- Email: [email protected]
Neoadjuvant Chemotherapy for Breast Cancer Increases the Rate of Breast Conservation: Results from the National Cancer Database
Neoadjuvant Chemotherapy for Breast Cancer Increases the Rate of Breast Conservation: Results from the National Cancer Database Brigid K Killelea, MD, MPH, FACS, Vicky Q Yang, MS, Sarah Mougalian, MD, Nina R Horowitz, MD, FACS, Lajos Pusztai, MD, DPhil, Anees B Chagpar, MD, MSc, MPH, MA, MBA, FACS, Donald R Lannin, MD, FACS Neoadjuvant chemotherapy has been shown to increase the rate of breast conservation in clinical trials and small institutional series, but it has never been studied on a national level. STUDY DESIGN: We performed a retrospective review of the National Cancer Database (NCDB). The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society and contains about 80% of the cancer cases in the United States. All women in the NCDB diagnosed with invasive breast cancer from 2006 through 2011, who underwent definitive breast surgery and received either neoadjuvant or adjuvant chemotherapy, excluding patients with distant metastases or T4 tumors, were included and rates of breast preservation were determined. RESULTS: Of 354,204 patients who met the inclusion criteria, 59,063 (16.7%) underwent neoadjuvant chemotherapy. This proportion steadily increased from 13.9% in 2006 to 20.5% in 2011 (p < 0.001). Receipt of neoadjuvant chemotherapy was associated with larger tumor size (7% cT1, 25% cT2, and 58% cT3; p < 0.001), more advanced nodal disease (11% cN0, 39% cN1-3; p < 0.001), younger patient age (21% <50 years vs 14% >50 years; p < 0.001), higher tumor grade (18% grade 3, 15% grade 2, vs 12% grade 1; p < 0.001), and estrogen receptor (ER)-negative tumors (21% ER negative vs 15% ER postive; p < 0.001). Multivariate logistic regression showed that when adjusted for the above variables, patients with tumors larger than 3 cm undergoing neoadjuvant chemotherapy were more likely to receive breast preservation than those who opted for primary surgery (odds ratio 1.7, 95% CI 1.6 to 1.8). CONCLUSIONS: Neoadjuvant chemotherapy increases breast preservation for patients with breast tumor size larger than 3 cm. (J Am Coll Surg 2015;-:1e7. 2015 by the American College of Surgeons) BACKGROUND:
performed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC), patients who undergo neoadjuvant chemotherapy typically have clinical response rates between 50% and 90% and pathologic complete response (pCR) rates from 4% to 30%.1-4 In these prospective studies, the rates of breast conservation for patients who received neoadjuvant chemotherapy compared with adjuvant therapy were 67% vs 60% (p ¼ 0.002), and 23% vs 18% (p not reported), respectively. Several smaller, single-institution studies have also demonstrated increased rates of lumpectomy after neoadjuvant chemotherapy.5-8 As systemic therapy becomes more targeted, the use of neoadjuvant chemotherapy for select patients has increased and pCR rates have improved,9 enabling more patients to potentially undergo breast preservation.
One of the benefits of neoadjuvant chemotherapy for operable breast cancer is that it may allow breast conservation in patients with tumors who would have otherwise required a mastectomy. Based on large randomized trials CME questions for this article available at http://jacscme.facs.org Disclosure Information: Authors have nothing to disclose. Timothy J Eberlein, Editor-in-Chief, has nothing to disclose. Presented at the 95th Annual Meeting of the New England Surgical Society, Stowe, VT, September 2014. Received October 30, 2014; Revised January 30, 2015; Accepted February 2, 2015. From the Departments of Surgery (Killelea, Horowitz, Chagpar, Lannin), Epidemiology (Yang), and Medicine (Mougalian, Pusztai), Yale University School of Medicine, and Yale Comprehensive Cancer Center, New Haven, CT 06520. Correspondence address: Brigid K Killelea, MD, MPH, FACS, Department of Surgery, Yale University School of Medicine, PO Box 208062, New Haven, CT 06520. email: [email protected]
ª 2015 by the American College of Surgeons Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jamcollsurg.2015.02.011 ISSN 1072-7515/15
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Killelea et al
Neoadjuvant Chemotherapy and Breast Preservation
There are many questions, however, that remain unanswered. How frequently are the results of these trials applied to increase breast preservation in general community practice? What is the lower limit of tumor size for which neoadjuvant chemotherapy increases breast preservation? The purpose of this study was to analyze national trends in the use of breast conservation therapy after neoadjuvant chemotherapy using the National Cancer Database (NCDB). In addition, we sought to identify clinicopathologic factors associated with higher rates of breast conservation.
