- Email: [email protected]
Is breast conservation therapy a viable option for patients with triple-receptor negative breast cancer?
Is breast conservation therapy a viable option for patients with triple-receptor negative breast cancer? Catherine C. Parker, MD,a Fred Ampil, MD,b Gary Burton, MD,c Benjamin D. L. Li, MD,a,d and Quyen D. Chu, MD,a,d Shreveport, LA
Background. Triple-receptor negative breast cancers (TNBC) are aggressive neoplasms that lack estrogenreceptor, progesterone-receptor, and HER-2 expressions. Comparative analysis of breast conservation therapy (BCT) versus mastectomy for TNBC is reported sparsely. We hypothesized that, despite its aggressive behavior, TNBC can be managed with BCT. Methods. Outcomes for 202 patients with TNBC who were treated with BCT or mastectomy were analyzed. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank, independent samples t test, Cox proportional hazard model, and Chi-square. Results. BCT was performed in 30% of patients. Isolated local recurrence rate for BCT and mastectomy was 0% and 10.6%, respectively (P = .02). Isolated regional recurrence rate for BCT and mastectomy was 1.6% and 1.4%, respectively (P = .61). Neither concomitant locoregional and distant recurrence rate (P = .73) nor isolated distant recurrence rate (P = .71) was significantly different between the BCT and mastectomy groups. The 5-year overall survival (OS) was better for the BCT group than the mastectomy group (89% vs 69%; P = .018); however, this was likely due to the mastectomy group having a larger neoplasm size (T3/T4: 4% BCT vs 27% mastectomy; P = .0002), advanced N-disease (N2/3: 8% BCT vs 25% mastectomy; P = .0003), and advanced stage of disease (stage 3: 8% BCT vs 35% mastectomy; P < .0001). On multivariate analysis, surgical approach had no effect on either disease-free survival (P = .60) or OS (P = .19); only t-stage was an independent predictor of disease-free survival (P = .02), while N-stage was an independent predictor for OS (P = .03). Conclusion. Despite TNBC’s aggressive behavior, breast conservation therapy is a viable option for selected patients with TNBC. (Surgery 2010;148:386-91.) From the Departments of Surgery,a Radiology,b Medicine,c and the Feist-Weiller Cancer Center,d Louisiana State University Health Sciences Center, Shreveport, LA
GENE EXPRESSION PROFILING has identified 5 subtypes of breast cancer: luminal A, luminal B, normal breast-like, HER-2/neu positive, and basal-like.1 Approximately 17--37% are basal-like, and these cancers are known to be aggressive biologically.2-4 ‘‘Triple-receptor negative cancers’’ (TNBC), the lexicon often used by clinicians to describe basal-like neoplasms, lack estrogen-receptor, progesterone-receptor, and ErbB-2/human epidermal
Presented at the 5th Annual Academic Surgical Congress, San Antonio, Texas, February 3–5, 2010. Accepted for publication May 27, 2010. Reprint requests: Quyen D. Chu, MD, Feist-Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail: qchu@ lsuhsc.edu. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.05.018
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growth factor receptor 2 (HER-2) expression. TNBCs are considered aggressive neoplasms because they tend to be of higher grade (based on the AJCC staging manual) and proliferation rate and are found more frequently in premenopausal women.5,6 The first and most effective targeted therapy is anti-estrogen hormonal therapy. Unfortunately, TNBC represent a challenge to current treatment regimens because the target molecules of traditional therapies are lacking in these neoplasms. For example, the drug trastuzumab targets HER2/neu positive neoplasms.7 Recent attention has also been to distinguish luminal from basal neoplasms. It has been found that TNBCs tend to be basal-like, which adds to the aggressive nature because basal neoplasms tend to also be of a higher grade.3,8,9 Although TNBC is reported to be aggressive, whether patients with such a neoplasm subtype qualify for breast conservation therapy (BCT) has not been
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well established. Several investigators demonstrated that BCT does not increase the locoregional recurrence (LRR) rate for patients with TNBC when compared to the other subtypes.10,11 Other investigators found, however, that LRR rate after BCT was significantly greater for those with TNBC compared to the other subtypes.12,13 The possible implication is that perhaps a more aggressive operative approach (ie, mastectomy) should be considered for such a patient; however, no studies to our knowledge have evaluated to see whether a mastectomy for such a cohort will achieve a better outcome over BCT. Therefore, the purpose of this current study is to compare outcomes (ie, rates of locoregional and distant recurrence and overall survival) between BCT and mastectomy for patients with TNBC. We hypothesize that BCTcan be a viable surgical option for the well selected patients with TNBC and that a mastectomy does not necessarily alter the aggressive course of the disease. METHODS A prospectively maintained breast cancer database was created in 1998 in order to track outcomes of patients treated by our group. Data on patients with stage 1--3 TNBC who were treated up to September 2008 were analyzed. Approval to analyze our database was obtained from our Institutional Review Board. Approximately 90% of patients were treated at the Feist-Weiller Cancer Center under the auspices of the Louisiana State University Health Sciences Center-Shreveport (FWCC/LSUHSC-S), while the remaining patients were treated at E.A. Conway Hospital, which is a sister safety-net hospital in Monroe, LA. Of the 803 patients in the database, 208 (26%) with TNBC were identified. Six patients were excluded from analysis due to their having either stage 0 (DCIS) disease, recurrence before 3 months, or incomplete data. Treatment and surveillance protocols were standardized to ensure study homogeneity. Compliance with treatment and surveillance protocols was over 90%. Standard treatment protocols for adjuvant and neoadjuvant chemotherapy and radiation therapy were offered to all patients. Operative treatment consisted of either a mastectomy (+ or -- axillary lymph node dissection in select cases) or BCT, lumpectomy with neoplasm-free margin, sentinel lymph node dissection and/or axillary lymph node dissection, and breast irradiation). All final specimens had negative margins. After BCT, fractionated megavoltage external beam irradiation (encompassing the whole breast) to a total dose of 50 Gy/25 fractions was administered using tangential treatment portals; the supraclavicular area is
