple negative disease. These findings may have implications for regional nodal management in patients with IBC and triple negative disease, and suggest that further study is indicated.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Bozzetti F, Saccozzi R, De Lena M, et al. Inflammatory cancer of the breast: analysis of 114 cases. J Surg Oncol 1981; 18:355-61. 2. Thomas WW Jr., McNeese MD, Fletcher GH, et al. Multimodal treatment for inflammatory breast cancer. Int J Radiat Oncol Biol Phys 1989; 17:739-45. 3. Bristol IJ, Woodward WA, Strom EA, et al. Locoregional treatment outcomes after multimodality management of inflammatory breast cancer. Int J Radiat Oncol Biol Phys 2008; 72:474-84. 4. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087-106. 5. Fleming RY, Asmar L, Buzdar AU, et al. Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma. Ann Surg Oncol 1997; 4:452-61.
6. Hasbini A, Le Pechoux C, Roche B, et al. Alternating chemotherapy and hyperfractionated accelerated radiotherapy in non-metastatic inflammatory breast cancer [in French with English abstract]. Cancer Radiother 2000; 4:265-73. 7. Thomas F, Arriagada R, Spielmann M, et al. Pattern of failure in patients with inflammatory breast cancer treated by alternating radiotherapy and chemotherapy. Cancer 1995; 76:2286-90. 8. Rehman S, Reddy CA, Tendulkar RD. Modern outcomes of inflammatory breast cancer. Int J Radiat Oncol Biol Phys 2012; 84:619-24. 9. Hance KW, Anderson WF, Devesa SS, et al. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst 2005; 97: 966-75. 10. Abramowitz MC, Li T, Morrow M, et al. Dermal lymphatic invasion and inflammatory breast cancer are independent predictors of outcome after postmastectomy radiation. Am J Clin Oncol 2009; 32:30-3. 11. Breast cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology—v.2.2013. National Comprehensive Cancer Network [Web site]. Available at: http://www.nccn.org/professionals/physician_gls/pdf/ breast.pdf. Access: April 12, 2013. 12. Wright JL, Takita C, Reis IM, et al. Predictors of locoregional outcome in patients receiving neoadjuvant therapy and post-mastectomy radiation. Cancer 2013; 119: 16-25. 13. The R Development Core Team. R: A Language and Environment for Statistical Computing. (http://www.R-project.org/) R Foundation for Statistical Computing. Version 2.8.0 (2008-10-20) ISBN 3-900051-07-0. 14. Cristofanilli M, Valero V, Buzdar AU, et al. Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the biology of a unique disease. Cancer 2007; 110:1436-44. 15. Damast S, Ho AY, Montgomery L, et al. Locoregional outcomes of inflammatory breast cancer patients treated with standard fractionation radiation and daily skin bolus in the taxane era. Int J Radiat Oncol Biol Phys 2010; 77:1105-12. 16. Wang X, Yu TK, Salehpour M, et al. Breast cancer regional radiation fields for supraclavicular and axillary lymph node treatment: is a posterior axillary boost field technique optimal? Int J Radiat Oncol Biol Phys 2009; 74:86-91. 17. Li J, Gonzalez-Angulo AM, Allen PK, et al. Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer. Oncologist 2011; 16:1675-83. 18. Zell JA, Tsang WY, Taylor TH, et al. Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry. Breast Cancer Res 2009; 11:R9.
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Risk Factors for Locoregional Failure in Patients With Inflammatory Breast Cancer Treated With Trimodality Therapy Kunal Saigal,1 Judith Hurley,2 Cristiane Takita,1 Isildinha M. Reis,3,4 Wei Zhao,4 Steven E. Rodgers,5 Jean L. Wright1 Abstract We describe the characteristics and locoregional outcomes of 463 patients with locally advanced breast cancer with inflammatory (14%, n = 66) and noninflammatory (86%, n = 397) presentations who completed trimodality therapy, including neoadjuvant therapy, mastectomy with axillary node dissection, and postmastectomy radiation. Patients with inflammatory disease exhibited a poorer axillary response to neoadjuvant therapy and were at elevated risk of regional recurrence, most commonly in the axilla. Future study should focus on optimizing regional nodal management in inflammatory breast cancer. Purpose: To compare patterns of local and regional failure between patients with inflammatory breast cancer (IBC) and non-IBC in patients treated with trimodality therapy. Materials and Methods: We reviewed records of 463 patients with stage II/III breast cancer, including IBC, who completed trimodality therapy from January 1999 to December 2009. Results: The median follow-up was 46.3 months (range, 4-152 months). Clinical stage was 29.4% (n = 136) II, 56.4% (n = 261) non-IBC III, 14.2% (n = 66) IBC, 30.5% (n = 141) cN0/Nx, and 69.5% (n = 322) N1-N3c. All the patients received neoadjuvant therapy and mastectomy (98%, n = 456 with axillary dissection), and all had postmastectomy radiation therapy to the chest wall with or without