- Email: [email protected]
Effect of breast-duct anatomy and wound-healing responses on local tumour recurrence after primary surgery for early breast cancer
Personal View
Effect of breast-duct anatomy and wound-healing responses on local tumour recurrence after primary surgery for early breast cancer Mariella Mannino, John Yarnold
Despite the improvement in outcome for women with early breast cancer undergoing breast conservation surgery and radiotherapy, there are significant gaps in our understanding of local tumour relapse. In this Personal View, we propose two hypotheses: early-onset changes in breast-duct anatomy limit the degree of intraductal spread and explain much of the substantial age-related difference in risk of local tumour relapse; and wound-healing proteins stimulate the growth of cancer cells left behind after surgery. These mechanisms help to explain why generous surgical margins offer no greater protection against local tumour relapse than narrow margins after complete microscopic tumour excision.
Introduction Local tumour excision followed by whole-breast radiotherapy is an effective alternative to mastectomy in terms of local tumour control and overall survival for most women with early breast cancer.1–4 During the past 20 years, several improvements in breast cancer management have contributed to a substantial decrease in local tumour relapse, defined here as the reappearance of malignant disease in the ipsilateral breast.5 Despite these achievements, there remains a limited comprehension of the underlying mechanisms of local relapse after breast-conservation surgery. In this Personal View, we focus on two hypotheses: intraductal spread and age-related changes in breast-duct anatomy (figure 1) contribute to the high local-relapse risk noted in young women after breast conservation surgery; and a stimulatory effect of wound healing on postsurgical residual disease contributes to the poor prognostic value of tumour-free margin width in relation to the risk of local relapse.
more than 60 years was 0·52 (95% CI 0·36–0·76), 0·28 (0·19–0·42), and 0·26 (0·17–0·40), respectively. In a combined analysis of the EORTC 10801 and the Danish Breast Cancer Cooperative Group (DBCG)-82TM trials, which tested breast-conservation treatment against radical mastectomy (N=1772), women in the breast-conservation group aged 35 years or less had a nine-times higher risk of local relapse than those aged more than 60 years.8 By contrast, no correlation is seen between patient age and local-relapse risk after mastectomy. In a univariate
Lancet Oncol 2009; 10: 425–29 Royal Marsden Hospital, Sutton, UK (M Mannino MD, Prof J Yarnold FRCR) Correspondence to: Prof John Yarnold, Department of Clinical Oncology, Royal Marsden Hospital, Sutton, SM2 5PT, UK [email protected]
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Intraductal spread and age-related changes in breast-duct anatomy Young age is strongly correlated with a high risk of recurrence after breast-conservation surgery, whether or not radiotherapy is given. This effect is shown clearly by an Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) systematic overview,6 which analysed the effect of radiotherapy and extent of surgery on local recurrence. 5-year local relapse after breast-conserving surgery alone in women aged less than 50 years, 50–59 years, 60–69 years, and 70 years or more was 33%, 23%, 16%, and 13%, respectively. In a recent European Organisation for Research and Treatment of Cancer (EORTC) trial (22881–10882),7 which tested tumour-bed boost radiotherapy in 5318 patients after breast-conserving surgery, a strong correlation between local relapse and age was confirmed in both univariate and multivariate analyses. By use of the under-40-year age group as a reference (hazard ratio [HR] 1·00), the HR for 5-year local relapse in patients aged 41–50 years, 51–60 years, and www.thelancet.com/oncology Vol 10 April 2009
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Figure 1: Three-dimensional reconstruction based on 2 mm-thick subgross sections of whole breasts Each Roman numeral and colour refers to a different independent duct system. Reproduced with permission of John Wiley & Sons Ltd on behalf of the Pathological Society of Great Britian and Ireland.11
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A
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Figure 2: Computed graphic three-dimensional image of a central type (A) and peripheral type (B) of intraductal extension of an invasive ductal carcinoma Intraductal tumour extends continuously through the mammary ductal tree from the primary invasive lesion in lateral and peripheral directions (yellow=normal ducts; pink=primary invasive tumour and ducts involved by associated intraductal tumour extension). Reproduced with permission of Wiley-Liss, Inc. a subsidiary of John Wiley and Sons, Inc.10