Parker et al 387
irradiated (to the same total dose) when indicated (ie, presence of disease in 4 or more axillary lymph nodes). Adjuvant systemic chemotherapy was offered and administered as indicated per current standard of care. Antiestrogen therapy and herceptin were not used in this cohort. TNBC is defined as neoplasms that lack estrogen, progesterone, and HER-2 expressions. The pathologic diagnosis was made by standardized immunohistochemistry technique. The HER-2 status is defined as 2 or more, using the Hercep program (Dako Corp., Carpinteria, CA). Estrogen receptor (ER) and progesterone receptor (PR) status was determined using immunohistochemical methods. Slides were stained and evaluated using the Dako Autostriker and the automated cellular imaging system. Activity greater than ten percent was considered positive. Patients were all offered similar surveillance regimen. The surveillance protocol consisted of a history and physical examination every 3 months for 3 years, every 6 months in years 4 and 5, and annually thereafter. Chest x-ray, mammogram, complete blood count, and liver function tests were obtained annually. Any additional radiologic and/or histologic evaluation was performed based on the patient’s examination and history. Clinical data were accrued and recorded prospectively and included age at diagnosis, stage, nodal status, grade, neoplasm size, BCT versus mastectomy, and receptor status. The study endpoints were cancer recurrence and death. Complete clinicopathologic data from the 202 patients who had stage 1--3 breast cancers according to AJCC (6th ed) were examined.5 Thirty patients underwent neoadjuvant chemotherapy. All patients treated with neoadjuvant chemotherapy underwent mastectomy and were staged pathologically. Outcomes for patients treated with BCT versus mastectomy were analyzed, with the primary endpoints being cancer recurrence and death. Local recurrence included any ipsilateral in-breast or chest wall recurrence. Regional recurrence included any nodal recurrence within the ipsilateral axilla, supraclavicular, infraclavicular, and/or internal mammary nodal regions. Those who were diagnosed with a distant recurrence within 4 months after a locoregional recurrence were considered to have locoregional recurrence and distant metastases (LRR and DM). Distant recurrences were those with evidence of distant recurrence alone. MedCalc software (Microsoft Inc., Redmond, WA) was used to perform statistical analyses. The mean age at diagnosis, grade, node status, stage, and neoplasm size were analyzed using the
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Table I. Distribution of patient and clinicopathologic characteristics BCT (N = 61) 30% Characteristics Mean age years (range) Tumor size (cm) Overall mean 3.3 Overall median 3.0 Mean Median Mean tumor grade Tumor grade (%) I (1) II (37) III (63) T-stage (%) T1 (28) T2 (53) T3 (13) T4 (6) N-stage (%) N0 (55) N1 (25) N2 (15) N3 (5) Stage distribution (%) Stage 1 (21) Stage 2 (52) Stage 3 (27) Recurrences (%) Local recurrences alone Regional recurrences alone Locoregional + distant Distant alone Systemic treatment (%) Adriamycin alone Adriamycin + taxane Taxane alone Others
55 (30–87)
2.4 2.1 2.6 0/56 (0) 21/56 (38) 35/56 (62)
Mastectomy (N = 141) 70% 56 (28–83)
3.7 3 2.6 1/128 (1) 47/128 (36) 80/128 (63)
27 32 1 2
(44) (52) (1) (3)
30 74 25 12
(21) (52) (18) (9)
47 9 5 0
(77) (15) (8) (0)
64 42 25 10
(45) (30) (18) (7)
23 (38) 33 (54) 5 (8)
19 (13) 73 (52) 49 (35)
0 1 3 8
(0) (1.6) (5) (13)
15 2 7 23
(10.6) (1.4) (5) (16)
17 18 1 25
(28) (29) (2) (41)
22 64 5 50
(16) (45) (4) (35)
independent sample t tests, while categorical data were analyzed with the Chi-square test. Overall survival (OS) was calculated from the date of operation to the date of death from any cause or date of last follow-up. Disease-free survival (DFS) was calculated from the date of operation to the date of first recurrence (local or distant) or date of last follow-up. Survival analysis was performed using Kaplan-Meier method, the log-rank test was used to compare the curves, and Cox proportional hazard regression models were applied for multivariate analysis. There was no violation of the underlying assumption of the Cox proportional hazards. Risk ratios and 95% confidence intervals were calculated from the model. A P value # .05 was considered statistically significant.
P value .80
<.001 .81
.8
.0002
.0003
<.0001
.02 .61 .73 .71
.12
RESULTS Two hundred and two patients with TNBC were identified. The mean follow-up time was 52.8 months. Thirty patients (15%) underwent neoadjuvant chemotherapy. Of these, 22 patients (73%) were pathologically stage 3 and 8 patients (27%) were pathologically stage 2. Twenty-one (70%) patients received post-mastectomy radiation, while the remaining patients either refused treatment or had
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100
Breast-Conserving Therapy
Survival Probability (%)
Survival Probability (%)
100 80 60 40 20
Mastectomy p=0.14
0 0
50
100
150
200
Time (months)
Fig 1. Disease-free survival for patients who had BCT or mastectomy.