METHODS The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society and contains about 80% of the cancer cases in the United States. After approval by the NCDB, patient de-identified data were downloaded from the website in January 2014 and analyzed in this study. Study population The population used for this study consisted of female patients with stage 1 to 3 invasive breast cancer diagnosed between 2006 and 2011, who underwent chemotherapy (either adjuvant or neoadjuvant) and definitive breast surgery (either mastectomy or lumpectomy). Patients who were clinical stage T4 were excluded because neoadjuvant chemotherapy followed by mastectomy is the standard of care for these patients. Treatment received Only patients who were known to have received chemotherapy were included in the study. Some, but not all, also received hormone therapy. The NCDB variable indicating the sequence of systemic therapy and surgery was used to determine the timing of chemotherapy. Patients who received both neoadjuvant and adjuvant therapy were classified in the neoadjuvant group. This variable, however, does not distinguish between chemotherapy and hormone therapy. Fortunately, other variables allowed determination of the time interval between diagnosis and chemotherapy, diagnosis and hormone therapy, and diagnosis and surgery. These variables confirmed that the sequence variable was internally consistent, and importantly, only about 1% of the group classified as receiving neoadjuvant chemotherapy actually received neoadjuvant hormone therapy followed by adjuvant chemotherapy. Tumor size and stage The NCDB variable, tumor size, is a combination of clinical and pathologic size. Tumor registrars were instructed
J Am Coll Surg
to use the pathologic size, if available, and if the patient had not had previous systemic therapy. However, if it was not available, or if neoadjuvant therapy had been given, they were instructed to use the best clinical size from imaging or physical exam before any treatment. The size was coded in 1-mm increments, but for this study, the size was converted to 10-mm increments, ie, from 1 mm to 10 mm, 11 mm to 20 mm, 21 mm to 30 mm, etc, so that breast preservation rates could be calculated for each size interval. The clinical American Joint Committee on Cancer stage was used to compare characteristics of the groups receiving adjuvant or neoadjuvant chemotherapy because we believed that comparing the pathologic stages would not be meaningful. However, the clinical American Joint Committee on Cancer stage information was missing for 26% of the study population. Statistical analysis Statistical analysis was performed with IBM SPSS version 19. Bivariate comparisons were performed with chisquare tests, and multivariable analysis for tumors larger than 3 cm was performed with binary logistic regression. Statistical tests were 2-sided, and values of p < 0.05 were considered significant.
RESULTS A total of 354,204 women in the NCDB met the study inclusion criteria. Characteristics of the overall group are shown in Table 1. The type of surgery and timing of chemotherapy are shown in Table 2. Over the study period, 169,376 (47.8%) patients underwent lumpectomy. Consistent with other national data demonstrating rising mastectomy rates in the US, the percentage of women who underwent lumpectomy decreased over time, from 51.3% in 2006 to 46.5% in 2011. There were 59,063 (16.7%) women who had neoadjuvant chemotherapy. Over the study period, the percentage of women who received neoadjuvant chemotherapy increased steadily, from 13.9% in 2006 to 20.5% in 2011 (p < 0.001). On univariate analysis, women who underwent breast conservation therapy tended to be older, African American, have private insurance, reside in New England, and receive treatment in a community setting (p < 0.001 for all). Women who received neoadjuvant chemotherapy tended to be younger, African American, be uninsured, reside in the southwestern part of the US, and receive treatment in an academic or research facility (p < 0.001 for all). Tumor characteristics associated with type of surgery and chemotherapy are shown in Table 3. Receipt of
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Characteristics
Total Age, y <50 >50 Race White Black Other Hispanic ethnicity Yes No Unknown Insurance None Private Medicaid Medicare Other government unknown Location New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific Facility type Community Comprehensive community cancer center Academic/research Other Year of diagnosis 2006 2007 2008 2009 2010 2011
n
%
354,204
100
135,840 218,364
38 62
288,108 46,938 19,158
81 13 5
21,012 305,403 27,789
6 86 8
9,189 237,246 28,196 70,576 3,923 5,074
3 67 8 20 1 1
20,831 52,365 77,663 64,406 9,153 28,275 28,705 15,852 43,474
6 15 22 18 6 8 8 4 12
37,798 209,468 103,905 3,033
11 59 29 1
59,649 61,292 61,327 62,359 55,102 54,475
17 17 17 18 16 15
neoadjuvant chemotherapy was clearly associated with larger tumor size: 7% of patients with clinical T1 tumors, vs 25% for T2, and 58% for T3, (p < 0.001). Receipt of neoadjuvant chemotherapy was also associated with more advanced nodal disease, younger age, higher tumor grade, and negative estrogen receptor status (all p < 0.001).
Neoadjuvant Chemotherapy and Breast Preservation
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As seen in Table 3, the majority of patients who received neoadjuvant chemotherapy had a mastectomy. Among the 59,063 women who had neoadjuvant chemotherapy, 38,144 (65%) had a mastectomy and 20,919 (35.4%) had a lumpectomy. Among those who had adjuvant chemotherapy, 50% had a lumpectomy and 50% had a mastectomy. Figure 1 shows that the likelihood of undergoing lumpectomy after adjuvant chemotherapy is related to tumor size. The majority of patients who presented with tumors smaller than 3 cm and received neoadjuvant chemotherapy had a mastectomy; however, for tumors larger than 3 cm, neoadjuvant chemotherapy consistently led to an increased rate of breast preservation. Table 4 shows a multivariable analysis of factors influencing breast conservation for tumors larger than 3 cm. After adjusting for all other demographic and tumorrelated variables, receipt of neoadjuvant chemotherapy was associated with a 70% increase in the odds of breast conservation surgery compared with receipt of adjuvant chemotherapy (odds ratio [OR] 1.7; 95% CI 1.6 to 1.8). For the years 2010 and 2011, a variable indicating whether or not neoadjuvant chemotherapy resulted in a pCR was added to the NCDB. During these years, a total of 7,880 patients received neoadjuvant chemotherapy, and the pCR rate was 29.7%. Among patients who had a pCR, the lumpectomy rate was 41.0% vs 26.8% if a pCR was not achieved (p < 0.001). Therefore, it appears that not only the receipt of neoadjuvant chemotherapy for larger tumors, but also the outcome of treatment, influenced rates of breast preservation.