analysis, done as part of a systematic overview by the EBCTCG, different age groups did not vary in 5-year local-relapse risk after mastectomy, regardless of whether radiotherapy was given.6 A similar absence of correlation was shown in a multivariate analysis of prognostic factors in women randomly assigned to mastectomy in the EORTC 10801 and DBCG-82TM trials.8 The different effect of age on local-relapse risk after breast-conservation surgery compared with mastectomy is informative, suggesting that the effect of age on local relapse is closely related to the surgical approach adopted in breast-conservation therapy. To understand this interaction, consideration of the pathological sources of local relapse after primary surgery for early breast cancer is useful, including residual foci of primary invasive carcinoma, ductal carcinoma in situ (DCIS), lymphatic emboli, and independent primary tumours. A multivariate analysis of data from a detailed central pathology review of 1724 of 5569 patients enrolled in the EORTC tumour-bed boost trial9 does not support a contribution of residual foci of the primary invasive carcinoma or of lymphatic emboli to the age effect, because no differences in the completeness of the excision of the invasive carcinoma, median microscopic invasive tumour-free margin, and presence of vascular invasion were shown in the various age groups. Additionally, in view of the distribution of breast cancer risk according to women’s age, independent primary tumours are unlikely to contribute to the higher local relapse rates noted in younger patients compared with older patients. The only factor related to sources of local relapse that is shown to 426
vary with age is intraductal disease, and the potential importance of this observation will now be considered further. A study analysing serial 2 mm-thick sections prepared from quadrantectomy specimens (mean number of sections per specimen 47·3, range 32–64) from 20 patients with invasive breast carcinoma,10 showed that intraductal tumour spread, when present, had a distance of extension that was inversely related to patient age, with the following values for women aged 30–39 years, 40–49 years, and 50 years or more: 22·7, 14·3, and 6·7–7·7 mm, respectively. Consistent with these findings are the results of the EORTC radiotherapy tumour-bed boost trial, which reported a higher frequency of moderate and extensive DCIS in young women, with the following proportions of incomplete excisions of DCIS in patients aged 35 years or less, 36–40 years, and more than 40 years: 35%, 21%, and 14%, respectively (p=0·008).9 These findings need to be interpreted in light of the recent advances in the characterisation of breast-duct anatomy, which have been accomplished thanks to improved three-dimensional (3D) imagereconstruction computer programs and the development of breast ductoscopy.11,12 According to 3D reconstructions based on 2 mm-thick subgross sections of whole breasts, duct systems are independent and end in a large collecting duct; each collecting duct has a separate opening in the nipple. The ductal systems vary greatly in size and extent (figure 1).11 These properties are consistent with findings of a pathology study that analysed the distribution of different dyes instilled into distinct nipple ducts of whole breasts after surgical removal.12 Strikingly, these showed no mixing of colours, suggesting minimum or no communication between different duct systems. The independence of single duct systems is confirmed by the distribution of DCIS within the breast. In a pilot study of in-vivo flexible ductoscopy with intraductal instillation of dye followed by pathological analysis of the excised mastectomy specimens, DCIS was circumscribed to a single duct system.13 In a 3D computer-based reconstruction study,14 which used serial 2 mm sections of an entire breast from a woman with pure DCIS, the lesions were also confined to a single duct–lobular system.14 Similar findings were shown in a series of patients undergoing operative breast endoscopy during lumpectomy.15 All lesions, even those that seemed to be non-contiguous in the preoperative mammography, were found in the same duct system. A graphic representation of intraductal spread of invasive breast carcinoma was obtained in the study on quadrantectomy specimens10 by use of a 3D reconstruction computer model (figure 2). In view of the anatomical evidence for the independence of duct systems and the pathological data describing intraductal spread associated with invasive disease, it is likely that the size and microenvironment of the involved duct system affect the extent and location of tumoral www.thelancet.com/oncology Vol 10 April 2009
Personal View
spread. If so, physiological involution of the duct system could be an underlying cause for less-extensive intraductal spread in older women and lower local-relapse risk compared with younger women. The gradual decrease in glandular and ductal tissue starts at around 30 years of age and continues after the menopause.16 A morphometric study on age-related changes in 58 normal breasts from autopsies of women aged between 10 and 80 years showed a gradual decline with increasing age in the mean diameter and volume of the average lobule and a decrease in the absolute volume of connective tissue and epithelium composing it.17 A histopathological study on involution of the breast in 102 women aged 50 to 104 years showed a progressive shortening of ductules within the lobules, accompanied by a tendency for dilation of small and terminal ducts, with accumulation of a colloid-like secretion in their lumens.18 Although no studies have yet investigated the role of involution on breast cancer progression, it is plausible to suggest that age-related morphometric and functional changes of the breast affect intraductal patterns of spread, contributing to