regional recurrences only (P = .61), locoregional and distant recurrences (P = .73), distant recurrences (P = .71), and type of systemic treatment (P = .12) were not statistically different between the 2 groups. The mean age of diagnosis for women undergoing BCT was 55 years (range, 30-87), and for those undergoing mastectomy was 56 years (range, 28--83). Almost two thirds of all patients (63%) had Grade 3 tumors. The overall mean neoplasm size was 3.3 cm with an overall median size of 3.0 cm. Compared to the BCT group, the mastectomy group had a statistically greater mean tumor size (3.7 cm vs 2.4 cm; P < .001), higher T-stage neoplasms (T3/T4 = 27% vs 4%; P = .0002), higher N-stage tumors (N2/N3 = 25% vs 8%; P = .0003), and higher stage disease (stage 3 = 35% vs 8%; P < .0001; Table I). Of the 61 BCT patients, 5 patients (8%) did not receive adjuvant radiation; 4 had refused it, while 1 patient developed a brain metastasis 19 months after resection of a T2N0 disease. Overall, 15 of 202 patients (7.4%) developed local recurrence as their only site of recurrences, all of whom had mastectomy (P = .02), and 3 patients developed regional recurrence as their only site of recurrences; 1 in the BCT group and 2 in the mastectomy group (P = .61). Taken together, there were 18 locoregional recurrences as the only site of recurrences. Concomitant locoregional and distant recurrences occurred in 3 patients (5%) in the BCT group and 7 patients (5%) in the mastectomy group (P = .73). Of the 13 regional recurrences, 10 (77%) occurred in node positive patients (5 N1, 4 N2, 1 N3 diseases). Distant site as the only manifestation of recurrences occurred in 8 patients (13%) in the BCT group and 23 patients (16%) in the mastectomy group (P = .71; Table I). Additionally, 41/202 (20.3%) experienced death. Of these, all but 9 patients died of recurrent diseases: 10% (6/63) in
Breast-Conserving Therapy
80 60 Mastectomy
40 20 p=0.018
0 0
50
100
150
200
250
Time (months)
Fig 2. Overall survival for patients who had BCT or mastectomy.
the BCT group and 25% (35/139) in the mastectomy group (P = .02). To determine whether the type of definitive operative therapy had an impact on outcome for patients with TNBC, we compared OS and DFS between those who had BCT with those who had a mastectomy (Figs 1 and 2). The 5-year DFS for the BCT and mastectomy group was 68% and 57%, respectively (P = .14). The median DFS has not been reached for BCT, and was 79 months for the mastectomy group (Fig 1). The 5-year OS was better for the BCT than for the mastectomy group (89% vs 69%; P = .018). The median OS time has not been reached for both groups (Fig 2). The difference in survival for the BCT group was likely due to the mastectomy group having a significantly greater tumor size, advanced nodal disease, and advanced stage of disease (Table I). The Cox proportional hazard model was used to compare type of definitive operative therapy, age at diagnosis, tumor grade, T-stage, N-stage, and postmastectomy radiation for risk of cancer recurrence and death (Tables II and III). Note that surgical approach was not an independent predictor of either DFS (P = .60) or OS (P = .19). T-stage was the only independent predictor of DFS (P = .02), while N-stage was the only independent predictor of OS (P = .03). DISCUSSION Human breast carcinomas are a heterogeneous group of neoplasms. Based on molecular subtyping, Perou et al recently classified breast cancer into 5 subtypes: luminal A and B, normal breastlike, HER-2 positive, and basal-like.1 The basal-like neoplasms arise from the outer basal layer of breast ducts and stain positively for basal cell cytokeratins.5,6,17 These neoplasms also have low
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Table II. Disease-free survival for patients with triple-receptor negative breast cancer who had breast-conserving therapy or mastectomy (Cox Proportional Hazard Model)
BCT Age at diagnosis Grade T-stage N Stage PMRT
Adjusted hazard ratio
95% CI
P value
0.84 1.00 1.19 1.51 1.25 1.25
0.45–1.57 0.98–1.03 0.70–2.03 1.07–2.14 0.95–1.65 0.60–2.61
.60 .51 .52 .02 .12 .55
PMRT, Postmastectomy radiation therapy.
Table III. Overall survival for patients with triplereceptor negative breast cancer who had breastconserving therapy or mastectomy (Cox Proportional Hazard Model)
BCT Age at diagnosis Grade T Stage N Stage PMRT
Adjusted hazard ratio
95% CI
P value
0.54 1.00 1.87 1.26 1.46 1.36
0.22–1.34 0.97–1.04 0.90–3.89 0.78–2.02 1.04–2.06 0.51–3.60
.19 .61 .10 .35 .03 .53
PMRT, Postmastectomy radiation therapy.