DISCUSSION To our knowledge, this is the first study looking at national trends in the use of neoadjuvant chemotherapy and its relationship to the type of breast surgery. We found that the use of neoadjuvant chemotherapy was associated with later stage at diagnosis, young age, high grade tumors, and negative estrogen receptor status. Adjusted analysis revealed that women with tumors larger than 3 cm who received neoadjuvant chemotherapy were more likely to have breast conservation therapy compared with those who underwent surgery first. Neoadjuvant chemotherapy was first given in the 1970s to patients with locally advanced, inoperable breast cancer in hopes of converting them to mastectomy.10 Based on favorable clinical tumor responses observed in these patients, the use of neoadjuvant chemotherapy was later expanded to include patients with large tumors to convert them to lumpectomy and/or decrease the extent of surgery required to excise the tumor. Data suggest that patients who undergo neoadjuvant chemotherapy for tumors
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Table 2.
Type of Operation and Chemotherapy by Patient Characteristics
Characteristic
Age, y <50 >50 Race White Black Other Hispanic ethnicity Yes No Unknown Insurance None Private Medicaid Medicare Other government unknown Location New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific Facility type Community Comprehensive community cancer center Academic/research Other Diagnosis, y 2006 2007 2008 2009 2010 2011
J Am Coll Surg
Neoadjuvant Chemotherapy and Breast Preservation
Mastectomy, n (%) n %
Type of operation Lumpectomy, n (%) n %
p Value*
Type of chemotherapy Neoadjuvant, n (%) Adjuvant, n (%) n % n %
<0.001 77,026 107,802
57 49
58,814 110,562
43 51
151,420 22,942 10,466
53 49 55
136,688 23,996 8,692
47 51 45
11,512 158,950 14,366
55 52 52
9,500 146,453 13,423
45 48 48
5,204 121,606 16,037 37,000 2,137 2,844
57 51 57 52 54 56
3,985 115,640 12,159 33,576 1,786 2,230
43 49 43 48 46 44
9,300 25,150 40,780 32,188 13,615 16,146 16,828 8,507 22,314
45 48 53 50 60 57 59 54 51
11,531 27,215 36,883 32,218 9,018 12,129 11,877 7,345 21,160
55 52 47 50 40 43 41 46 49
18,996
50
18,802
109,095 55,154 1,583
52 53 52
29,046 31,131 32,284 33,472 29,763 29,132
49 51 57 54 54 53
p Value*
<0.001 28,225 30,838
21 14
107,615 187,526
79 86
45,567 9,994 3,502
16 21 18
242,541 36,944 15,656
84 79 82
4,550 50,324 4,189
22 16 15
16,462 255,079 23,600
78 84 85
2,261 39,838 6,578 8,761 701 924
25 17 23 12 18 18
6,928 197,408 21,618 61,815 3,222 4,150
75 83 77 88 82 82
3,409 7,515 13,975 9,892 3,649 4,340 6,089 2,491 7,703
16 14 18 15 16 15 21 16 18
17,422 44,850 63,688 54,514 18,984 23,935 22,616 13,361 35,771
84 86 82 85 84 85 79 84 82
50
4,905
13
32,893
87
100,373 48,751 1,450
48 47 48
33,941 19,803 414
16 19 14
175,527 84,102 2,619
84 81 86
30,603 30,161 29,043 28,887 25,339 25,343
51 49 47 46 46 47
8,283 9,146 9,558 10,408 10,500 11,168
14 15 16 17 19 20
51,366 52,146 51,769 51,951 44,602 43,307
86 85 84 83 81 80
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
*p Value for chi-square test.
greater than 2 cm have less tissue resected than those who receive adjuvant chemotherapy.11 Clinical experience with neoadjuvant chemotherapy demonstrated that tumors could successfully be downstaged and select patients could
be safely converted to breast conserving therapy. Additionally, the response to systemic therapy could be monitored by following the tumor response in the breast before surgery.
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Type of Operation and Chemotherapy by Tumor and Treatment Characteristics
Characteristic
Clinical tumor size T1 T2 T3 Clinical nodal status N0 N1 N2 N3 Grade 1 2 3 Estrogen receptor Positive Negative Progesterone receptor Positive Negative Type of chemotherapy Adjuvant Neoadjuvant
Mastectomy n %
Type of operation Lumpectomy n %
p Value*
Type of chemotherapy Neoadjuvant Adjuvant n % n %
<0.001 52,296 61,227 20,070
41 57 83
74,061 45,825 4,182
59 43 17
85,445 36,164 8,692 4,002
47 63 71 76
97,500 21,052 3,508 1,273
53 37 29 24
16,708 68,652 89,394
50 53 51
16,732 60,464 85,336
50 47 49
123,879 56,050
53 50
109,733 56,199
47 50
103,535 75,360
53 51
91,968 73,248
47 49
146,684 38,144
50 65
148,457 20,919
50 35
p Value*
<0.001 9,276 26,961 14,109
7 25 58
117,081 80,091 10,143
93 75 42
20,910 22,026 4,636 2,237
11 38 38 42
162,035 35,190 7,564 3,038
89 62 62 58
3,863 18,974 31,182
12 15 18
29,577 110,142 143,548
88 85 82
34,120 23,031
15 21
199,492 89,218
85 79
27,820 29,056
14 20
167,683 119,552
86 80
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001 d d
d d
*p Value for chi-square test.