supraclavicular nodes (82.5%, n = 382) with or without axilla (6%, n = 28). The median chest wall dose was 60.4 Gy. Patients with IBC presented with larger tumors (P < .001) and exhibited a poorer response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 (P ¼ .003) and more had 4 positive nodes (P < .001). Four-year cumulative incidence of locoregional recurrence was 5.9%, with 25 locoregional events, 9 of which had a regional component. On multivariate analysis, triple-negative disease (hazard ratio [HR] 7.75, P < .0001) and residual pathologic nodes (HR 7.10, P < .001) were associated with an increased risk of locoregional recurrence, but IBC was not. However, on multivariate analysis, the 4-year cumulative incidence of regional recurrence specifically was significantly higher in IBC (HR 9.87, P ¼ .005). Conclusion: In this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after neoadjuvant therapy and were at greater risk of regional recurrence. Future study should focus on optimizing regional nodal management in IBC. Clinical Breast Cancer, Vol. 13, No. 5, 335-43 ª 2013 Elsevier Inc. All rights reserved. Keywords: Breast cancer, Inflammatory breast cancer, Locoregional recurrence, Neoadjuvant chemotherapy, Postmastectomy radiation
Introduction Inflammatory breast cancer (IBC) is a relatively uncommon clinical and pathologic entity that is distinct from other locally
advanced breast cancers, and presents unique therapeutic challenges. Historically, the diagnosis was considered uniformly fatal due to its propensity for rapid local progression and early distant
Presented as an oral presentation at the American Radium Society Annual Meeting, Palm Beach, FL, May 2011
Submitted: Nov 28, 2012; Revised: Apr 15, 2013; Accepted: Apr 16, 2013; Epub: Jul 10, 2013
1
Department of Radiation Oncology Division of Hematology and Oncology, Department of Medicine Division of Biostatistics, Department of Epidemiology and Public Health and Sylvester 4 Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center 5 Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 2 3
1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.04.002
Address for correspondence: Jean L. Wright, MD, Department of Radiation Oncology, University of Miami School of Medicine, 1475 NW 12 Avenue, Suite 1500, Miami, FL 33136 Fax: 305-243-4363; e-mail contact: [email protected]
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Locoregional Outcomes in Inflammatory Breast Cancer dissemination.1 The locally advanced presentation, along with the high propensity for early distant failure with initial local therapy, led to a change in the treatment paradigm toward initial systemic therapy. Trimodality therapy that consists of neoadjuvant chemotherapy (NAT), followed by definitive surgery, consolidated with postmastectomy radiation therapy (PMRT) has become the standard of care for patients with newly diagnosed nonmetastatic IBC.2 It is clear that completion of trimodality therapy is critical to locoregional control, but, even in the setting of trimodality therapy, locoregional failure remains more common among patients with IBC compared with other presentations.3 Optimizing locoregional outcome thus is paramount because these failures can ultimately lead to substantial morbidity, disease progression, and death.4-7 In the case of IBC, in which the risk of locoregional recurrence (LRR) is greater than other locally advanced breast cancers, the incremental gains of locoregional control are theoretically greater. Due to the rarity of IBC, there remains limited prospective data to determine optimal treatment algorithms, particularly in regard to PMRT; management, therefore, is based on single institution retrospective series that addressed specific treatment-related questions.3,8-10 The optimal delivery of PMRT in the post-NAT setting remains an area with limited definitive conclusions in both patients with IBC and those with non-IBC alike. Although it is clear that patients with locally advanced presentations benefit from PMRT4 and that consensus guidelines strongly recommend inclusion of the supraclavicular (SCV) nodes in PMRT fields, the selection criteria for patients to receive comprehensive nodal irradiation, including the full axilla (levels I/II/III) and/or the internal mammary chain, remains a controversial area in breast cancer radiation therapy.11 We previously reported locoregional outcomes in a large cohort of patients with breast cancer who completed trimodality therapy, including NAT, mastectomy, and PMRT.12 In this analysis, we compared patterns of locoregional failures between patients with IBC and with the non-IBC presentations. By identifying which patients are at greatest risk for local and regional failures, we aimed to determine which patients may benefit most from comprehensive irradiation of the full axilla as a component of PMRT.