expression of ER, PR, and HER-2 receptor. Triplereceptor negative breast cancers, the term often used to refer to basal-like breast cancers, are those that lack ER, PR, and HER-2 expressions when examined by immunohistochemical analysis. Although basal-like neoplasms and TNBC are interchangeable terminologies, they are not necessarily synonymous; however, from a practical clinical perspective, TNBC is the terminology frequently used in lieu of basal-like breast cancers. Breast conservation therapy (BCT) has been established as an acceptable surgical modality for patients with operable breast cancer.14 Given TNBC’s aggressive features,3,6,8,9 there is a concern that perhaps a more aggressive surgical approach (ie, mastectomy) should be considered because of the possibility that BCT might put patients at a higher risk for developing locoregional recurrence. To evaluate the effectiveness of BCT in controlling locoregional recurrences, several investigators compared the rates of locoregional recurrences between TNBC subtype with other breast cancer subtypes.10-13 Both Haffty et al10 and Freedman et al11 found no significant differences in the local control rates between TNBC and the other subtypes when BCT was performed. Comparing 117 patients with TNBC
Table IV. Literature review of locoregional recurrence rates for conservatively managed TNBC Authors
N
LRR rates (%)
Nguyen et al (2008)12 Freedman et al (2009)11 Solin et al (2009)13 Parker et al (2010)
89 98 90 63
7 3 8 2
with 365 patients with non-TNBC, Haffty et al10 found that, as expected, the TNBC cohort had a poorer outcome compared to the other subtypes (distant metastasis-free rate 67% for TNBC vs 82% for other subtypes; P = .002) and that the triplenegative subtype was an independent predictor of distant metastasis (P = .002) and cause-specific survival (P = .047). The local relapse-free survival was similar, however, for the 2 groups (83% for both TNBC and non-TNBC subtypes). Similarly, Freedman et al compared outcomes for 753 breast cancer patients who underwent BCT.11 Patients were grouped based on receptor statuses: Group 1 (600 patients) = ER or PR (+), Group 2 (55 patients) = ER and PR (--) but HER-2 (+), and Group 3 (98 patients) = TNBC. Despite a difference in rates of first distant metastases between the groups (3%, 12%, and 7% for Groups 1, 2, and 3, respectively; P = .009), the isolated 5-year locoregional recurrence was not significantly different (2.3%, 4.6%, and 3.2%, respectively) between the 3 groups.11 Nguyen et al12 and Solin et al13 appear to have a divergent point of view. These investigators demonstrated that the locoregional failure rate after BCT was significantly greater in the TNBC subtype than the less aggressive neoplasm subtypes. Nguyen et al reported that following BCT, the overall 5-year local recurrence rate was 7.1% for the basal subtype vs 0.8% for luminal A, 1.5% for luminal B, and 8.4% for HER-2 subtype.12 On multivariable analysis using luminal A as baseline, HER-2 (P = .012) and basal (P = .009) subtypes were associated with increased local recurrence, and luminal B (P = .007) and basal (P = .035) subtypes were associated with increased distant metastases.12 Solin et al compared outcomes of 90 TNBC patients with 429 non-TNBC patients who had BCT and found that the local failure rate after BCT was significantly greater for the TNBC group compared with the non-TNBC group. The 8-year rate of any local failure was 8% for TNBC vs 4% for non-TNBC (P = .041) and the 8-year rate of freedom from distant metastases was 81% for TNBC vs 92% for non-TNBC (P = .0066).13 These latter 2 studies raised an important question, mainly that given the propensity of developing a
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greater locoregional failure rate in patients with TNBC undergoing BCT, should a mastectomy have been performed at the onset? To answer such a question, one would need to randomize TNBC patients to receive either BCT or mastectomy. Since we have not found such a trial, we sought to perform a retrospective analysis of a cohort of patients with TNBC and compared their outcomes based on the surgical approach (ie, BCT versus mastectomy). As would be expected from any retrospective studies, we noted an imbalance in the clinicopathologic characteristics between those who had BCT and those who had mastectomies. The mastectomy cohort had a poorer OS, which is partly due to this group having a greater tumor size, advanced nodal disease, and advanced stage of disease; however, we noted that the surgical approach did not have an impact on the development of distant metastases; the rates of developing concomitant locoregional recurrences or isolated distant recurrences were not significantly different between those who had BCT or mastectomies. Furthermore, on multivariate analysis, after adjusting for age at diagnosis, grade, T-stage, N-stage, and receipt of post-mastectomy radiation, surgical approach was not an independent predictor of either disease-free survival or overall survival. Considering all of these data together, it would appear that biology dictates outcome after appropriate treatment rather than the surgical procedure. We believe that despite its aggressive nature, patients with TNBC should not be denied the option of undergoing BCT. Gleaning from our data, those with small tumors (median 2.1 cm) and/or likely to have N0 or N1 disease may be suitable candidates for BCT. In our experience, the locoregional failure rate for patients with TNBC after BCT was very low (1.6%). We had no isolated local relapse and only 1 patient had an isolated regional recurrence (supraclavicular recurrence). Other investigators have also reported a low locoregional recurrence rate of 3.2% and 8.0% (Table IV). About 15% of our patients had neoadjuvant chemotherapy, all of whom had mastectomies, while 70% received postmastectomy radiation therapy (PMRT). Although PMRT has the potential to significantly decrease the incidence of locoregional recurrence among high-risk individuals with TNBC, it does not improve overall survival.15 In our experience, we found that on multivariate analysis, PMRT was not an independent predictor of either diseasefree survival or overall survival; however, this finding may be due to a lack of adequate power. In conclusion, we demonstrated that despite its aggressive behavior, TNBC can be managed surgically with BCT for selected patients. Because the
rate of locoregional recurrence is low and surgical approach does not appear to impact on overall survival, suitable patients with TNBC should be given the option of breast conservation therapy.
REFERENCES 1. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52. 2. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population based study. Proc Natl Acad Sci USA 2003;100:10393-8. 3. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869-74. 4. van ’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530-6. 5. Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual. 6th ed. New York: Springer; 2002. 6. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D Conway K, et al. Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502. 7. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. 8. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer 2007;109:25-32. 9. Matos I, Dufloth R, Alvarenga M, Zeferino LC, Schmitt F. p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 2005;447:688-94. 10. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006;24:5652-7. 11. Freedman GM, Anderson PR, Li T, Nicolaou N. Locoregional recurrence of triple-negative breast cancer after breastconserving surgery and radiation. Cancer 2009;115:946-51. 12. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breastconserving therapy. J Clin Oncol 2008;26:2373-8. 13. Solin LJ, Hwang WT, Vapiwala N. Outcome after breast conservation treatment with radiation for women with triplenegative early-stage invasive breast carcinoma. Clin Breast Cancer 2009;9:96-100. 14. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41. 15. Kyndi M, Sørensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J. Danish Breast Cancer Cooperative Group. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1419-26.