Since that time, randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) were conducted in
Figure 1. Rates of breast preservation by tumor size. Blue line, adjuvant; orange line, neoadjuvant.
hopes that neoadjuvant chemotherapy would improve disease-free survival and overall survival. Although increased survival rates with neoadjuvant chemotherapy were not demonstrated, the data from these trials have demonstrated higher rates of breast conservation for these patients. Our observed national rate of breast conservation therapy among patients who underwent neoadjuvant chemotherapy of 35% is consistent with these data. In this study, we observed steadily increasing rates in the use of neoadjuvant chemotherapy across the United States, particularly for larger tumors. However, it is interesting to note that even for patients with extensive lymph node involvement and T3 tumors, approximately 60% and 42% received adjuvant chemotherapy, respectively. The reason that preoperative chemotherapy is not given to these patients more often is likely multifactorial, and includes patient preference, physician preference, hormone receptor status, tumor grade, and patient comorbidities, all of which could make initial surgery a better option than initial systemic chemotherapy. To our knowledge, this is the largest study looking at breast preservation with neoadjuvant chemotherapy across a range of tumor sizes. Although it is accepted that
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Neoadjuvant Chemotherapy and Breast Preservation
Table 4. Multivariable Analysis of Breast Preservation for Tumors Larger than Three Centimeters Variable
Age, y >50 <50 Race White Black Other Hispanic ethnicity No Yes Unknown Tumor characteristics Size (each cm increase) Clinical nodal status N0 N1 N2 N3 Grade 1 2 3 Estrogen receptor Negative Positive Type of chemotherapy Adjuvant Neoadjuvant
Odds ratio
95% CI
p Value
Reference 0.81
0.78e0.84
<0.001
Reference 1.57 0.91
1.49e1.65 0.84e0.98
<0.001 0.019
Reference 1.15 1.11
1.07e1.24 1.03e1.19
<0.001 0.007
0.72
0.71e0.73
<0.001
Reference 0.62 0.47 0.37
0.60e0.65 0.43e0.50 0.33e0.41
<0.001 <0.001 <0.001
Reference 1.03 1.34
0.95e1.11 1.24e1.45
0.513 <0.001
Reference 0.85
0.81e0.90
<0.001
Reference 1.70
1.64e1.77
<0.001
neoadjuvant chemotherapy increases rates of breast preservation for T3 tumors, this study shows that with respect to breast conservation therapy, it is beneficial for any clinical tumor size larger than 3 cm. This is consistent with a single-institution study demonstrating benefit for tumors between 2 and 4 cm.8 National Comprehensive Cancer Network guidelines also state that for stage IIA, IIB, and certain stage IIIA patients, if breast conservation is desired by the patient, preoperative chemotherapy should be considered. Our observations in this study further support this recommendation. We also report that the small proportion of women with tumors less than 3 cm, who underwent neoadjuvant chemotherapy, were also more likely to undergo mastectomy. It is not clear why women with small tumors would choose both neoadjuvant chemotherapy and mastectomy, but there are several possible explanations. Some women may have had multifocal or multicentric disease, although the largest focus was still small. Others may
J Am Coll Surg
have undergone neoadjuvant chemotherapy because of positive nodes, or triple negative or Her2 overexpressing tumors and also chose mastectomy because of the more aggressive biology despite a small tumor size. Some patients may have changed their preference for surgical treatment during the chemotherapy period. Last, it is also possible that some of this is due to incorrect data entry in the NCDB. The registrars are instructed to code the pre-chemotherapy tumor size for patients undergoing neoadjuvant chemotherapy. However, if they inadvertently coded the post-chemotherapy pathologic size, it is possible that some large tumors actually were considered as small tumors in this analysis. Recently, there has been interest in using the rate of pCR as a surrogate endpoint for event-free survival and overall survival.12 Strong correlations have been described between pCR and improved outcomes in patients with aggressive breast cancer subtypes, including the triple negative tumors and human epidermal growth factor receptor 2 (Her2) positive tumors, which tend to occur more commonly in younger women. We observed a correlation between pCR and lumpectomy rates. Although we also observed that younger women were more likely to undergo mastectomy, it will be interesting to see if a greater proportion of younger women elect breast conserving surgery in the future, as more of them are treated with newer anti Her2 agents, even for smaller tumors. Our study has some limitations. One of the drawbacks of breast conservation therapy after neoadjuvant chemotherapy is that it can be difficult to predict the extent and distribution of residual tumor, if any, before surgery. For example, although some tumors shrink concentrically, others show a patchy or discontinuous response over an area similar to the original tumor size, in a so called “swiss cheese” pattern. The latter type of response in the breast can make attainment of negative margins challenging. We are unable to comment on the number of patients who underwent neoadjuvant chemotherapy in hopes of pursuing a lumpectomy, but who ultimately had a mastectomy due to positive margins. Also, we did not study the use of neoadjuvant endocrine therapy, which can be an effective way to downstage estrogen receptor positive tumors, and its relationship to type of surgery.
CONCLUSIONS In summary, we observed increasing use of neoadjuvant chemotherapy among patients in the NCDB over the years 2006 to 2011. Neoadjuvant chemotherapy is associated with higher rates of breast preservation, particularly for large tumors, and should be considered for any breast tumor larger than 3 cm.
