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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2650-2655 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.2271 Residual Ductal Carcinoma In Situ in Patients With Complete Eradication of Invasive Breast Cancer After Neoadjuvant Chemotherapy Does Not Adversely Affect Patient Outcome
From the Departments of Breast Medical Oncology, Pathology, and Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Lajos Pusztai, MD, The University of Texas M.D. Anderson Cancer Center, Department of Breast Medical Oncology, Unit 1354, PO Box 301439, Houston, TX 77230-1439; e-mail: lpusztai{at}mdanderson.org
Purpose: To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer. Patients and Methods: Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS). Results: The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63). Conclusion: Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.
The extent of pathologic response to neoadjuvant (preoperative) chemotherapy is a direct measure of drug sensitivity and correlates with survival.1-4 Pathologic complete response (pCR) in particular heralds excellent long-term survival.5,6 This end point is increasingly adopted as a measure of activity for neoadjuvant chemotherapy regimens and also for biomarker studies to discover predictors of response to therapy.7-10 However, the definition of pCR remains controversial. The National Surgical Adjuvant Bowel and Breast Project defines pCR as no residual invasive cancer in the breast but allows for ductal carcinoma in situ (DCIS) and for positive axillary lymph nodes. pCR in the breast correlates closely with the absence of metastatic lymph nodes in the axilla; however, the small subset of patients who have positive nodes, despite complete response (CR) in the breast, have high recurrence rates.11 Inclusion of these patients in the pCR category weakens the prognostic and predictive value of this end point. Other investigators adopted a narrower definition that includes only patients with no residual invasive cancer in the breast or lymph nodes, but residual DCIS is still considered pCR.2,5,12,13 A recent consensus statement by an expert panel suggested that the definition of pCR must not include any residual invasive or in situ cancer in the breast or lymph nodes.14 Exclusion of patients with residual DCIS from the definition of pCR results in a scientifically pure definition; however, it also weakens the clinical utility of this outcome. pCR, by any definition, is uncommon. The reported pCR rates range from 10% to 25% for most chemotherapy regimens.15 A restrictive and purist definition of CR further reduces the number of informative patients. This is particularly relevant for biomarker studies and when pCR is used as an early surrogate for long-term benefit from chemotherapy. In the absence of a sufficient number of surrogate events, these studies become severely underpowered. A critical question that remains unanswered is whether inclusion of patients with residual DCIS among patients with pCR results in decreased recurrence-free or overall survival (OS). Few studies have examined this question, and none did so with a large enough sample size to draw a definite conclusion. The purpose of our study was to assess whether the presence of residual DCIS after preoperative chemotherapy affects the outcome of patients with pCR in invasive cancer.
Patients Two thousand three hundred two patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Canter between 1980 and 2004 were included in this analysis. Patients gave informed consent for inclusion of their results in a prospectively maintained database. The database includes all patients who received neoadjuvant chemotherapy on a series of sequentially conducted prospective clinical trials or as standard of care.5,16 The follow-up information on disease status was last updated in December 2005. The M.D. Anderson Cancer Canter Institutional Review Board approved the retrospective review of these patients. Patient characteristics are listed in Table 1. The median age of all patients was 49 years (range, 15 to 83 years). Fifty-two percent of patients were postmenopausal at time of the diagnosis of breast cancer. Of the 2,302 patients, 66.3% were white, 14.9% were Hispanic, 14.2% were black, and 2.5% were Asian. The race was not recorded in 2% of patients.
Treatment One thousand two hundred patients (52.1%) received anthracycline-based chemotherapy without a taxane, 971 patients (42.2%) received a combination of anthracycline and taxane, and 131 patients (5.7%) received single-agent paclitaxel preoperative chemotherapy. Patients who received single-agent paclitaxel preoperatively also received four courses of anthracycline-based adjuvant chemotherapy. The treatment regimens included fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 856 patients; FAC and paclitaxel in 567 patients; vincristine, doxorubicin, cyclophosphamide, and prednisone in 128 patients; paclitaxel, fluorouracil, epirubicin, and cyclophosphamide in 88 patients; doxorubicin and docetaxel in 87 patients; doxorubicin and cyclophosphamide in 79 patients; docetaxel and FAC in 62 patients; and doxorubicin and docetaxel in 65 patients. Two hundred thirty-eight patients received a variety of less commonly used combination chemotherapy regimens. No patients received preoperative trastuzumab.