Background. Triple-receptor negative breast cancers (TNBC) are aggressive neoplasms that lack estrogenreceptor, progesterone-receptor, and HER-2 expressions. Comparative analysis of breast conservation therapy (BCT) versus mastectomy for TNBC is reported sparsely. We hypothesized that, despite its aggressive behavior, TNBC can be managed with BCT. Methods. Outcomes for 202 patients with TNBC who were treated with BCT or mastectomy were analyzed. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank, independent samples t test, Cox proportional hazard model, and Chi-square. Results. BCT was performed in 30% of patients. Isolated local recurrence rate for BCT and mastectomy was 0% and 10.6%, respectively (P = .02). Isolated regional recurrence rate for BCT and mastectomy was 1.6% and 1.4%, respectively (P = .61). Neither concomitant locoregional and distant recurrence rate (P = .73) nor isolated distant recurrence rate (P = .71) was significantly different between the BCT and mastectomy groups. The 5-year overall survival (OS) was better for the BCT group than the mastectomy group (89% vs 69%; P = .018); however, this was likely due to the mastectomy group having a larger neoplasm size (T3/T4: 4% BCT vs 27% mastectomy; P = .0002), advanced N-disease (N2/3: 8% BCT vs 25% mastectomy; P = .0003), and advanced stage of disease (stage 3: 8% BCT vs 35% mastectomy; P < .0001). On multivariate analysis, surgical approach had no effect on either disease-free survival (P = .60) or OS (P = .19); only t-stage was an independent predictor of disease-free survival (P = .02), while N-stage was an independent predictor for OS (P = .03). Conclusion. Despite TNBC’s aggressive behavior, breast conservation therapy is a viable option for selected patients with TNBC. (Surgery 2010;148:386-91.) From the Departments of Surgery,a Radiology,b Medicine,c and the Feist-Weiller Cancer Center,d Louisiana State University Health Sciences Center, Shreveport, LA
GENE EXPRESSION PROFILING has identified 5 subtypes of breast cancer: luminal A, luminal B, normal breast-like, HER-2/neu positive, and basal-like.1 Approximately 17--37% are basal-like, and these cancers are known to be aggressive biologically.2-4 ‘‘Triple-receptor negative cancers’’ (TNBC), the lexicon often used by clinicians to describe basal-like neoplasms, lack estrogen-receptor, progesterone-receptor, and ErbB-2/human epidermal
Presented at the 5th Annual Academic Surgical Congress, San Antonio, Texas, February 3–5, 2010. Accepted for publication May 27, 2010. Reprint requests: Quyen D. Chu, MD, Feist-Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail: qchu@ lsuhsc.edu. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.05.018
386 SURGERY
growth factor receptor 2 (HER-2) expression. TNBCs are considered aggressive neoplasms because they tend to be of higher grade (based on the AJCC staging manual) and proliferation rate and are found more frequently in premenopausal women.5,6 The first and most effective targeted therapy is anti-estrogen hormonal therapy. Unfortunately, TNBC represent a challenge to current treatment regimens because the target molecules of traditional therapies are lacking in these neoplasms. For example, the drug trastuzumab targets HER2/neu positive neoplasms.7 Recent attention has also been to distinguish luminal from basal neoplasms. It has been found that TNBCs tend to be basal-like, which adds to the aggressive nature because basal neoplasms tend to also be of a higher grade.3,8,9 Although TNBC is reported to be aggressive, whether patients with such a neoplasm subtype qualify for breast conservation therapy (BCT) has not been
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well established. Several investigators demonstrated that BCT does not increase the locoregional recurrence (LRR) rate for patients with TNBC when compared to the other subtypes.10,11 Other investigators found, however, that LRR rate after BCT was significantly greater for those with TNBC compared to the other subtypes.12,13 The possible implication is that perhaps a more aggressive operative approach (ie, mastectomy) should be considered for such a patient; however, no studies to our knowledge have evaluated to see whether a mastectomy for such a cohort will achieve a better outcome over BCT. Therefore, the purpose of this current study is to compare outcomes (ie, rates of locoregional and distant recurrence and overall survival) between BCT and mastectomy for patients with TNBC. We hypothesize that BCTcan be a viable surgical option for the well selected patients with TNBC and that a mastectomy does not necessarily alter the aggressive course of the disease. METHODS A prospectively maintained breast cancer database was created in 1998 in order to track outcomes of patients treated by our group. Data on patients with stage 1--3 TNBC who were treated up to September 2008 were analyzed. Approval to analyze our database was obtained from our Institutional Review Board. Approximately 90% of patients were treated at the Feist-Weiller Cancer Center under the auspices of the Louisiana State University Health Sciences Center-Shreveport (FWCC/LSUHSC-S), while the remaining patients were treated at E.A. Conway Hospital, which is a sister safety-net hospital in Monroe, LA. Of the 803 patients in the database, 208 (26%) with TNBC were identified. Six patients were excluded from analysis due to their having either stage 0 (DCIS) disease, recurrence before 3 months, or incomplete data. Treatment and surveillance protocols were standardized to ensure study homogeneity. Compliance with treatment and surveillance protocols was over 90%. Standard treatment protocols for adjuvant and neoadjuvant chemotherapy and radiation therapy were offered to all patients. Operative treatment consisted of either a mastectomy (+ or -- axillary lymph node dissection in select cases) or BCT, lumpectomy with neoplasm-free margin, sentinel lymph node dissection and/or axillary lymph node dissection, and breast irradiation). All final specimens had negative margins. After BCT, fractionated megavoltage external beam irradiation (encompassing the whole breast) to a total dose of 50 Gy/25 fractions was administered using tangential treatment portals; the supraclavicular area is