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Author Contributions Study conception and design: Killelea, Chagpar, Lannin Acquisition of data: Killelea, Yang, Lannin Analysis and interpretation of data: Killelea, Yang, Mougalian, Horowitz, Pusztai, Chagpar, Lannin Drafting of manuscript: Killelea, Yang, Lannin Critical revision: Killelea, Mougalian, Horowitz, Chagpar, Lannin REFERENCES 1. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15: 2483e2493. 2. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008; 26:778e785. 3. van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001;19:4224e4237. 4. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24:2019e2027. 5. Miller KD, McCaskill-Stenens W, Sisk J, et al. Combination versus sequential doxorubicin and docetaxel as primary
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6. 7.
8.
9.
10.
11.
12.
7
chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol 1999;17: 3033e3037. Heys SD, Hutcheon AW, Sarkar TK, et al. Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial. Clin Breast Cancer 2002;3[Suppl 2]:S69e74. Powles TJ, Hickish TF, Makris A, et al. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995;13: 547e552. Christy CJ, Thorsteinsson D, Grube BJ, et al. Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter. Ann Surg Oncol 2009;16: 697e702. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23:3676e3685. De Lena M, Zucali R, Vignaotti G, et al. Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol 1978;1:53e59. Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg 2006;244: 464e470. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164e172.
performed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC), patients who undergo neoadjuvant chemotherapy typically have clinical response rates between 50% and 90% and pathologic complete response (pCR) rates from 4% to 30%.1-4 In these prospective studies, the rates of breast conservation for patients who received neoadjuvant chemotherapy compared with adjuvant therapy were 67% vs 60% (p ¼ 0.002), and 23% vs 18% (p not reported), respectively. Several smaller, single-institution studies have also demonstrated increased rates of lumpectomy after neoadjuvant chemotherapy.5-8 As systemic therapy becomes more targeted, the use of neoadjuvant chemotherapy for select patients has increased and pCR rates have improved,9 enabling more patients to potentially undergo breast preservation.
One of the benefits of neoadjuvant chemotherapy for operable breast cancer is that it may allow breast conservation in patients with tumors who would have otherwise required a mastectomy. Based on large randomized trials CME questions for this article available at http://jacscme.facs.org Disclosure Information: Authors have nothing to disclose. Timothy J Eberlein, Editor-in-Chief, has nothing to disclose. Presented at the 95th Annual Meeting of the New England Surgical Society, Stowe, VT, September 2014. Received October 30, 2014; Revised January 30, 2015; Accepted February 2, 2015. From the Departments of Surgery (Killelea, Horowitz, Chagpar, Lannin), Epidemiology (Yang), and Medicine (Mougalian, Pusztai), Yale University School of Medicine, and Yale Comprehensive Cancer Center, New Haven, CT 06520. Correspondence address: Brigid K Killelea, MD, MPH, FACS, Department of Surgery, Yale University School of Medicine, PO Box 208062, New Haven, CT 06520. email: [email protected]
ª 2015 by the American College of Surgeons Published by Elsevier Inc.
1
http://dx.doi.org/10.1016/j.jamcollsurg.2015.02.011 ISSN 1072-7515/15
2
Killelea et al
Neoadjuvant Chemotherapy and Breast Preservation
There are many questions, however, that remain unanswered. How frequently are the results of these trials applied to increase breast preservation in general community practice? What is the lower limit of tumor size for which neoadjuvant chemotherapy increases breast preservation? The purpose of this study was to analyze national trends in the use of breast conservation therapy after neoadjuvant chemotherapy using the National Cancer Database (NCDB). In addition, we sought to identify clinicopathologic factors associated with higher rates of breast conservation.
METHODS The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society and contains about 80% of the cancer cases in the United States. After approval by the NCDB, patient de-identified data were downloaded from the website in January 2014 and analyzed in this study. Study population The population used for this study consisted of female patients with stage 1 to 3 invasive breast cancer diagnosed between 2006 and 2011, who underwent chemotherapy (either adjuvant or neoadjuvant) and definitive breast surgery (either mastectomy or lumpectomy). Patients who were clinical stage T4 were excluded because neoadjuvant chemotherapy followed by mastectomy is the standard of care for these patients. Treatment received Only patients who were known to have received chemotherapy were included in the study. Some, but not all, also received hormone therapy. The NCDB variable indicating the sequence of systemic therapy and surgery was used to determine the timing of chemotherapy. Patients who received both neoadjuvant and adjuvant therapy were classified in the neoadjuvant group. This variable, however, does not distinguish between chemotherapy and hormone therapy. Fortunately, other variables allowed determination of the time interval between diagnosis and chemotherapy, diagnosis and hormone therapy, and diagnosis and surgery. These variables confirmed that the sequence variable was internally consistent, and importantly, only about 1% of the group classified as receiving neoadjuvant chemotherapy actually received neoadjuvant hormone therapy followed by adjuvant chemotherapy. Tumor size and stage The NCDB variable, tumor size, is a combination of clinical and pathologic size. Tumor registrars were instructed
J Am Coll Surg
to use the pathologic size, if available, and if the patient had not had previous systemic therapy. However, if it was not available, or if neoadjuvant therapy had been given, they were instructed to use the best clinical size from imaging or physical exam before any treatment. The size was coded in 1-mm increments, but for this study, the size was converted to 10-mm increments, ie, from 1 mm to 10 mm, 11 mm to 20 mm, 21 mm to 30 mm, etc, so that breast preservation rates could be calculated for each size interval. The clinical American Joint Committee on Cancer stage was used to compare characteristics of the groups receiving adjuvant or neoadjuvant chemotherapy because we believed that comparing the pathologic stages would not be meaningful. However, the clinical American Joint Committee on Cancer stage information was missing for 26% of the study population. Statistical analysis Statistical analysis was performed with IBM SPSS version 19. Bivariate comparisons were performed with chisquare tests, and multivariable analysis for tumors larger than 3 cm was performed with binary logistic regression. Statistical tests were 2-sided, and values of p < 0.05 were considered significant.