the lower efficacy of conventional surgical techniques in younger patients compared with older women. Intraductal patterns of spread and interpatient variation in ductal anatomy are not taken into consideration by conventional surgical techniques, which consist mainly of removing a spheroidal volume with the primary tumour at its centre or a cylindrical volume extending from the skin surface to the underlying fascia with the primary tumour on its central axis. In view of the data presented above, it would be of interest to test if a resection oriented to the affected duct system is beneficial compared with the standard approach in younger patients. Extending this concept to the entire local therapeutic intervention would also have important implications for curative radiotherapy. During the past 10–15 years, much research on clinical radiation has focused on the tumour bed as the sole target of the intervention (so-called partial-breast radiotherapy) or as the target of an additional booster dose after whole-breast radiotherapy. The definition of the clinical target volume for both of these approaches is still purely geometrical— ie, a radial margin is added to the surgical cavity, in the same way that the surgeon currently widens resected margins. As for surgery, the anatomical and pathological data suggest that there is clearly scope for investigating if a shift to an anatomical or functional definition of the clinical target volume would be beneficial in younger patients. Any changes in local treatment would need to be supported and tested in conjunction with preoperative and intraoperative imaging techniques, including ultrasonography and ductoscopy. An intraductal approach also offers the possibility of developing new therapeutic interventions, including resection of intraductal disease via intraoperative ductoscopy in women undergoing lumpectomy and intraductal administration of cytotoxic drugs.19 www.thelancet.com/oncology Vol 10 April 2009
Stimulatory effect of wound healing on postsurgical residual disease Although it is widely recognised that positive margins are unacceptable,20 attempts to improve local control by increasing tumour-free resection margins have not yielded the expected gains, regardless of patient age. This is most clearly and reliably seen in retrospective analyses of margin status in three large randomised clinical trials. In univariate and multivariate analyses, neither a narrower tumour-free microscopic margin around the invasive carcinoma recorded at central pathology review of 1724 women (EORTC 22881/10882),7 nor microscopic involvement of the excision margins in 879 women (EORTC 10801 and DBCG-82TM),8 was associated with increased local relapse after breast-conservation surgery and breast radiotherapy. The only randomised trial (Milan II) testing more extensive versus less extensive breast-conservation surgery (quadrantectomy vs lumpectomy), both followed by radiotherapy, suggested a significant benefit for quadrantectomy.21 However, interpretation of this trial is confounded by significant differences in the radiotherapy delivered to the two trial populations. An additional and important limitation is that the published work on breast-conservation treatment does not allow firm conclusions to be drawn relating to the significance of margin width in the absence of radiotherapy.5 In view of the fact that it is not possible to estimate quantitatively how residual disease is modified by radiotherapy, the absence of a clear effect of margin width on local control suggests that survival and growth of postsurgical residual disease is not affected solely by its burden, raising a possible role for tumour–host interactions in determining local-relapse risk. More than 20 years ago, a suggestion was made that a fundamental step in cancer progression, tumour stroma generation, is linked to cross-talk between the tumour and the host. A postulation was formed that extravascular deposition of fibrin-fibronectin gel in the tumour signals the host to initiate a wound-healing response which, in turn, enables the tumour to acquire its stroma.22 The effect of wound healing on tumour growth has been clearly shown in a study of mice,23 which assessed the number of cells from three different tumour models (Meth A sarcoma, KHT sarcoma, and B-16 melanoma) needed to induce tumours at 50% of the injected sites (TD/50) when introduced into surgically wounded tissue compared with unwounded tissue. Cell-dilution assays showed that the TD/50 ratios in unwounded and wounded tissues were 3:1, 5:1, and 11:1, in Meth A sarcoma, KHT sarcoma, and B-16 melanoma, respectively. Clinical studies relating local relapse to the wound-healing process date back to the 1940s, when a retrospective analysis of skin grafting in conjunction with a wider removal of skin during mastectomy reported lower local recurrence after smaller resections, allowing primary closure of mastectomy flaps.24 More recent 427
Personal View
Search strategy and selection criteria Data for this Personal View were identified by a search of Pubmed, using the following search terms: “breast-conservation surgery”, “age”, “local relapse”, “breast-duct anatomy”, “breast involution”, and “wound healing”. A further search was done of related articles and references from relevant papers. No date restrictions were used. Only papers in English were included.