Patients and Methods
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This retrospective review was approved by the University of Miami Institutional Review Board. We reviewed the medical records of patients with breast cancer who completed trimodality therapy that consisted of NAT, followed by mastectomy and PMRT, between January 1999 and December 2009 at Jackson Memorial Hospital and at the University of Miami Sylvester Comprehensive Cancer Center. We identified 463 patients, 66 (14.2%) of whom presented with IBC, 261 (56.4%) with stage III non-IBC, and 136 (29.4%) with stage II non-IBC. We collected data on patient demographics, disease and treatment characteristics, and clinical outcome. Clinical staging at the time of diagnosis was determined by physical examination. The diagnosis of IBC was made in patients who presented with a rapid onset (typically, < 3 months) of breast edema, erythema, clinical evidence of dermal-lymphatic invasion (peau d’orange) with or without a palpable breast mass, accompanied by a pathologic diagnosis of breast cancer. Patients with
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neglected locally advanced breast tumors with the above findings were not considered to have IBC. Tumor size, if applicable, was determined by physical examination. Sentinel node biopsy was not performed before NAT. In general, a metastatic workup, including computed tomography of the chest, abdomen, and pelvis; bone scan; and appropriate laboratories was performed. For patients with clinically suspicious axillary nodes, fine needle aspiration was performed in selected cases, although this was not a standard procedure during the treatment period assessed; clinically suspicious nodes that were negative on fine needle aspiration were staged as cN0. After NAT, surgery most often consisted of a modified radical mastectomy with a level I/II axillary lymph node dissection with histologic assessment of the primary tumor, surgical margins, and axillary lymph nodes. Staging was performed per the American Joint Committee of Cancer TNM classification, 6th edition. All the patients underwent NAT, mastectomy, and PMRT. PMRT was delivered by using 2- or 3-dimensional techniques via megavoltage linear accelerators. The chest wall was treated by using standard opposed tangential fields with a tissue equivalent bolus (1 cm every other day) to ensure adequate coverage of the skin. A boost dose was delivered to the mastectomy scar in the majority (89%) of cases with a margin of 2-3 cm by using a clinical setup with an en-face electron beam of 6-9 MeV, depending on patient anatomy, prescribed to the 90% isodose line. The SCV field was treated by using a matched photon anterior or anterior-oblique field prescribed to a fixed depth, typically 3-5 cm. Most patients were treated with 2-dimensional techniques by using bony anatomy as landmarks. The lateral edge of the SCV field was typically placed at the coracoid process, and the match line between tangential chest wall fields and the SCV field was typically placed below the head of the clavicle. During the time of this study, it was not customary at our institution to specifically target the internal mammary lymph nodes with PMRT. When the axilla was specifically targeted, it was done by using deeper tangents to cover the level I/II axilla, with the lateral edge of the SCV field lateral to the humeral head, and a standard posterior axillary boost (PAB) field, which was opposed to the SCV field intended to cover the level III axilla, and prescribed with the corresponding daily dose necessary to deliver the full SCV field dose at mid-plane depth. All the fields were treated by using standard daily fractions of 1.8-2 Gy. Follow-up was determined from the date of diagnosis. The date of progression was selected as the date of the first event, including LRR, distant metastasis, or death. Local recurrence (LR) was defined as tumor recurrence in the chest wall. Regional recurrence (RR) was defined as recurrence in the axilla, internal mammary nodes, or SCV fossa. LR and RR were defined together as LRR. Progression-free survival (PFS) was defined as the elapsed time from the date of diagnosis to earliest occurrence of LRR, distant metastasis, or death from any cause. Patients alive without evidence of progression were censored at the date of last contact. Overall survival (OS) was defined as the time from diagnosis to death due to any cause, with surviving patients censored at the date of the last contact. PFS and OS were estimated by the Kaplan-Meier method. The rate of LRR with or without distant failure was estimated by the method of cumulative incidence using the “cuminc” procedure in the R statistical package “cmprsk,”13 with only death as a competing risk. The effect of potential prognostic factors was
Kunal Saigal et al examined by the Gray test, which compares cumulative incidence curves, or the test of Fine and Gray,14 based on the competing risk Cox proportional hazards regression method implemented in the “crr” procedure in the “cmprsk” package. Potential prognostic factors included in the analysis were age, race, ethnicity, menopausal status, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, clinical tumor stage, clinical nodal stage, pathologic complete response in the breast and/or axilla (defined as the absence of invasive disease), pathologic nodal stage, pathologic tumor size, surgical margin status, and IBC diagnosis. Statistical analyses were conducted by using SAS software version 9.3 (SAS Institute Inc, Cary, NC) and R software version 2.15.0.
Results Patient and Disease Characteristics of the Whole Cohort The median follow-up for the entire cohort of 464 patients who received NAT, mastectomy, and PMRT was 46.6 months (range, 3.7-152 months); 39.4 months (range, 10.9-136.7 months) for patients with IBC, 43.2 months (range, 7.7-131.7 months) for patients with non-IBC stage III disease, and 56.4 months (range, 3.7-152 months) for patients with stage II disease. Among the 355 patients alive without evidence of disease, the median follow-up was 50.5 months (range, 3.7-152 months). Among the 355 patients alive without evidence of disease, the median follow-up was 50.5 months. Patient demographics and tumor characteristics are presented in Table 1. The median age at diagnosis was 50 years, and 55% (n = 254) were pre- or perimenopausal; 25.5% (n = 118) of patients were black, 74.5% (n = 345) were white or other, and 58.5% were Hispanic. Clinical stage at presentation among the entire cohort was as follows: stage II non-IBC, 29.4% (n = 136); stage III non-IBC, 56.4% (n = 261); and IBC, 14.2% (n = 66). Nodal staging was as follows: 30.5% (n = 141) were cN0/Nx, 43.2% (n = 200) cN1, 22% (n = 102) N2, and 4.3% (n = 20) N3. Tumor histology was ductal in 82.1% (n = 380), lobular in 7.8% (n = 36), and other in 10.1% (n = 47). Receptor status was 53.8% (n = 249) ERþ, 39.5% (n = 179) PRþ, and 24.4% (n = 112) HER2þ. The triple-negative phenotype was seen in 32% (n = 148). The mean and median clinically measured tumor sizes at presentation were 7.3 and 6.0 cm, respectively.
Patients with IBC vs. Non-IBC Sixty-six (14.2%) of patients presented with IBC, 261 (56.4%) presented with stage III non-IBC, and 136 (29.4%) presented with stage II non-IBC. Patient characteristics of IBC vs. non-IBC patients are shown in Table 1. The patients with IBC were similar to the patients with non-IBC with respect to race; ethnicity; histology; ER, PR, and HER2 status; and receptor status combinations. There were no differences in treatment regimens, surgical margin status, axillary surgery performed, or total radiation dose delivered. However, patients with IBC were older (P ¼ .009), more often postmenopausal (P ¼ .004), and had larger tumors at presentation (P < .001) when compared with patients with non-IBC presentation.