RESULTS A total of 354,204 women in the NCDB met the study inclusion criteria. Characteristics of the overall group are shown in Table 1. The type of surgery and timing of chemotherapy are shown in Table 2. Over the study period, 169,376 (47.8%) patients underwent lumpectomy. Consistent with other national data demonstrating rising mastectomy rates in the US, the percentage of women who underwent lumpectomy decreased over time, from 51.3% in 2006 to 46.5% in 2011. There were 59,063 (16.7%) women who had neoadjuvant chemotherapy. Over the study period, the percentage of women who received neoadjuvant chemotherapy increased steadily, from 13.9% in 2006 to 20.5% in 2011 (p < 0.001). On univariate analysis, women who underwent breast conservation therapy tended to be older, African American, have private insurance, reside in New England, and receive treatment in a community setting (p < 0.001 for all). Women who received neoadjuvant chemotherapy tended to be younger, African American, be uninsured, reside in the southwestern part of the US, and receive treatment in an academic or research facility (p < 0.001 for all). Tumor characteristics associated with type of surgery and chemotherapy are shown in Table 3. Receipt of
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2015
Patient Characteristics
Characteristics
Total Age, y <50 >50 Race White Black Other Hispanic ethnicity Yes No Unknown Insurance None Private Medicaid Medicare Other government unknown Location New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific Facility type Community Comprehensive community cancer center Academic/research Other Year of diagnosis 2006 2007 2008 2009 2010 2011
n
%
354,204
100
135,840 218,364
38 62
288,108 46,938 19,158
81 13 5
21,012 305,403 27,789
6 86 8
9,189 237,246 28,196 70,576 3,923 5,074
3 67 8 20 1 1
20,831 52,365 77,663 64,406 9,153 28,275 28,705 15,852 43,474
6 15 22 18 6 8 8 4 12
37,798 209,468 103,905 3,033
11 59 29 1
59,649 61,292 61,327 62,359 55,102 54,475
17 17 17 18 16 15
neoadjuvant chemotherapy was clearly associated with larger tumor size: 7% of patients with clinical T1 tumors, vs 25% for T2, and 58% for T3, (p < 0.001). Receipt of neoadjuvant chemotherapy was also associated with more advanced nodal disease, younger age, higher tumor grade, and negative estrogen receptor status (all p < 0.001).
Neoadjuvant Chemotherapy and Breast Preservation
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As seen in Table 3, the majority of patients who received neoadjuvant chemotherapy had a mastectomy. Among the 59,063 women who had neoadjuvant chemotherapy, 38,144 (65%) had a mastectomy and 20,919 (35.4%) had a lumpectomy. Among those who had adjuvant chemotherapy, 50% had a lumpectomy and 50% had a mastectomy. Figure 1 shows that the likelihood of undergoing lumpectomy after adjuvant chemotherapy is related to tumor size. The majority of patients who presented with tumors smaller than 3 cm and received neoadjuvant chemotherapy had a mastectomy; however, for tumors larger than 3 cm, neoadjuvant chemotherapy consistently led to an increased rate of breast preservation. Table 4 shows a multivariable analysis of factors influencing breast conservation for tumors larger than 3 cm. After adjusting for all other demographic and tumorrelated variables, receipt of neoadjuvant chemotherapy was associated with a 70% increase in the odds of breast conservation surgery compared with receipt of adjuvant chemotherapy (odds ratio [OR] 1.7; 95% CI 1.6 to 1.8). For the years 2010 and 2011, a variable indicating whether or not neoadjuvant chemotherapy resulted in a pCR was added to the NCDB. During these years, a total of 7,880 patients received neoadjuvant chemotherapy, and the pCR rate was 29.7%. Among patients who had a pCR, the lumpectomy rate was 41.0% vs 26.8% if a pCR was not achieved (p < 0.001). Therefore, it appears that not only the receipt of neoadjuvant chemotherapy for larger tumors, but also the outcome of treatment, influenced rates of breast preservation.
DISCUSSION To our knowledge, this is the first study looking at national trends in the use of neoadjuvant chemotherapy and its relationship to the type of breast surgery. We found that the use of neoadjuvant chemotherapy was associated with later stage at diagnosis, young age, high grade tumors, and negative estrogen receptor status. Adjusted analysis revealed that women with tumors larger than 3 cm who received neoadjuvant chemotherapy were more likely to have breast conservation therapy compared with those who underwent surgery first. Neoadjuvant chemotherapy was first given in the 1970s to patients with locally advanced, inoperable breast cancer in hopes of converting them to mastectomy.10 Based on favorable clinical tumor responses observed in these patients, the use of neoadjuvant chemotherapy was later expanded to include patients with large tumors to convert them to lumpectomy and/or decrease the extent of surgery required to excise the tumor. Data suggest that patients who undergo neoadjuvant chemotherapy for tumors
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Table 2.