support for a connection between wound healing and local tumour recurrence comes from a study that showed the ability of a supervised wound-response gene-expression signature in predicting local relapse in individual patients.25 By simply classifying tumours as having an activated or a quiescent wound-response signature, this gene-expression profile was able to discriminate between patients with a high or low 10-year local-relapse risk. When analysed in a multivariate analysis with age (<40 vs ≥40 years), tumour size (T2 vs T1), and tumour-bed boost radiotherapy (no vs yes), the wound-response gene-expression signature was the most powerful predictor for local relapse (HR 16 [95% CI 1·9–125]) and independent of the other factors. Further evidence for surgery-induced modifications of breast cancer cell growth is provided by a study of proliferation differences, measured by immunohistochemical staining of Ki-67, in sections of primary tumour compared with residual disease in re-excision specimens.26 Increased proliferation was noted in re-excised specimens, which over-expressed ERBB2, compared with primary tumours. Consistent with these findings are the results of an in-vitro study done by the same group investigating the effect of wound-drainage fluids, collected from 13 patients 24 h after surgery, on several breast cancer cell lines.26 Proliferation was induced in all cell lines, most strongly in those over-expressing ERBB2. Most importantly, the investigators noted that the degree of induced cell proliferation was proportional to the amount of surgical damage assessed by creatine phosphokinase levels in drainage fluids. The stimulating effect of wound fluid on breast cancer cells has been confirmed by another study investigating possible mechanisms of action of intraoperative radiotherapy in patients undergoing breast-conserving surgery.27 Wound fluid collected during the first 24 h after surgery stimulated proliferation of breast cancer cell lines in 2D cell cultures and 3D Matrigel or collagen matrices. In the 3D matrices, wound fluid was also shown to stimulate cancer cell motility (increasing speed and number of moving cells) and invasion ability. These stimulatory effects were not noted when wound fluid was collected from patients treated with intraoperative radiotherapy. The findings of this study suggest that radiotherapy can modify the wound environment, counterbalancing the 428
possible negative effect of surgery-induced wound healing on tumour progression. The significance of these experimental findings is that they offer an explanation for the absence of a protective effect of wider surgical margins after complete microscopic tumour excision. Wider resection margins might even be counter-productive in a proportion of patients, due to a stimulatory effect of the wound-healing environment on residual cancer cells. Volume-displacement and volume-replacement techniques might also modify the behaviour of residual disease. To our knowledge, no systematic investigation has compared local relapse after various techniques of oncoplastic breast surgery and standard breastconserving surgery. The effect of radiotherapy in blocking the release of stimulatory factors in wound fluid might depend on radiotherapy being delivered at the time of surgery, rather than days or weeks later. Finally, in view of these postulated effects of radiotherapy on tumour-wound interactions, concomitant systemic or local (intraductal) administration of growth-factor inhibitors or anti-inflammatory drugs might enhance its efficacy.
Conclusion Better understanding of the spatial organisation of breastduct anatomy and the intraductal spread of primary invasive breast cancer, offers an explanation for the increased risk of local relapse in younger women treated with breast-conserving surgery and radiotherapy compared with older women. The therapeutic implications are that taking account of patterns of intraduct permeation at primary surgery might decrease the increased risk of local relapse, especially in women under the age of 50 years. Regardless of age, an increase in the radial margins of primary-tumour resection does not seem to offer greater protection against local relapse due to the stimulatory effects of factors released from the surgical wound. If confirmed, this explanation has interesting implications for both surgery and radiotherapy. Contributors The authors contributed equally to the design and writing of the manuscript. Conflicts of interest The authors declared no conflicts of interest. Acknowledgments We wish to acknowledge the contributions of Marc van de Vijver at the Academic Medical Centre, Amsterdam, Holland, and Alain Fourquet at the Institut Curie, Paris, France, for comments and ideas contributing to this Personal View. References 1 Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–32. 2 Fisher B, Anderson S, Bryant J, 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.