Treatment Characteristics All the patients included in this analysis completed aggressive trimodality therapy. Forty-four percent (n = 205) of patients
received platinum, anthracycline, and taxane-based chemotherapy as their primary regimen; 20% (n = 91) received anthracycline and taxane-based chemotherapy; 20% (n = 93) received a platinum, taxane, and trastuzumab-containing regimen; and 16% (n = 74) received other regimens. Of note, 86% of patients with HER2þ tumors received a trastuzumab-containing regimen. There was no significant difference in chemotherapy regimens received by patients with IBC vs. non-IBC (P ¼ .213). After NAT, all the patients underwent mastectomy, and 98% underwent axillary lymph node dissection, which yielded a median of 17 lymph nodes. After surgery, all the patients received PMRT to the chest wall, usually followed by a boost to the mastectomy scar, a median chest wall dose of 60.4 Gy (range, 46.8-74.4 Gy). The SCV field was treated to a median dose of 45 Gy (range, 45-50.4 Gy) in 82.5% (n = 382) of the patients. Six percent (28) of the patients received a standard PAB field, a mean estimated total dose at mid plane of 45 Gy (range, 45-50.4 Gy). The response to treatment is summarized in Table 2. Patients with IBC were less likely to respond to NAT, particularly in the axilla, where 52% (n = 34) of patients with IBC remained with 4 or more positive axillary lymph nodes after NAT compared with 29% (n = 76) of patients with stage III non-IBC and 20% (n = 27) of those with stage II (P < .001). Correspondingly, patients with IBC were less likely to achieve a pathologic complete response in the axilla (P ¼ .003). There was no significant difference in the rate of pathologic complete response in the breast (P ¼ .295) or in the breast and axilla (P ¼ .593) among patients with IBC and non-IBC presentations.
Clinical Outcomes: Locoregional LRs were relatively uncommon. For the entire group, there were 25 locoregional events (Table 3). Twelve of these were isolated LRR, and 13 occurred synchronously (within 3 months), with distant failure; no LRR was detected after distant failure. The overall 4-year cumulative incidence of LRR was 5.8% (95% CI, 3.8%-8.4%). The cumulative incidence of LRR was significantly greater in patients with IBC (4-year rate: 12.1% IBC vs. 6.1% nonIBC stage III vs. 2.6% non-IBC stage II; P ¼ .033) (Table 4; Figure 1A). Other factors that led to statistically significant increased incidence of LRR among the whole cohort included ERe status (9.4% vs. 2.9%; P ¼ .006), PRe status (8.4% vs. 2.2%; P ¼ .014), triple-negative status (12.9% vs. 2.6%; P < .001), persistent positive nodal disease at the time of surgery (8.5% vs. 2.5%; P ¼ .003), and pathologic tumor size > 2 cm (8.7% vs. 3.9%; P ¼ .045). On multivariate analysis (Table 5), triple-negative status (HR [hazard ratio] 7.75; P < .0001) and residual pathologic disease in the lymph nodes (HR 7.10; P < .001) were associated with increased risk of LRR. On univariate analysis, the cumulative incidence of LRR was significantly greater in patients with IBC (P ¼ .003); however, in the multivariate model with adjustment for triple-negative status and N0 disease after NAT, IBC was no longer predictive of LRR (HR 1.34; P ¼ .540). Of the 25 LRR events, 16 were isolated LRs, 3 were LRs plus RRs, and 6 were only RRs (Table 3). These 25 LRR events included 6 patients without distant failure at the last evaluation (median follow-up from LRR of 6.4 months; range, 2.6-17.2 months), and 6 patients who developed distant failure after LRR (median time from
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Locoregional Outcomes in Inflammatory Breast Cancer Table 1 Demographics and Tumor Characteristics: Overall and by Stage Total
IBC
Non-IBC, CS III
Non-IBC, CS II
Pa
463 (100)
66 (14.2)
261 (56.4)
136 (29.4)
NA
Black
118 (25.5)
16 (24.2)
74 (28.4)
28 (20.6)
White þ other