Type of Operation and Chemotherapy by Patient Characteristics
Characteristic
Age, y <50 >50 Race White Black Other Hispanic ethnicity Yes No Unknown Insurance None Private Medicaid Medicare Other government unknown Location New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific Facility type Community Comprehensive community cancer center Academic/research Other Diagnosis, y 2006 2007 2008 2009 2010 2011
J Am Coll Surg
Neoadjuvant Chemotherapy and Breast Preservation
Mastectomy, n (%) n %
Type of operation Lumpectomy, n (%) n %
p Value*
Type of chemotherapy Neoadjuvant, n (%) Adjuvant, n (%) n % n %
<0.001 77,026 107,802
57 49
58,814 110,562
43 51
151,420 22,942 10,466
53 49 55
136,688 23,996 8,692
47 51 45
11,512 158,950 14,366
55 52 52
9,500 146,453 13,423
45 48 48
5,204 121,606 16,037 37,000 2,137 2,844
57 51 57 52 54 56
3,985 115,640 12,159 33,576 1,786 2,230
43 49 43 48 46 44
9,300 25,150 40,780 32,188 13,615 16,146 16,828 8,507 22,314
45 48 53 50 60 57 59 54 51
11,531 27,215 36,883 32,218 9,018 12,129 11,877 7,345 21,160
55 52 47 50 40 43 41 46 49
18,996
50
18,802
109,095 55,154 1,583
52 53 52
29,046 31,131 32,284 33,472 29,763 29,132
49 51 57 54 54 53
p Value*
<0.001 28,225 30,838
21 14
107,615 187,526
79 86
45,567 9,994 3,502
16 21 18
242,541 36,944 15,656
84 79 82
4,550 50,324 4,189
22 16 15
16,462 255,079 23,600
78 84 85
2,261 39,838 6,578 8,761 701 924
25 17 23 12 18 18
6,928 197,408 21,618 61,815 3,222 4,150
75 83 77 88 82 82
3,409 7,515 13,975 9,892 3,649 4,340 6,089 2,491 7,703
16 14 18 15 16 15 21 16 18
17,422 44,850 63,688 54,514 18,984 23,935 22,616 13,361 35,771
84 86 82 85 84 85 79 84 82
50
4,905
13
32,893
87
100,373 48,751 1,450
48 47 48
33,941 19,803 414
16 19 14
175,527 84,102 2,619
84 81 86
30,603 30,161 29,043 28,887 25,339 25,343
51 49 47 46 46 47
8,283 9,146 9,558 10,408 10,500 11,168
14 15 16 17 19 20
51,366 52,146 51,769 51,951 44,602 43,307
86 85 84 83 81 80
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
*p Value for chi-square test.
greater than 2 cm have less tissue resected than those who receive adjuvant chemotherapy.11 Clinical experience with neoadjuvant chemotherapy demonstrated that tumors could successfully be downstaged and select patients could
be safely converted to breast conserving therapy. Additionally, the response to systemic therapy could be monitored by following the tumor response in the breast before surgery.
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Table 3.
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Neoadjuvant Chemotherapy and Breast Preservation
5
Type of Operation and Chemotherapy by Tumor and Treatment Characteristics
Characteristic
Clinical tumor size T1 T2 T3 Clinical nodal status N0 N1 N2 N3 Grade 1 2 3 Estrogen receptor Positive Negative Progesterone receptor Positive Negative Type of chemotherapy Adjuvant Neoadjuvant
Mastectomy n %
Type of operation Lumpectomy n %
p Value*
Type of chemotherapy Neoadjuvant Adjuvant n % n %
<0.001 52,296 61,227 20,070
41 57 83
74,061 45,825 4,182
59 43 17
85,445 36,164 8,692 4,002
47 63 71 76
97,500 21,052 3,508 1,273
53 37 29 24
16,708 68,652 89,394
50 53 51
16,732 60,464 85,336
50 47 49
123,879 56,050
53 50
109,733 56,199
47 50
103,535 75,360
53 51
91,968 73,248
47 49
146,684 38,144
50 65
148,457 20,919
50 35
p Value*
<0.001 9,276 26,961 14,109
7 25 58
117,081 80,091 10,143
93 75 42
20,910 22,026 4,636 2,237
11 38 38 42
162,035 35,190 7,564 3,038
89 62 62 58
3,863 18,974 31,182
12 15 18
29,577 110,142 143,548
88 85 82
34,120 23,031
15 21
199,492 89,218
85 79
27,820 29,056
14 20
167,683 119,552
86 80
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001 d d
d d
*p Value for chi-square test.