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Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. Cancer 2003; 98: 697–702. Arriagada R, Lê MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996; 14: 1558–64. Mannino M, Yarnold JR. Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld? Radiother Oncol 2009; 90: 14–22. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Antonini N, Jones H, Horiot JC, et al. Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiother Oncol 2007; 82: 265–71. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol 2001; 19: 1688–97. Vrieling C, Collette L, Fourquet A, et al. Can patient-, treatmentand pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients? Eur J Cancer 2003; 39: 932–44. Ohtake T, Abe R, Kimijima I, et al. Intraductal extension of primary invasive breast carcinoma treated by breast-conservative surgery. Computer graphic three-dimensional reconstruction of the mammary duct-lobular systems. Cancer 1995; 76: 32–45. Going JJ, Moffat DF. Escaping from Flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol 2004; 203: 538–44. Love SM, Barsky SH. Anatomy of the nipple and breast ducts revisited. Cancer 2004; 101: 1947–57. Love SM, Barsky SH. Breast-duct endoscopy to study stages of cancerous breast disease. Lancet 1996; 348: 997–99. Ohtake T, Kimijima I, Fukushima T, et al. Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery. Cancer 2001; 91: 2263–72.
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Dooley WC. Routine operative breast endoscopy during lumpectomy. Ann Surg Oncol 2003; 10: 38–42. Henson DE, Tarone RE. On the possible role of involution in the natural history of breast cancer. Cancer 1993; 71 (6 suppl): 2154–56. Hutson SW, Cowen PN, Bird CC. Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. J Clin Pathol 1985; 38: 281–87. Cowan DF, Herbert TA. Involution of the breast in women aged 50 to 104 years: a histopathological study of 102 cases. Surg Pathol 1989; 2: 323–33. King BL, Love SM, Rochman S, Kim JA. The Fourth International Symposium on the Intraductal Approach to Breast Cancer, Santa Barbara, California, 10–13 March 2005. Breast Cancer Res 2005; 7: 198–204. Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002; 184: 383–93. Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 1995; 31A: 1574–79. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650–59. Baker DG, Masterson TM, Pace R, Constable WC, Wanebo H. The influence of the surgical wound on local tumor recurrence. Surgery 1989; 106: 525–32. Conway H, Neumann CG. Evaluation of skin grafting in the technique of radical mastectomy in relation to local recurrence of carcinoma. Surg Gynecol Obstet 1949; 88: 45–49. Nuyten DS, Kreike B, Hart AA, et al. Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 2006; 8: R62. Tagliabue E, Agresti R, Carcangiu ML, et al. Role of HER2 in wound-induced breast carcinoma proliferation. Lancet 2003; 362: 527–33. Belletti B, Vaidya JS, D’Andrea S, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008; 14: 1325–32.
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Effect of breast-duct anatomy and wound-healing responses on local tumour recurrence after primary surgery for early breast cancer Mariella Mannino, John Yarnold
Despite the improvement in outcome for women with early breast cancer undergoing breast conservation surgery and radiotherapy, there are significant gaps in our understanding of local tumour relapse. In this Personal View, we propose two hypotheses: early-onset changes in breast-duct anatomy limit the degree of intraductal spread and explain much of the substantial age-related difference in risk of local tumour relapse; and wound-healing proteins stimulate the growth of cancer cells left behind after surgery. These mechanisms help to explain why generous surgical margins offer no greater protection against local tumour relapse than narrow margins after complete microscopic tumour excision.
Introduction Local tumour excision followed by whole-breast radiotherapy is an effective alternative to mastectomy in terms of local tumour control and overall survival for most women with early breast cancer.1–4 During the past 20 years, several improvements in breast cancer management have contributed to a substantial decrease in local tumour relapse, defined here as the reappearance of malignant disease in the ipsilateral breast.5 Despite these achievements, there remains a limited comprehension of the underlying mechanisms of local relapse after breast-conservation surgery. In this Personal View, we focus on two hypotheses: intraductal spread and age-related changes in breast-duct anatomy (figure 1) contribute to the high local-relapse risk noted in young women after breast conservation surgery; and a stimulatory effect of wound healing on postsurgical residual disease contributes to the poor prognostic value of tumour-free margin width in relation to the risk of local relapse.