345 (74.5)
50 (75.8)
187 (71.6)
108 (79.4)
Variable Total patients, no. (%) Race, no. (%)
.235
Ethnicity, no. (%) Hispanic
271 (58.5)
36 (54.5)
149 (57.1)
86 (63.2)
Non-Hispanic
192 (41.5)
30 (45.5)
112 (42.9)
50 (36.8)
.388
Age at diagnosis, no. (%) 50 years
239 (51.6)
26 (39.4)
129 (49.4)
84 (61.8)
> 50 years
224 (48.4)
40 (60.6)
132 (50.6)
52 (38.2)
50.5 9.9
53.4 9.7a
50.6 10.2
50.0 (25, 81)
52.5 (25.0, 75)
51.0 (27, 80)
48.0 (26, 81)
Pre-/perimenopausal
254 (54.9)
29 (43.9)
135 (51.7)
90 (66.2)
Postmenopausal
209 (45.1)
37 (56.1)
126 (48.3)
46 (33.8)
Ductal
380 (82.1)
61 (92.4)
212 (81.2)
107 (78.7)
Lobular
36 (7.8)
2 (3.0)
21 (8.0)
13 (9.6)
Metaplastic
13 (2.8)
2 (3.0)
7 (2.7)
4 (2.9)
Medullary
15 (3.2)
1 (1.5)
10 (3.8)
4 (2.9)
Other
19 (4.1)
e
11 (4.2)
8 (5.9)
Mean (SD) age, years Median (min, max) age, years
48.9 9.0a
.007 .009
Menopause status, no. (%) .004
Histology, no. (%) .380
cT stage, no. (%) Tx
1 (0.2)
e
1 (0.4)
e
T1
10 (2.2)
e
9 (3.4)
1 (0.7)
T2
73 (15.8)
e
21 (8.0)
52 (38.2)
T3
245 (52.9)
e
162 (62.1)
83 (61.0)
T4a-c
68 (14.7)
e
68 (26.1)
e
T4d (IBC)
66 (14.3)
66 (100)
e
e
7.3 4.1
10.5 5.5b
7.4 3.9b
5.7 2.6b
6.0 (0.5, 32.0)
10.0 (2.0, 26.0)
7 (0.5, 32.0)
5 (1.2, 17.0)
N0, Nx
141 (30.5)
14 (21.2)
21 (8.0)
106 (77.9)
N1
200 (43.2)
24 (36.4)
147 (56.3)
29 (21.3)
N2
102 (22.0)
22 (33.3)
79 (30.3)
1 (0.7)
NA
Tumor size, cm Mean (SD) Median (min, max)
< .001
Clinical N stage, no. (%)
N3 N1-N3
< .001
20 (4.3)
6 (9.1)
14 (5.4)
e
322 (69.5)
52 (78.8)
240 (92.0)
30 (22.1)
< .001 .120
ER, no. (%) Negative
214 (46.2)
34 (51.5)
127 (48.7)
53 (39.0)
Positive
249 (53.8)
32 (48.5)
134 (51.3)
83 (61.0)
PR, no. (%) Negative
274 (60.5)
43 (65.2)
159 (62.6)
72 (54.1)
Positive
179 (39.5)
23 (34.8)
95 (37.4)
61 (45.9)
Missing
10
e
7
3
Negative
347 (75.6)
52 (78.8)
186 (72.1)
109 (80.7)
Positive
112 (24.4)
14 (21.2)
72 (27.9)
26 (19.3)
Missing
4
e
3
1
.190
HER2, no. (%)
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Clinical Breast Cancer October 2013
.134
Kunal Saigal et al Table 1 Continued Variable
Total
IBC
Non-IBC, CS III
Non-IBC, CS II
Pa
Triple negative ER-PR-HER2-
148 (32.0)
26 (39.4)
83 (31.8)
39 (28.9)
Other combinations
314 (68.0)
40 (60.6)
178 (68.2)
96 (71.1)
1
e
e
1
Missing
.323
Abbreviations: CS ¼ clinical stage; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; IBC ¼ inflammatory breast cancer (clinical T4d); max ¼ maximum; min ¼ minimum; NA ¼ not applicable; PR ¼ progesterone receptor. a P value from the c2 test, the Fisher exact test, or analysis of variance. b Significant difference (P < .005) by Tukey pairwise mean comparison.
Table 2 Response to Neoadjuvant Chemotherapy Total, no. (%)
IBC, no. (%)
Non-IBC, CS III, no. (%)
Non-IBC, CS II, no. (%)
Pa
463 (100)
66 (14.2)
261 (56.4)
136 (29.4)
NA
Neoadjuvant
247 (53.3)
28 (42.4)
134 (51.3)
85 (62.5)
Neoadjuvant and adjuvant
216 (46.7)
38 (57.6)
127 (48.7)
51 (37.5)
Variable Total patients Chemotherapy sequence
.167
Chemotherapy regimen 205 (44.3)
38 (57.6)
104 (39.8)
63 (46.3)
Anthracycline/taxane-containing
Platinum/anthracycline/taxane-containing
91 (19.7)
10 (15.2)
52 (19.9)
29 (21.3)
Trastuzumab-containing
93 (20.1)
11 (16.7)
59 (22.6)
23 (16.9)
Other
74 (16.0)
7 (10.6)
46 (17.6)
21 (15.4)
.213
No. positive lymph nodes 0
204 (44.3)
18 (27.7)
114 (43.7)
72 (53.3)
1-3
120 (26.0)
13 (20.0)
71 (27.2)
36 (26.7)
4þ
137 (29.7)
34 (52.3)
76 (29.1)
27 (20.0)
2
1
e
1
pCR
128 (27.6)
13 (19.7)
76 (29.1)
39 (28.7)
No pCR
335 (72.4)
53 (80.3)
185 (70.9)
97 (71.3)
pCR
204 (44.1)
18 (27.3)
114 (43.7)
72 (52.9)
No pCR
259 (55.9)
48 (72.7)
147 (56.3)
64 (47.1)
90 (19.4)
10 (15.2)
54 (20.7)
26 (19.1)
373 (80.6)
56 (84.8)
207 (79.3)
110 (80.9)
Missing
< .001
pCR in breast .295
pCR in axilla .003
pCR in breast and axilla pCR No pCR
.593
Abbreviations: CS ¼ clinical stage; IBC ¼ inflammatory breast cancer; NA ¼ not available; pCR ¼ pathologic complete response. a P value from the c2 test.