After completion of neoadjuvant chemotherapy, patients who were considered candidates for breast conservation therapy (BCT) were offered breast-conserving surgery with axillary lymph node dissection or, more recently, with sentinel lymph node biopsy for clinically node-negative patients (n = 698). Patients who had contraindications to radiation therapy or had multicentric disease at presentation, extensive suspicious microcalcification on mammography, residual skin edema after chemotherapy, or residual tumor size too large to allow for resection with adequate cosmesis were considered inappropriate for BCT. These patients and individuals who did not desire BCT underwent mastectomy (n = 1,579). In 25 patients (1.1%), the type of surgery could not be ascertained. If the surgical margins were involved with invasive or in situ cancer or were close (< 2 mm), repeat resection was performed to assure clear margins as per institutional treatment guidelines. All patients treated with BCT received whole-breast irradiation. For patients treated with mastectomy, chest wall and regional nodal irradiation, including the supraclavicular fossa, was performed if the patient presented with clinical stage III disease or there were
Pathology Assessment
Statistics
Pathologic Response Of the 2,302 patients, 199 (9%) had no residual invasive or in situ cancer in the breast and lymph nodes (hereafter referred to as pCR). Seventy-eight patients (3%) had persistent DCIS but no residual invasive cancer in the breast or nodes (pCR+DCIS). Two thousand twenty-five patients (88%) had various extents of residual invasive cancer. Some component of DCIS was present in the pathology of 983 patients (43%) after chemotherapy, including the 78 patients with residual DCIS alone. Patients with pCR were more likely to have ER-negative breast cancer (84%) than patients with pCR+DCIS (60%; P < .001; Table 2). There is no clear biologic explanation for this difference. However, the ER status of invasive cancer and adjacent DCIS is frequently (but not always) concordant. ER-negative invasive cancers are usually more sensitive to chemotherapy than ER-positive disease, and invasive cancer in general may be more sensitive to chemotherapy than DCIS. It is tempting to speculate that ER-positive DCIS is a particularly chemotherapy-resistant entity that can survive treatment even when the adjacent ER-positive invasive cancer is completely eradicated. Breast-conserving surgery was also more frequent in patients with pCR (58%) than in patients with pCR+DCIS (38%; P = .006). A possible explanation for this is that patients with residual DCIS may have had more extensive residual imaging and clinical abnormalities, and therefore, a more conservative surgical approach was taken.
Survival Analysis The mean follow-up time was 250 months for all patients, and it was 201 months for patients with pCR and 212 months for patients with pCR+DCIS. Seventy-six percent of all patients were alive at 5 years, and 63% were alive at 10 years. The 5-year OS rate for patients who achieved pCR was 92% (95% CI, 85% to 96%) and was not significantly different from the rate of patients who had pCR+DCIS (92.5%; 95% CI, 81% to 98%). The 10-year OS rates were also essentially identical (92%; 95% CI, 85% to 96% for pCR v 92.5%; 95% CI, 81% to 98% for pCR+DCIS; P = .92; Fig 1). There were nine deaths among the patients with pCR and four deaths among patients with pCR+DCIS at a mean follow-up time of 201 and 212 months, respectively. Patients with any residual invasive cancer had significantly poorer 5- and 10-year survival rates (74%; 95% CI, 72% to 77%; and 60%; 95% CI, 56% to 63%, respectively) compared with patients with pCR (with or without DCIS; P < .001). In the Cox proportional hazards models for the entire population, smaller initial clinical tumor size (P < .001), ER-positive status (P < .001), lobular histology (P = .02), pCR regardless of presence of residual DCIS (P < .001), and type of surgery performed (P = .002) were significantly associated with longer OS.