more than 60 years was 0·52 (95% CI 0·36–0·76), 0·28 (0·19–0·42), and 0·26 (0·17–0·40), respectively. In a combined analysis of the EORTC 10801 and the Danish Breast Cancer Cooperative Group (DBCG)-82TM trials, which tested breast-conservation treatment against radical mastectomy (N=1772), women in the breast-conservation group aged 35 years or less had a nine-times higher risk of local relapse than those aged more than 60 years.8 By contrast, no correlation is seen between patient age and local-relapse risk after mastectomy. In a univariate
Lancet Oncol 2009; 10: 425–29 Royal Marsden Hospital, Sutton, UK (M Mannino MD, Prof J Yarnold FRCR) Correspondence to: Prof John Yarnold, Department of Clinical Oncology, Royal Marsden Hospital, Sutton, SM2 5PT, UK [email protected]
I
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III X
Intraductal spread and age-related changes in breast-duct anatomy Young age is strongly correlated with a high risk of recurrence after breast-conservation surgery, whether or not radiotherapy is given. This effect is shown clearly by an Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) systematic overview,6 which analysed the effect of radiotherapy and extent of surgery on local recurrence. 5-year local relapse after breast-conserving surgery alone in women aged less than 50 years, 50–59 years, 60–69 years, and 70 years or more was 33%, 23%, 16%, and 13%, respectively. In a recent European Organisation for Research and Treatment of Cancer (EORTC) trial (22881–10882),7 which tested tumour-bed boost radiotherapy in 5318 patients after breast-conserving surgery, a strong correlation between local relapse and age was confirmed in both univariate and multivariate analyses. By use of the under-40-year age group as a reference (hazard ratio [HR] 1·00), the HR for 5-year local relapse in patients aged 41–50 years, 51–60 years, and www.thelancet.com/oncology Vol 10 April 2009
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Figure 1: Three-dimensional reconstruction based on 2 mm-thick subgross sections of whole breasts Each Roman numeral and colour refers to a different independent duct system. Reproduced with permission of John Wiley & Sons Ltd on behalf of the Pathological Society of Great Britian and Ireland.11
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A
B
Figure 2: Computed graphic three-dimensional image of a central type (A) and peripheral type (B) of intraductal extension of an invasive ductal carcinoma Intraductal tumour extends continuously through the mammary ductal tree from the primary invasive lesion in lateral and peripheral directions (yellow=normal ducts; pink=primary invasive tumour and ducts involved by associated intraductal tumour extension). Reproduced with permission of Wiley-Liss, Inc. a subsidiary of John Wiley and Sons, Inc.10
analysis, done as part of a systematic overview by the EBCTCG, different age groups did not vary in 5-year local-relapse risk after mastectomy, regardless of whether radiotherapy was given.6 A similar absence of correlation was shown in a multivariate analysis of prognostic factors in women randomly assigned to mastectomy in the EORTC 10801 and DBCG-82TM trials.8 The different effect of age on local-relapse risk after breast-conservation surgery compared with mastectomy is informative, suggesting that the effect of age on local relapse is closely related to the surgical approach adopted in breast-conservation therapy. To understand this interaction, consideration of the pathological sources of local relapse after primary surgery for early breast cancer is useful, including residual foci of primary invasive carcinoma, ductal carcinoma in situ (DCIS), lymphatic emboli, and independent primary tumours. A multivariate analysis of data from a detailed central pathology review of 1724 of 5569 patients enrolled in the EORTC tumour-bed boost trial9 does not support a contribution of residual foci of the primary invasive carcinoma or of lymphatic emboli to the age effect, because no differences in the completeness of the excision of the invasive carcinoma, median microscopic invasive tumour-free margin, and presence of vascular invasion were shown in the various age groups. Additionally, in view of the distribution of breast cancer risk according to women’s age, independent primary tumours are unlikely to contribute to the higher local relapse rates noted in younger patients compared with older patients. The only factor related to sources of local relapse that is shown to 426
vary with age is intraductal disease, and the potential importance of this observation will now be considered further. A study analysing serial 2 mm-thick sections prepared from quadrantectomy specimens (mean number of sections per specimen 47·3, range 32–64) from 20 patients with invasive breast carcinoma,10 showed that intraductal tumour spread, when present, had a distance of extension that was inversely related to patient age, with the following values for women aged 30–39 years, 40–49 years, and 50 years or more: 22·7, 14·3, and 6·7–7·7 mm, respectively. Consistent with these findings are the results of the EORTC radiotherapy tumour-bed boost trial, which reported a higher frequency of moderate and extensive DCIS in young women, with the following proportions of incomplete excisions of DCIS in patients aged 35 years or less, 36–40 years, and more than 40 years: 35%, 21%, and 14%, respectively (p=0·008).9 These findings need to be interpreted in light of the recent advances in the characterisation of breast-duct anatomy, which have been accomplished thanks to improved three-dimensional (3D) imagereconstruction