LRR to distant 9 months; range, 3.4-18 months). The remaining 13 patients were considered to have simultaneous LRR and distant failure. We further analyzed locoregional outcome by analyzing local and regional outcomes separately. With respect to LR, the overall 4-year cumulative incidence was 3.7% (Table 4, Figure 1B). When LR was analyzed alone, IBC lost its statistical significance as a predictor of recurrence (1.8% IBC vs. 5.1% non-IBC stage III vs. 1.8% non-IBC stage II; P ¼ .103). Predictors of LR were triple-negative disease (7.5% vs. 1.9%; P ¼ .007) and persistent positive nodal disease at the time of surgery (5.5% vs. 1.3%; P ¼ .009), and these 2 factors retained significance on multivariate analysis. With respect to RR, the overall 4-year cumulative incidence was only 2.2% (Table 4). There were 9 RRs; 3 SCVs, 3 axillary, and 3 synchronous SCVs and/or axillary recurrences. No internal mammary
lymph node recurrences were identified. RRs occurred predominantly in women with IBC, with 1 of the 3 SCV failures and 5 of 6 axillary recurrences occurring in patients with IBC (Table 3). The 4-year cumulative incidence of RR in patients with IBC was significantly higher than in patients with non-IBC (10.3% IBC vs. 0.9% in nonIBC stage III vs. 0.8% non-IBC stage II; P < .0001) (Table 4, Figure 1C). Other factors predictive of RR included ERe status (3.7% vs. 0.9%; P ¼ .051), PRe status (3.6% vs. 0%; P ¼ .016), triple-negative status (5.3% vs. 0.7%; P ¼ .003), clinical node positivity (3.1% vs. 0%; P ¼ .043), and pathologic tumor size > 2 cm (4.6% vs. 0.5%; P ¼ .003) (Table 4). Despite the low incidence of RR overall, there was a clear association between inflammatory presentation and risk of RR that was maintained on multivariate analysis (HR 9.87; P ¼ .005). This also was true of triple-negative disease (HR 9.84; P ¼ .005) (Table 5). All axillary
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Locoregional Outcomes in Inflammatory Breast Cancer Table 3 Locoregional Recurrences: Overall and in Patients With IBC vs. Non-IBC
Recurrences
Events in 66 Patients with IBC
Events in 261 Patients with Non-IBC, CS III
16
1
13
2
3
2
1
e
Total Events
Events in 136 Patients with Non-IBC, CS II
Locoregional Local only Local þ regional Regional only
6
4
1
1
25
7
15
3
SCV
3
1
1
1
Axilla
3
2
1
e
SCV þ axilla
3
3
Total
9
6
Total Regional
e 2
1
Abbreviations: CS ¼ clinical stage; IBC ¼ inflammatory breast cancer; SCV ¼ supraclavicular field.
recurrences were in patients who had not received radiation therapy targeted to the axilla (PAB field).
Clinical Outcomes: Overall For the entire cohort, 4-year PFS was 76.5% (95% CI, 71.9%80.5%), and OS 86.3% (95% CI, 82.3%-89.5%). The 4-year PFS was 60.3% (95% CI, 46.3%-71.8%) in IBC, 74.1% (95% CI, 67.4%-79.7%) in non-IBC stage III, and 88% (95% CI, 80.5%92.7%) in stage II (P < .001). Four-year OS was 71.9% (95% CI, 57.4%-82.3%) in IBC, 85% (95% CI, 78.9%-89.5%) in non-IBC stage III, and 94.7% (95% CI, 88.5%-97.6%) in stage II (P ¼ .002). Among the 25 patients with LRR (with or without metastasis), the 4-year survival was only 17.8% (95% CI, 3.3%-41.7%) (Figure 1D).