Since that time, randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) were conducted in
Figure 1. Rates of breast preservation by tumor size. Blue line, adjuvant; orange line, neoadjuvant.
hopes that neoadjuvant chemotherapy would improve disease-free survival and overall survival. Although increased survival rates with neoadjuvant chemotherapy were not demonstrated, the data from these trials have demonstrated higher rates of breast conservation for these patients. Our observed national rate of breast conservation therapy among patients who underwent neoadjuvant chemotherapy of 35% is consistent with these data. In this study, we observed steadily increasing rates in the use of neoadjuvant chemotherapy across the United States, particularly for larger tumors. However, it is interesting to note that even for patients with extensive lymph node involvement and T3 tumors, approximately 60% and 42% received adjuvant chemotherapy, respectively. The reason that preoperative chemotherapy is not given to these patients more often is likely multifactorial, and includes patient preference, physician preference, hormone receptor status, tumor grade, and patient comorbidities, all of which could make initial surgery a better option than initial systemic chemotherapy. To our knowledge, this is the largest study looking at breast preservation with neoadjuvant chemotherapy across a range of tumor sizes. Although it is accepted that
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Neoadjuvant Chemotherapy and Breast Preservation
Table 4. Multivariable Analysis of Breast Preservation for Tumors Larger than Three Centimeters Variable
Age, y >50 <50 Race White Black Other Hispanic ethnicity No Yes Unknown Tumor characteristics Size (each cm increase) Clinical nodal status N0 N1 N2 N3 Grade 1 2 3 Estrogen receptor Negative Positive Type of chemotherapy Adjuvant Neoadjuvant
Odds ratio
95% CI
p Value
Reference 0.81
0.78e0.84
<0.001
Reference 1.57 0.91
1.49e1.65 0.84e0.98
<0.001 0.019
Reference 1.15 1.11
1.07e1.24 1.03e1.19
<0.001 0.007
0.72
0.71e0.73
<0.001
Reference 0.62 0.47 0.37
0.60e0.65 0.43e0.50 0.33e0.41
<0.001 <0.001 <0.001
Reference 1.03 1.34
0.95e1.11 1.24e1.45
0.513 <0.001
Reference 0.85
0.81e0.90
<0.001
Reference 1.70
1.64e1.77
<0.001
neoadjuvant chemotherapy increases rates of breast preservation for T3 tumors, this study shows that with respect to breast conservation therapy, it is beneficial for any clinical tumor size larger than 3 cm. This is consistent with a single-institution study demonstrating benefit for tumors between 2 and 4 cm.8 National Comprehensive Cancer Network guidelines also state that for stage IIA, IIB, and certain stage IIIA patients, if breast conservation is desired by the patient, preoperative chemotherapy should be considered. Our observations in this study further support this recommendation. We also report that the small proportion of women with tumors less than 3 cm, who underwent neoadjuvant chemotherapy, were also more likely to undergo mastectomy. It is not clear why women with small tumors would choose both neoadjuvant chemotherapy and mastectomy, but there are several possible explanations. Some women may have had multifocal or multicentric disease, although the largest focus was still small. Others may
J Am Coll Surg
have undergone neoadjuvant chemotherapy because of positive nodes, or triple negative or Her2 overexpressing tumors and also chose mastectomy because of the more aggressive biology despite a small tumor size. Some patients may have changed their preference for surgical treatment during the chemotherapy period. Last, it is also possible that some of this is due to incorrect data entry in the NCDB. The registrars are instructed to code the pre-chemotherapy tumor size for patients undergoing neoadjuvant chemotherapy. However, if they inadvertently coded the post-chemotherapy pathologic size, it is possible that some large tumors actually were considered as small tumors in this analysis. Recently, there has been interest in using the rate of pCR as a surrogate endpoint for event-free survival and overall survival.12 Strong correlations have been described between pCR and improved outcomes in patients with aggressive breast cancer subtypes, including the triple negative tumors and human epidermal growth factor receptor 2 (Her2) positive tumors, which tend to occur more commonly in younger women. We observed a correlation between pCR and lumpectomy rates. Although we also observed that younger women were more likely to undergo mastectomy, it will be interesting to see if a greater proportion of younger women elect breast conserving surgery in the future, as more of them are treated with newer anti Her2 agents, even for smaller tumors. Our study has some limitations. One of the drawbacks of breast conservation therapy after neoadjuvant chemotherapy is that it can be difficult to predict the extent and distribution of residual tumor, if any, before surgery. For example, although some tumors shrink concentrically, others show a patchy or discontinuous response over an area similar to the original tumor size, in a so called “swiss cheese” pattern. The latter type of response in the breast can make attainment of negative margins challenging. We are unable to comment on the number of patients who underwent neoadjuvant chemotherapy in hopes of pursuing a lumpectomy, but who ultimately had a mastectomy due to positive margins. Also, we did not study the use of neoadjuvant endocrine therapy, which can be an effective way to downstage estrogen receptor positive tumors, and its relationship to type of surgery.
CONCLUSIONS In summary, we observed increasing use of neoadjuvant chemotherapy among patients in the NCDB over the years 2006 to 2011. Neoadjuvant chemotherapy is associated with higher rates of breast preservation, particularly for large tumors, and should be considered for any breast tumor larger than 3 cm.
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Author Contributions Study conception and design: Killelea, Chagpar, Lannin Acquisition of data: Killelea, Yang, Lannin Analysis and interpretation of data: Killelea, Yang, Mougalian, Horowitz, Pusztai, Chagpar, Lannin Drafting of manuscript: Killelea, Yang, Lannin Critical revision: Killelea, Mougalian, Horowitz, Chagpar, Lannin REFERENCES 1. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15: 2483e2493. 2. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008; 26:778e785. 3. van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001;19:4224e4237. 4. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24:2019e2027. 5. Miller KD, McCaskill-Stenens W, Sisk J, et al. Combination versus sequential doxorubicin and docetaxel as primary
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