computer programs and the development of breast ductoscopy.11,12 According to 3D reconstructions based on 2 mm-thick subgross sections of whole breasts, duct systems are independent and end in a large collecting duct; each collecting duct has a separate opening in the nipple. The ductal systems vary greatly in size and extent (figure 1).11 These properties are consistent with findings of a pathology study that analysed the distribution of different dyes instilled into distinct nipple ducts of whole breasts after surgical removal.12 Strikingly, these showed no mixing of colours, suggesting minimum or no communication between different duct systems. The independence of single duct systems is confirmed by the distribution of DCIS within the breast. In a pilot study of in-vivo flexible ductoscopy with intraductal instillation of dye followed by pathological analysis of the excised mastectomy specimens, DCIS was circumscribed to a single duct system.13 In a 3D computer-based reconstruction study,14 which used serial 2 mm sections of an entire breast from a woman with pure DCIS, the lesions were also confined to a single duct–lobular system.14 Similar findings were shown in a series of patients undergoing operative breast endoscopy during lumpectomy.15 All lesions, even those that seemed to be non-contiguous in the preoperative mammography, were found in the same duct system. A graphic representation of intraductal spread of invasive breast carcinoma was obtained in the study on quadrantectomy specimens10 by use of a 3D reconstruction computer model (figure 2). In view of the anatomical evidence for the independence of duct systems and the pathological data describing intraductal spread associated with invasive disease, it is likely that the size and microenvironment of the involved duct system affect the extent and location of tumoral www.thelancet.com/oncology Vol 10 April 2009
Personal View
spread. If so, physiological involution of the duct system could be an underlying cause for less-extensive intraductal spread in older women and lower local-relapse risk compared with younger women. The gradual decrease in glandular and ductal tissue starts at around 30 years of age and continues after the menopause.16 A morphometric study on age-related changes in 58 normal breasts from autopsies of women aged between 10 and 80 years showed a gradual decline with increasing age in the mean diameter and volume of the average lobule and a decrease in the absolute volume of connective tissue and epithelium composing it.17 A histopathological study on involution of the breast in 102 women aged 50 to 104 years showed a progressive shortening of ductules within the lobules, accompanied by a tendency for dilation of small and terminal ducts, with accumulation of a colloid-like secretion in their lumens.18 Although no studies have yet investigated the role of involution on breast cancer progression, it is plausible to suggest that age-related morphometric and functional changes of the breast affect intraductal patterns of spread, contributing to the lower efficacy of conventional surgical techniques in younger patients compared with older women. Intraductal patterns of spread and interpatient variation in ductal anatomy are not taken into consideration by conventional surgical techniques, which consist mainly of removing a spheroidal volume with the primary tumour at its centre or a cylindrical volume extending from the skin surface to the underlying fascia with the primary tumour on its central axis. In view of the data presented above, it would be of interest to test if a resection oriented to the affected duct system is beneficial compared with the standard approach in younger patients. Extending this concept to the entire local therapeutic intervention would also have important implications for curative radiotherapy. During the past 10–15 years, much research on clinical radiation has focused on the tumour bed as the sole target of the intervention (so-called partial-breast radiotherapy) or as the target of an additional booster dose after whole-breast radiotherapy. The definition of the clinical target volume for both of these approaches is still purely geometrical— ie, a radial margin is added to the surgical cavity, in the same way that the surgeon currently widens resected margins. As for surgery, the anatomical and pathological data suggest that there is clearly scope for investigating if a shift to an anatomical or functional definition of the clinical target volume would be beneficial in younger patients. Any changes in local treatment would need to be supported and tested in conjunction with preoperative and intraoperative imaging techniques, including ultrasonography and ductoscopy. An intraductal approach also offers the possibility of developing new therapeutic interventions, including resection of intraductal disease via intraoperative ductoscopy in women undergoing lumpectomy and intraductal administration of cytotoxic drugs.19 www.thelancet.com/oncology Vol 10 April 2009