Discussion This analysis represents a large retrospective series of patients with stage II/III and IBC who completed aggressive trimodality therapy that consists of NAT, mastectomy, and PMRT. Overall, patients with IBC were quite similar to those with non-IBC presentations in terms of demographics and receptor status. However, patients with IBC presented with larger primary tumors and more advanced nodal disease, and were accordingly less likely to exhibit a complete response to NAT, particularly in the axilla. Although locoregional failures occurred rarely for the entire cohort, patients with IBC remained at increased risk of LRR (P ¼ .033). IBC has been predictive of risk of LRR in multiple series, including a similar series to the current report by Cristofanilli et al.14 The fewer than expected failures is likely explained by the stringent inclusion criteria of only those patients who completed trimodality therapy in this analysis. This observation is supported by data from the MD Anderson Cancer Center that compared patients with IBC who received trimodality therapy with those who did not. Locoregional control was significantly greater in the group of patients who completed trimodality therapy (84% vs. 51%; P < .0001), and completing therapy was significantly related to improved survival at 5 years (51% vs. 24%; P < .0001).4 Recent publications from the Cleveland Clinic group as well as Memorial Sloan Kettering revealed 5-year locoregional control rates of 83%
340
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Clinical Breast Cancer October 2013
and 87%, respectively in patients completing trimodality therapy, similar to that observed in the current series.8,15 Despite the low rates of LRR and RR overall, patients with IBC presentations were at increased risk of RR. IBC was not a significant predictor of LR or LRR on multivariate analysis. However, when RR was analyzed individually, IBC had strong statistical significance as a predictor. Among patients with IBC and with RR, axillary recurrences were most common, despite the fact that complete axillary dissections that yielded a median of 17 nodes were performed in 98% of patients. This fact, along with the greater burden of residual positive disease in the axilla ( 4 positive nodes) observed in patients with IBC after NAT, suggests that these patients could potentially benefit from comprehensive nodal irradiation therapy to the full axilla, even after axillary dissection; this is an avenue for future study. It is important to acknowledge that it is unclear if radiation therapy to the axilla would have prevented the axillary recurrences observed in this cohort. Important advances have been made in radiation planning for complete coverage of axillary nodes, and it is now clear that the traditional approach to axillary coverage by using a traditional PAB field is not optimal in many cases.16 Thus, the technique used to treat the axilla in our series does not reflect the more modern approach to axillary treatment based on computed tomographyebased lymph node contouring, which can accurately assess the radiation dose to axillary nodal basins. In addition, although the most common lateral border of the SCV field was the coracoid process, in some cases, the lateral border was placed lateral to the humeral head, thus including large portions of the axilla in the field. The majority of patients included in this series were treated at a county hospital where 2-dimensional planning was most common for breast cancer treatment during the period reviewed; thus, it is a limitation of the study that we cannot accurately assess the axillary dose received. Our data highlight the value of achieving long-term logoregional control, which is demonstrated by the poor 5-year survival in patients who experienced an LRR (17.8%) compared with that in patients without a locoregional event (90%) (P < .0001). Although this survival difference may be explained by the aggressive biology of recurrent disease in this locally advanced population, it is clear that locoregional control relates to long-term survival,4 and efforts to improve axillary control may prove of
Kunal Saigal et al Table 4 The 48-Month Cumulative Incidence of LRR (With or Without DM), LR, and RR LRR (25 events) Prognostic Factor
Rate (95% CI)
LR (16 events) P
a
Rate (95% CI)
RR (with or without LR) (9 events) P
a
Rate (95% CI)
Pa
5.9 (3.8-8.4)
e
3.7 (2.1-5.9)
e
2.2 (1.1-3.9)
e
Non-IBC, CS II
2.6 (0.7-6.9)
.033
1.8 (0.3-5.8)
.103
0.8 (0.1-4.1)
< .0001
Non-IBC, CS III
6.1 (3.5-9.7)
5.1 (2.8-8.5)
0.9 (0.2-3.0)
12.1 (5.2-22.0)
1.8 (0.1-8.5)
10.3 (4.1-19.7)
All patients Presentation
IBC ER Positive
2.9 (1.2-5.8)
Negative
9.4 (5.8-14.1)
.006
2.0 (0.6-4.7)
.057
5.8 (3.0-9.7)
0.9 (0.2-3.0)
.051
3.7 (1.6-7.1)
PR Positive
2.2 (0.6-5.9)
Negative
8.4 (5.4-12.3)
.014
2.2 (0.6-5.9)
.237
4.8 (2.6-7.9)
0.0 (NE)
.016
3.6 (1.8-6.5)
HER2 Positive
2.0 (0.4-6.5)
Negative
7.1 (4.6-10.4)
.053
1.0 (0.1-4.7)
.090
4.6 (2.6-7.4)
1.1 (0.1-5.2)
.359
2.6 (1.2-4.8)
Triple negative No TN
2.6 (1.2-5.1)
TN
< .001
12.9 (7.8-19.3)
1.9 (0.7-4.2)
.007
7.5 (3.9-13.0)
0.7 (0.1-2.4)
.003
5.3 (2.3-10.1)
Clinical nodes N0, Nx
1.8 (0.3-5.7)
N1
6.7 (3.7-11.1)
3.9 (1.7-7.5)
2.8 (1.1-6.1)
N2-N3
9.2 (4.6-15.6)
5.5 (2.2-11.1)
3.6 (1.2-8.4)
N0, Nx
1.8 (0.3-5.7)
N1-3
7.7 (4.9-11.1)
.026
.010
1.8 (0.3-5.8)
1.8 (0.3-5.8)
.216
.099
4.5 (2.5-7.4)
0.0 (NE)
0.0 (NE)
.111
.043
3.1 (1.5-5.7)
Positive lymph nodes at surgery 0 (pN0)
2.5 (0.8-6.0)
1-3
6.3 (2.8-11.8)
.005
1.3 (0.3-4.4) 5.3 (2.2-10.6)
.032
1.0 (0.1-4.8)
1.2 (0.2-4.0)
4þ
10.4 (5.8-16.5)
5.7 (2.5-10.7)
4.7 (1.9-9.4)
.053
pCR in axilla Yes
2.5 (0.8-6.0)
No
8.5 (5.3-12.5)
.003
1.3 (0.3-4.4)
.010
5.5 (3.1-9.0)
1.2 (0.2-4.0)
.182
2.9 (1.3-5.7)
pCR in breast Yes
3.1 (0.8-8.1)
No
6.9 (4.4-10.1)
.078
3.1 (0.8-8.1)
.441
3.9 (2.1-6.6)
0.0 (NE)
.065
2.8 (1.5-5.4)
pCR in breast and axilla Yes
3.2 (0.6-10.1)
No
6.5 (4.2-9.4)
.155
3.3 (0.6-10.1)
.516
3.8 (2.1-6.2)
0.0 (NA)
.147
2.7 (1.3-4.8)
Clinical and pathologic node stage cNx/cN0 / pN0 þ
1.7 (0.1-8.0)
.001
1.7 (0.1-8.0)
.014
0.0 (NE)
cNx/cN0 / pN
1.8 (0.1-8.5)
1.8 (0.1-8.5)
0.0 (NE)
cNþ / pN0
3.0 (0.8-7.8)
1.0 (0.1-4.9)
2.0 (0.4-6.4)
cNþ / pNþ
10.7 (6.7-15.8)
6.8 (3.7-11.2)
3.9 (1.7-7.5)
.125
Pathologic tumor size 2 cm
3.9 (1.9-7.0)
> 2 cm
8.7 (5.1-13.5)
.046
3.4 (1.6-6.4) 4.1 (1.8-7.8)
.826
0.5 (0.1-2.5)
.003
4.6 (2.2-8.5)
Abbreviations: CS ¼ clinical stage; DM ¼ distant metastasis; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; IBC ¼ inflammatory breast cancer; LR ¼ local recurrence; LRR: locoregional recurrence; NA ¼ not available; NE ¼ not estimable; pCR ¼ pathologic complete response; PR ¼ progesterone receptor; RR ¼ regional recurrence; TN ¼ triple negative. a P value from univariate analysis by using the Gray test, with LRR, LR, RR, isolated DM, and death as competing risk for failure.