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irradiated (to the same total dose) when indicated (ie, presence of disease in 4 or more axillary lymph nodes). Adjuvant systemic chemotherapy was offered and administered as indicated per current standard of care. Antiestrogen therapy and herceptin were not used in this cohort. TNBC is defined as neoplasms that lack estrogen, progesterone, and HER-2 expressions. The pathologic diagnosis was made by standardized immunohistochemistry technique. The HER-2 status is defined as 2 or more, using the Hercep program (Dako Corp., Carpinteria, CA). Estrogen receptor (ER) and progesterone receptor (PR) status was determined using immunohistochemical methods. Slides were stained and evaluated using the Dako Autostriker and the automated cellular imaging system. Activity greater than ten percent was considered positive. Patients were all offered similar surveillance regimen. The surveillance protocol consisted of a history and physical examination every 3 months for 3 years, every 6 months in years 4 and 5, and annually thereafter. Chest x-ray, mammogram, complete blood count, and liver function tests were obtained annually. Any additional radiologic and/or histologic evaluation was performed based on the patient’s examination and history. Clinical data were accrued and recorded prospectively and included age at diagnosis, stage, nodal status, grade, neoplasm size, BCT versus mastectomy, and receptor status. The study endpoints were cancer recurrence and death. Complete clinicopathologic data from the 202 patients who had stage 1--3 breast cancers according to AJCC (6th ed) were examined.5 Thirty patients underwent neoadjuvant chemotherapy. All patients treated with neoadjuvant chemotherapy underwent mastectomy and were staged pathologically. Outcomes for patients treated with BCT versus mastectomy were analyzed, with the primary endpoints being cancer recurrence and death. Local recurrence included any ipsilateral in-breast or chest wall recurrence. Regional recurrence included any nodal recurrence within the ipsilateral axilla, supraclavicular, infraclavicular, and/or internal mammary nodal regions. Those who were diagnosed with a distant recurrence within 4 months after a locoregional recurrence were considered to have locoregional recurrence and distant metastases (LRR and DM). Distant recurrences were those with evidence of distant recurrence alone. MedCalc software (Microsoft Inc., Redmond, WA) was used to perform statistical analyses. The mean age at diagnosis, grade, node status, stage, and neoplasm size were analyzed using the
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Table I. Distribution of patient and clinicopathologic characteristics BCT (N = 61) 30% Characteristics Mean age years (range) Tumor size (cm) Overall mean 3.3 Overall median 3.0 Mean Median Mean tumor grade Tumor grade (%) I (1) II (37) III (63) T-stage (%) T1 (28) T2 (53) T3 (13) T4 (6) N-stage (%) N0 (55) N1 (25) N2 (15) N3 (5) Stage distribution (%) Stage 1 (21) Stage 2 (52) Stage 3 (27) Recurrences (%) Local recurrences alone Regional recurrences alone Locoregional + distant Distant alone Systemic treatment (%) Adriamycin alone Adriamycin + taxane Taxane alone Others
55 (30–87)
2.4 2.1 2.6 0/56 (0) 21/56 (38) 35/56 (62)
Mastectomy (N = 141) 70% 56 (28–83)
3.7 3 2.6 1/128 (1) 47/128 (36) 80/128 (63)
27 32 1 2
(44) (52) (1) (3)
30 74 25 12
(21) (52) (18) (9)
47 9 5 0
(77) (15) (8) (0)
64 42 25 10
(45) (30) (18) (7)
23 (38) 33 (54) 5 (8)
19 (13) 73 (52) 49 (35)
0 1 3 8
(0) (1.6) (5) (13)
15 2 7 23
(10.6) (1.4) (5) (16)
17 18 1 25
(28) (29) (2) (41)
22 64 5 50
(16) (45) (4) (35)
independent sample t tests, while categorical data were analyzed with the Chi-square test. Overall survival (OS) was calculated from the date of operation to the date of death from any cause or date of last follow-up. Disease-free survival (DFS) was calculated from the date of operation to the date of first recurrence (local or distant) or date of last follow-up. Survival analysis was performed using Kaplan-Meier method, the log-rank test was used to compare the curves, and Cox proportional hazard regression models were applied for multivariate analysis. There was no violation of the underlying assumption of the Cox proportional hazards. Risk ratios and 95% confidence intervals were calculated from the model. A P value # .05 was considered statistically significant.
P value .80
<.001 .81
.8
.0002
.0003
<.0001
.02 .61 .73 .71
.12
RESULTS Two hundred and two patients with TNBC were identified. The mean follow-up time was 52.8 months. Thirty patients (15%) underwent neoadjuvant chemotherapy. Of these, 22 patients (73%) were pathologically stage 3 and 8 patients (27%) were pathologically stage 2. Twenty-one (70%) patients received post-mastectomy radiation, while the remaining patients either refused treatment or had
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100
Breast-Conserving Therapy
Survival Probability (%)
Survival Probability (%)
100 80 60 40 20
Mastectomy p=0.14
0 0
50
100
150
200
Time (months)
Fig 1. Disease-free survival for patients who had BCT or mastectomy.