The mean DFS time was 175 months for all patients. Sixty-three percent of patients (95% CI, 61% to 65%) were disease free at 5 years, and 53% were disease free at 10 years. The 5- and 10-year DFS rates were identical for the patients with pCR versus pCR+DCIS (87% v 87% and 81% v 82%, respectively; P = .89; Fig 2). The mean DFS was similar for patients who had pCR with DCIS compared with patients with pCR without DCIS at median follow-up times of 194 months (eight events) and 181 months (19 events; P = .99). Patients with residual invasive disease had significantly lower DFS rates (60%; 95% CI, 58% to 63%; P < .001) than patients with pCR (pCR or pCR+DCIS). We used the 95% CIs for the Kaplan-Meier estimates to compute an approximate variance for the difference in the two 5-year estimates and thereby the 95% CI for the difference. The difference is 0.2%, with approximate 95% CIs from –11% to 9%. Thus, there are adequate data to exclude differences in 5-year survival probabilities of more than approximately 10% but not smaller differences. In multivariate analysis, smaller initial clinical tumor size (P < .001), ER-positive status (P < .001), older age (P = .04), and pCR with or without DCIS (P < .001) were significantly associated with longer DFS.
The locoregional recurrence-free survival rates at 5 years were also not different between patients with pCR (93%; 95% CI, 86% to 96%) and pCR+DCIS (91%; 95% CI, 77% to 96%; P = .63; Fig 3). In the group with pCR+DCIS, five patients (6%) experienced local recurrence, including one recurrence in a supraclavicular node, three in the breast, and one on the chest wall. In the group with pCR (without residual DCIS), 11 patients (5%) developed local recurrence, including eight in the breast, one on the chest wall, and two in the axillary lymph nodes.
We examined OS, DFS, and local recurrence-free survival of breast cancer patients with pCR with (n = 79) or without (n = 199) residual DCIS after neoadjuvant chemotherapy. The 5- and 10-year survival rates were essentially identical for these two groups and also not significantly different for any other outcome. Patients with pCR, regardless of the presence or absence of DCIS, had significantly better OS and DFS than patients with residual invasive cancer. These observations are consistent with several previously published results of smaller patient series. A recent study compared the prognosis of 30 patients with pCR and 20 patients with pCR+DCIS after neoadjuvant chemotherapy in a similar manner to our study.18 The investigators observed no significant difference in 5-year OS and DFS rates between the two groups; however, because of the small sample size, they could not draw a definitive conclusion from the study. Another small study compared the combined outcome of 15 patients with pCR (n = 10) and pCR+DCIS (n = 5) with the outcome of patients who had residual invasive cancer (n = 61) and also reported significantly better DFS for the pCR groups regardless of presence or absence of DCIS.19 These findings are in clear contrast with the findings of studies that examined the impact of positive lymph nodes after preoperative chemotherapy. Even if no residual invasive cancer is found in the breast, positive nodes predict for poor prognosis.11,20 Inclusion of patients with positive nodes in the definition of pCR weakens its prognostic value and results in a less than optimal early surrogate. Considering that DCIS is by definition a local disease, it is not surprising that residual DCIS after chemotherapy has little impact on OS or distant metastatic recurrence. In fact, the OS of patients with DCIS (without invasive cancer) is identical to or even slightly higher than the general population based on the US National Cancer Institute Surveillance, Epidemiology, and End Results data.21 However, local recurrences may occur in 5% to 15% of patients with DCIS who have undergone breast-conserving surgery and radiation therapy.22,23 Therefore, it was important to examine whether local recurrence rates differed among patients with residual DCIS and patients with no residual invasive or in situ cancer. We observed no difference in locoregional recurrence rates between these two response groups. It is important to emphasize that the risk of local recurrence after DCIS depends not only on the size and histologic features of the lesion but also on the type of therapy that is administered.24 Recurrence after mastectomy