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Locoregional Outcomes in Inflammatory Breast Cancer Figure 1 Comparison of Cumulative Incidence of Locoregional Failure (A), Local Failure (B), and Regional Failure (C) Between Patients With Inflammatory and Those With Noninflammatory Breast Cancer. (D) Comparison of OS for Patients With and Those Without Locoregional Failure
Abbreviations: IBC ¼ inflammatory breast cancer; LR ¼ local failure; LRR ¼ locoregional failure; OS ¼ overall survival: RR¼ regional failure.
Table 5 Multivariate Analysis of Predictors of Local Regional Recurrence (n [ 462)a LRR (with or without DM) Variable, Multivariate Analysis Non-IBC CS III vs. non-IBC CS II IBC vs. non-IBC TN vs. not TN No pCR vs. pCR axilla
HR (95% CI) 2.17 1.34 7.75 7.10
(0.65-7.22) (0.54-3.33) (3.27-18.39) (2.47-20.44)
P .210 .540 < .0001 < .001
LR HR (95% CI) 2.72 0.19 6.52 10.11
(0.55-11.22) (0.03-1.38) (2.31-18.39) (2.19-46.58)
RR (with or without LR) P .170 .100 < .001 .003
HR (95% CI) 0.85 9.87 9.84 3.55
(0.08-8.81) (2.03-48.09) (2.02-47.92) (0.87-14.52)
P .890 .005 .005 .078
Abbreviations: CS ¼ clinical stage; DM ¼ distant metastasis; HR ¼ hazard ratio; IBC ¼ inflammatory breast cancer; LR ¼ local recurrence; LRR ¼ locoregional recurrence; pCR ¼ pathologic complete response; RR ¼ regional recurrence; TN ¼ triple negative. a The Fine and Gray Cox regression analysis, with LRR, LR, RR, isolated DM, and death as a competing risk for failure.
342
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benefit in this population. Nonetheless, the potential benefit of full axillary radiation must be weighed against its morbidity, primarily a higher risk of developing lymphedema. It is notable that, in our series, the rate of triple-negative and HER2þ tumors was similar between the IBC and non-IBC groups, whereas other series have documented markedly elevated rates of HER2þ and higher incidences of triple-negative phenotype in IBC tumors.17,18 In our series, only 20% of the IBC tumors were HER2þand 36% were triple negative. One possible explanation for this disparity may be the unique racial and ethnic makeup of our cohort, which is largely composed of Hispanic patients. Our study is limited by its retrospective nature and relatively small number of failure events. Although we can make inferences from the pattern of failures noted, it is difficult to draw firm conclusions on optimal PMRT delivery.
Clinical Breast Cancer October 2013
Conclusion In this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after NAT and were at greater risk of axillary RR. We suggest that future studies should focus on optimal management of the axilla, including the potential for radiation to the full axilla in patients with IBC who exhibit a poor nodal response to NAT. Our results also demonstrate the importance of locoregional control as it relates to survival outcomes and highlight the significance of optimizing outcomes with local and regional adjuvant therapies.
Clinical Practice Points We described the characteristics and locoregional outcomes of
463 patients with locally advanced breast cancer with inflammatory (IBC) and noninflammatory presentations who
Kunal Saigal et al completed trimodality therapy, including neoadjuvant therapy, mastectomy with axillary node dissection, and postmastectomy radiation. Patients with IBC exhibited a poorer nodal response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 and more had 4 positive nodes (P < .001). On multivariate analysis, triple-negative disease and residual pathologic nodes after chemotherapy were associated with an increased risk of locoregional recurrence, but IBC was not. However the 4-year cumulative incidence of regional recurrence specifically was significantly higher in patients with IBC and triple negative disease. These findings may have implications for regional nodal management in patients with IBC and triple negative disease, and suggest that further study is indicated.
Disclosure The authors have stated that they have no conflicts of interest.
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