regional recurrences only (P = .61), locoregional and distant recurrences (P = .73), distant recurrences (P = .71), and type of systemic treatment (P = .12) were not statistically different between the 2 groups. The mean age of diagnosis for women undergoing BCT was 55 years (range, 30-87), and for those undergoing mastectomy was 56 years (range, 28--83). Almost two thirds of all patients (63%) had Grade 3 tumors. The overall mean neoplasm size was 3.3 cm with an overall median size of 3.0 cm. Compared to the BCT group, the mastectomy group had a statistically greater mean tumor size (3.7 cm vs 2.4 cm; P < .001), higher T-stage neoplasms (T3/T4 = 27% vs 4%; P = .0002), higher N-stage tumors (N2/N3 = 25% vs 8%; P = .0003), and higher stage disease (stage 3 = 35% vs 8%; P < .0001; Table I). Of the 61 BCT patients, 5 patients (8%) did not receive adjuvant radiation; 4 had refused it, while 1 patient developed a brain metastasis 19 months after resection of a T2N0 disease. Overall, 15 of 202 patients (7.4%) developed local recurrence as their only site of recurrences, all of whom had mastectomy (P = .02), and 3 patients developed regional recurrence as their only site of recurrences; 1 in the BCT group and 2 in the mastectomy group (P = .61). Taken together, there were 18 locoregional recurrences as the only site of recurrences. Concomitant locoregional and distant recurrences occurred in 3 patients (5%) in the BCT group and 7 patients (5%) in the mastectomy group (P = .73). Of the 13 regional recurrences, 10 (77%) occurred in node positive patients (5 N1, 4 N2, 1 N3 diseases). Distant site as the only manifestation of recurrences occurred in 8 patients (13%) in the BCT group and 23 patients (16%) in the mastectomy group (P = .71; Table I). Additionally, 41/202 (20.3%) experienced death. Of these, all but 9 patients died of recurrent diseases: 10% (6/63) in
Breast-Conserving Therapy
80 60 Mastectomy
40 20 p=0.018
0 0
50
100
150
200
250
Time (months)
Fig 2. Overall survival for patients who had BCT or mastectomy.
the BCT group and 25% (35/139) in the mastectomy group (P = .02). To determine whether the type of definitive operative therapy had an impact on outcome for patients with TNBC, we compared OS and DFS between those who had BCT with those who had a mastectomy (Figs 1 and 2). The 5-year DFS for the BCT and mastectomy group was 68% and 57%, respectively (P = .14). The median DFS has not been reached for BCT, and was 79 months for the mastectomy group (Fig 1). The 5-year OS was better for the BCT than for the mastectomy group (89% vs 69%; P = .018). The median OS time has not been reached for both groups (Fig 2). The difference in survival for the BCT group was likely due to the mastectomy group having a significantly greater tumor size, advanced nodal disease, and advanced stage of disease (Table I). The Cox proportional hazard model was used to compare type of definitive operative therapy, age at diagnosis, tumor grade, T-stage, N-stage, and postmastectomy radiation for risk of cancer recurrence and death (Tables II and III). Note that surgical approach was not an independent predictor of either DFS (P = .60) or OS (P = .19). T-stage was the only independent predictor of DFS (P = .02), while N-stage was the only independent predictor of OS (P = .03). DISCUSSION Human breast carcinomas are a heterogeneous group of neoplasms. Based on molecular subtyping, Perou et al recently classified breast cancer into 5 subtypes: luminal A and B, normal breastlike, HER-2 positive, and basal-like.1 The basal-like neoplasms arise from the outer basal layer of breast ducts and stain positively for basal cell cytokeratins.5,6,17 These neoplasms also have low
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Table II. Disease-free survival for patients with triple-receptor negative breast cancer who had breast-conserving therapy or mastectomy (Cox Proportional Hazard Model)
BCT Age at diagnosis Grade T-stage N Stage PMRT
Adjusted hazard ratio
95% CI
P value
0.84 1.00 1.19 1.51 1.25 1.25
0.45–1.57 0.98–1.03 0.70–2.03 1.07–2.14 0.95–1.65 0.60–2.61
.60 .51 .52 .02 .12 .55
PMRT, Postmastectomy radiation therapy.
Table III. Overall survival for patients with triplereceptor negative breast cancer who had breastconserving therapy or mastectomy (Cox Proportional Hazard Model)
BCT Age at diagnosis Grade T Stage N Stage PMRT
Adjusted hazard ratio
95% CI
P value
0.54 1.00 1.87 1.26 1.46 1.36
0.22–1.34 0.97–1.04 0.90–3.89 0.78–2.02 1.04–2.06 0.51–3.60
.19 .61 .10 .35 .03 .53
PMRT, Postmastectomy radiation therapy.