is low, and achievement of clear surgical margins, postlumpectomy radiation, and 5 years of adjuvant tamoxifen can each reduce the risk of recurrence after BCT.22-25 In the current study, most patients with pCR+DCIS had mastectomy, and all patients who underwent BCT had clear margins and completed postlumpectomy radiation therapy, and all ER-positive postmenopausal women were recommended to receive 5 years of adjuvant tamoxifen that was indicated for their invasive cancer. It is biologically quite intriguing that DCIS, not unlike normal breast epithelium, often survives chemotherapy. Differences in proliferation rate cannot fully explain the greater chemotherapy resistance of in situ cancer because these lesions frequently have growth fractions higher than corresponding normal tissues and similar to that seen in invasive cancers.26,27 It is possible that physiologic resistance mechanisms that protect normal cells from cytotoxic insults remain more intact in in situ cancers compared with invasive tumors.28 However, greater drug resistance of these tumors may be of limited clinical relevance because, by definition, in situ cancers do not metastasize. Occasionally, distant recurrences have been observed after treatment for DCIS in the absence of any local invasive recurrence.29 However, the relationship between the metastatic cancer and the preceding DCIS remains uncertain. It is plausible that, in some patients, a small but aggressive primary invasive cancer went undetected during the original diagnosis. It is also possible that these incidents represent unknown primary cancers and the personal history of DCIS is a mere coincidence. In conclusion, we found no evidence in our analysis or in the published literature that residual DCIS confers any significant adverse prognostic effect for patients who experience complete eradication of the invasive cancer from the breast and lymph nodes after preoperative chemotherapy. Not including these patients in the pCR category could result in discarding close to 40% of informative patients (78 of 277 pCR eligible patients in the current study). Furthermore, inclusion of patients with persistent DCIS but no residual invasive cancer in the breast within the residual disease category will inflate the outcome for this group and can also confound the results of biomarker studies that aim to discover predictors of response. Given these considerations, we feel that it is justified to include residual DCIS in the definition of pCR when this outcome is used as an early surrogate for long-term survival.
The author(s) indicated no potential conflicts of interest.
Conception and design: Chafika Mazouni, Lajos Pusztai Provision of study materials or patients: Ana M. Gonzalez-Angulo, Shu Wan-Kau Collection and assembly of data: Chafika Mazouni, Shu Wan-Kau, Florentia Peintinger Data analysis and interpretation: Chafika Mazouni, Lajos Pusztai, W. Fraser Symmans Manuscript writing: Chafika Mazouni, Florentia Peintinger, Gabriel N. Hortobagyi, Lajos Pusztai Final approval of manuscript: Fabrice Andre, Ana M. Gonzalez-Angulo, W. Fraser Symmans, Funda Meric-Bernstam, Vicente Valero, Gabriel N. Hortobagyi, Lajos Pusztai
Supported by Grant No. RO1-CA106290 from the National Cancer Institute and by the Breast Cancer Research Foundation, the Gilder Foundation, the Dee Simmons Fund, and the Nellie B. Connally Breast Cancer Research Fund. Also supported by grants from the Fondation de France and Federation Nationale des Centres de Lutte Contre le Cancer, Paris, France (C.M. and F.A.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract] 2. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic neoadjuvant tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999 3. Carey LA, Metzger R, Dees EC, et al: American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst 97:1137-1142, 2005 4. Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: A unicentre randomized trial with a 124-month median follow-up—Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol 10:47-52, 1999 5. Guarneri V, Broglio K, Kau SW, et al: Prognostic value of pathologic complete response after neoadjuvant chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24:1037-1044, 2006 6. Amat S, Abrial C, Penault-Llorca F, et al: High prognostic significance of residual disease after neoadjuvant chemotherapy: A retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat 94:255-263, 2005[CrossRef][Medline] 7. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003 8. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983-5992, 2005 9. Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284-2293, 2004 10. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23:7265-7277, 2005 11. Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic significance of complete axillary down-staging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 20:1304-1310, 2002 12. Ogston KN, Miller ID, Payne S, et al: A new histological grading system to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival. Breast 12:320-327, 2003[CrossRef][Medline] 13. Sataloff DM, Mason BA, Prestipino AJ, et al: Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: A determinant of outcome. J Am Coll Surg 180:297-306, 1995[Medline] 14. Kaufmann M, Hortobagyi GN, Goldhirsch A, et al: Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: An update. J Clin Oncol 24:1940-1949, 2006 15. Estevez LG, Gradishar WJ: Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer. Clin Cancer Res 10:3249-3261, 2004 16. Valero V, Buzdar AU, McNeese M, et al: Primary chemotherapy in the treatment of breast cancer: The University of Texas M.D. Anderson Cancer Center experience. Clin Breast Cancer 3:S63-S68, 2002 (suppl 2)[Medline] 17. Black MM, Speer FD: Nuclear structure in cancer tissues. Surg Gynecol Obstet 105:97-102, 1957[Medline] 18. Jones RL, Lakhani SR, Ring AE, et al: Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Br J Cancer 94:358-362, 2006[CrossRef][Medline] 19. Chollet P, Amat S, Cure H, et al: Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer. Br J Cancer 86:1041-1046, 2002[CrossRef][Medline] 20. Hennessy BT, Hortobagyi GN, Rouzier R, et al: Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 23:9304-9311, 2005 21. Ernster VL, Barclay J, Kerlikowske K, et al: Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 275:913-918, 1996[Abstract] 22. Hetelekidis S, Schnitt SJ, Morrow M, et al: Management of ductal carcinoma in situ. CA Cancer J Clin 45:244-253, 1995[Abstract] 23. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999[CrossRef][Medline] 24. Kerlikowske K, Molinaro A, Cha I, et al: Characteristics associated with recurrence among women with ductal carcinoma in situ treated by lumpectomy. J Natl Cancer Inst 95:1692-1702, 2003 25. National Comprehensive Cancer Network: Practice Guidelines in Oncology: Breast Cancer, Version 2, 2007. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf 26. Rudas M, Neumayer R, Gnant MF, et al: p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast. Eur J Cancer 33:39-44, 1997[CrossRef][Medline] 27. Cardillo MR, Stamp GW, Pignatelli M: Proliferating cell nuclear antigen in benign breast disease. Eur J Gynaecol Oncol 16:476-481, 1995[Medline] 28. Pusztai L, Siddik ZH, Mills GB, et al: Physiologic and pathologic drug resistance in ovarian carcinoma: A hypothesis based on a clonal progression model. Acta Oncol 37:629-640, 1998[CrossRef][Medline] 29. Cody HS, Klauber-DeMore N, Borgen PI, et al: Is it really duct carcinoma in situ? Ann Surg Oncol 8:617-619, 2001 Submitted July 10, 2006; accepted April 4, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
four positive lymph nodes or 
2 test (for binary variables) or Wilcoxon rank sum test (for ordinal variables) was used to determine associations between patient characteristics and pCR groups. Median follow-up time was calculated as the median observation time among all patients. OS was measured from the date of pathologic response assessment after neoadjuvant chemotherapy (ie, surgery date) to the date of death or last follow-up. Patients who did not undergo surgery were considered to have residual disease for the analysis. For all other patients, disease-free survival (DFS) was measured from the date of surgery to the date of first local or distant recurrence. Recurrences in the ipsilateral breast or chest wall or lymph nodes were considered to be locoregional recurrences. The actuarial rates of survival and recurrence were calculated according to the Kaplan-Meier method, and comparisons were made using the log-rank test. A multivariable analysis using the Cox proportional hazards regression model was used to determine predictive factors of survival. All reported P values are two sided. All statistical analyses were performed using R software version 2.0.0 (The R Foundation for Statistical Computing, Vienna, Austria). 