expression of ER, PR, and HER-2 receptor. Triplereceptor negative breast cancers, the term often used to refer to basal-like breast cancers, are those that lack ER, PR, and HER-2 expressions when examined by immunohistochemical analysis. Although basal-like neoplasms and TNBC are interchangeable terminologies, they are not necessarily synonymous; however, from a practical clinical perspective, TNBC is the terminology frequently used in lieu of basal-like breast cancers. Breast conservation therapy (BCT) has been established as an acceptable surgical modality for patients with operable breast cancer.14 Given TNBC’s aggressive features,3,6,8,9 there is a concern that perhaps a more aggressive surgical approach (ie, mastectomy) should be considered because of the possibility that BCT might put patients at a higher risk for developing locoregional recurrence. To evaluate the effectiveness of BCT in controlling locoregional recurrences, several investigators compared the rates of locoregional recurrences between TNBC subtype with other breast cancer subtypes.10-13 Both Haffty et al10 and Freedman et al11 found no significant differences in the local control rates between TNBC and the other subtypes when BCT was performed. Comparing 117 patients with TNBC
Table IV. Literature review of locoregional recurrence rates for conservatively managed TNBC Authors
N
LRR rates (%)
Nguyen et al (2008)12 Freedman et al (2009)11 Solin et al (2009)13 Parker et al (2010)
89 98 90 63
7 3 8 2
with 365 patients with non-TNBC, Haffty et al10 found that, as expected, the TNBC cohort had a poorer outcome compared to the other subtypes (distant metastasis-free rate 67% for TNBC vs 82% for other subtypes; P = .002) and that the triplenegative subtype was an independent predictor of distant metastasis (P = .002) and cause-specific survival (P = .047). The local relapse-free survival was similar, however, for the 2 groups (83% for both TNBC and non-TNBC subtypes). Similarly, Freedman et al compared outcomes for 753 breast cancer patients who underwent BCT.11 Patients were grouped based on receptor statuses: Group 1 (600 patients) = ER or PR (+), Group 2 (55 patients) = ER and PR (--) but HER-2 (+), and Group 3 (98 patients) = TNBC. Despite a difference in rates of first distant metastases between the groups (3%, 12%, and 7% for Groups 1, 2, and 3, respectively; P = .009), the isolated 5-year locoregional recurrence was not significantly different (2.3%, 4.6%, and 3.2%, respectively) between the 3 groups.11 Nguyen et al12 and Solin et al13 appear to have a divergent point of view. These investigators demonstrated that the locoregional failure rate after BCT was significantly greater in the TNBC subtype than the less aggressive neoplasm subtypes. Nguyen et al reported that following BCT, the overall 5-year local recurrence rate was 7.1% for the basal subtype vs 0.8% for luminal A, 1.5% for luminal B, and 8.4% for HER-2 subtype.12 On multivariable analysis using luminal A as baseline, HER-2 (P = .012) and basal (P = .009) subtypes were associated with increased local recurrence, and luminal B (P = .007) and basal (P = .035) subtypes were associated with increased distant metastases.12 Solin et al compared outcomes of 90 TNBC patients with 429 non-TNBC patients who had BCT and found that the local failure rate after BCT was significantly greater for the TNBC group compared with the non-TNBC group. The 8-year rate of any local failure was 8% for TNBC vs 4% for non-TNBC (P = .041) and the 8-year rate of freedom from distant metastases was 81% for TNBC vs 92% for non-TNBC (P = .0066).13 These latter 2 studies raised an important question, mainly that given the propensity of developing a
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greater locoregional failure rate in patients with TNBC undergoing BCT, should a mastectomy have been performed at the onset? To answer such a question, one would need to randomize TNBC patients to receive either BCT or mastectomy. Since we have not found such a trial, we sought to perform a retrospective analysis of a cohort of patients with TNBC and compared their outcomes based on the surgical approach (ie, BCT versus mastectomy). As would be expected from any retrospective studies, we noted an imbalance in the clinicopathologic characteristics between those who had BCT and those who had mastectomies. The mastectomy cohort had a poorer OS, which is partly due to this group having a greater tumor size, advanced nodal disease, and advanced stage of disease; however, we noted that the surgical approach did not have an impact on the development of distant metastases; the rates of developing concomitant locoregional recurrences or isolated distant recurrences were not significantly different between those who had BCT or mastectomies. Furthermore, on multivariate analysis, after adjusting for age at diagnosis, grade, T-stage, N-stage, and receipt of post-mastectomy radiation, surgical approach was not an independent predictor of either disease-free survival or overall survival. Considering all of these data together, it would appear that biology dictates outcome after appropriate treatment rather than the surgical procedure. We believe that despite its aggressive nature, patients with TNBC should not be denied the option of undergoing BCT. Gleaning from our data, those with small tumors (median 2.1 cm) and/or likely to have N0 or N1 disease may be suitable candidates for BCT. In our experience, the locoregional failure rate for patients with TNBC after BCT was very low (1.6%). We had no isolated local relapse and only 1 patient had an isolated regional recurrence (supraclavicular recurrence). Other investigators have also reported a low locoregional recurrence rate of 3.2% and 8.0% (Table IV). About 15% of our patients had neoadjuvant chemotherapy, all of whom had mastectomies, while 70% received postmastectomy radiation therapy (PMRT). Although PMRT has the potential to significantly decrease the incidence of locoregional recurrence among high-risk individuals with TNBC, it does not improve overall survival.15 In our experience, we found that on multivariate analysis, PMRT was not an independent predictor of either diseasefree survival or overall survival; however, this finding may be due to a lack of adequate power. In conclusion, we demonstrated that despite its aggressive behavior, TNBC can be managed surgically with BCT for selected patients. Because the
rate of locoregional recurrence is low and surgical approach does not appear to impact on overall survival, suitable patients with TNBC should be given the option of breast conservation therapy.
REFERENCES 1. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52. 2. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population based study. Proc Natl Acad Sci USA 2003;100:10393-8. 3. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869-74. 4. van ’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530-6. 5. Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual. 6th ed. New York: Springer; 2002. 6. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D Conway K, et al. Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502. 7. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. 8. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer 2007;109:25-32. 9. Matos I, Dufloth R, Alvarenga M, Zeferino LC, Schmitt F. p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 2005;447:688-94. 10. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006;24:5652-7. 11. Freedman GM, Anderson PR, Li T, Nicolaou N. Locoregional recurrence of triple-negative breast cancer after breastconserving surgery and radiation. Cancer 2009;115:946-51. 12. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breastconserving therapy. J Clin Oncol 2008;26:2373-8. 13. Solin LJ, Hwang WT, Vapiwala N. Outcome after breast conservation treatment with radiation for women with triplenegative early-stage invasive breast carcinoma. Clin Breast Cancer 2009;9:96-100. 14. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41. 15. Kyndi M, Sørensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J. Danish Breast Cancer Cooperative Group. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1419-26.