Stimulatory effect of wound healing on postsurgical residual disease Although it is widely recognised that positive margins are unacceptable,20 attempts to improve local control by increasing tumour-free resection margins have not yielded the expected gains, regardless of patient age. This is most clearly and reliably seen in retrospective analyses of margin status in three large randomised clinical trials. In univariate and multivariate analyses, neither a narrower tumour-free microscopic margin around the invasive carcinoma recorded at central pathology review of 1724 women (EORTC 22881/10882),7 nor microscopic involvement of the excision margins in 879 women (EORTC 10801 and DBCG-82TM),8 was associated with increased local relapse after breast-conservation surgery and breast radiotherapy. The only randomised trial (Milan II) testing more extensive versus less extensive breast-conservation surgery (quadrantectomy vs lumpectomy), both followed by radiotherapy, suggested a significant benefit for quadrantectomy.21 However, interpretation of this trial is confounded by significant differences in the radiotherapy delivered to the two trial populations. An additional and important limitation is that the published work on breast-conservation treatment does not allow firm conclusions to be drawn relating to the significance of margin width in the absence of radiotherapy.5 In view of the fact that it is not possible to estimate quantitatively how residual disease is modified by radiotherapy, the absence of a clear effect of margin width on local control suggests that survival and growth of postsurgical residual disease is not affected solely by its burden, raising a possible role for tumour–host interactions in determining local-relapse risk. More than 20 years ago, a suggestion was made that a fundamental step in cancer progression, tumour stroma generation, is linked to cross-talk between the tumour and the host. A postulation was formed that extravascular deposition of fibrin-fibronectin gel in the tumour signals the host to initiate a wound-healing response which, in turn, enables the tumour to acquire its stroma.22 The effect of wound healing on tumour growth has been clearly shown in a study of mice,23 which assessed the number of cells from three different tumour models (Meth A sarcoma, KHT sarcoma, and B-16 melanoma) needed to induce tumours at 50% of the injected sites (TD/50) when introduced into surgically wounded tissue compared with unwounded tissue. Cell-dilution assays showed that the TD/50 ratios in unwounded and wounded tissues were 3:1, 5:1, and 11:1, in Meth A sarcoma, KHT sarcoma, and B-16 melanoma, respectively. Clinical studies relating local relapse to the wound-healing process date back to the 1940s, when a retrospective analysis of skin grafting in conjunction with a wider removal of skin during mastectomy reported lower local recurrence after smaller resections, allowing primary closure of mastectomy flaps.24 More recent 427
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Search strategy and selection criteria Data for this Personal View were identified by a search of Pubmed, using the following search terms: “breast-conservation surgery”, “age”, “local relapse”, “breast-duct anatomy”, “breast involution”, and “wound healing”. A further search was done of related articles and references from relevant papers. No date restrictions were used. Only papers in English were included.
support for a connection between wound healing and local tumour recurrence comes from a study that showed the ability of a supervised wound-response gene-expression signature in predicting local relapse in individual patients.25 By simply classifying tumours as having an activated or a quiescent wound-response signature, this gene-expression profile was able to discriminate between patients with a high or low 10-year local-relapse risk. When analysed in a multivariate analysis with age (<40 vs ≥40 years), tumour size (T2 vs T1), and tumour-bed boost radiotherapy (no vs yes), the wound-response gene-expression signature was the most powerful predictor for local relapse (HR 16 [95% CI 1·9–125]) and independent of the other factors. Further evidence for surgery-induced modifications of breast cancer cell growth is provided by a study of proliferation differences, measured by immunohistochemical staining of Ki-67, in sections of primary tumour compared with residual disease in re-excision specimens.26 Increased proliferation was noted in re-excised specimens, which over-expressed ERBB2, compared with primary tumours. Consistent with these findings are the results of an in-vitro study done by the same group investigating the effect of wound-drainage fluids, collected from 13 patients 24 h after surgery, on several breast cancer cell lines.26 Proliferation was induced in all cell lines, most strongly in those over-expressing ERBB2. Most importantly, the investigators noted that the degree of induced cell proliferation was proportional to the amount of surgical damage assessed by creatine phosphokinase levels in drainage fluids. The stimulating effect of wound fluid on breast cancer cells has been confirmed by another study investigating possible mechanisms of action of intraoperative radiotherapy in patients undergoing breast-conserving surgery.27 Wound fluid collected during the first 24 h after surgery stimulated proliferation of breast cancer cell lines in 2D cell cultures and 3D Matrigel or collagen matrices. In the 3D matrices, wound fluid was also shown to stimulate cancer cell motility (increasing speed and number of moving cells) and invasion ability. These stimulatory effects were not noted when wound fluid was collected from patients treated with intraoperative radiotherapy. The findings of this study suggest that radiotherapy can modify the wound environment, counterbalancing the 428
possible negative effect of surgery-induced wound healing on tumour progression. The significance of these experimental findings is that they offer an explanation for the absence of a protective effect of wider surgical margins after complete microscopic tumour excision. Wider resection margins might even be counter-productive in a proportion of patients, due to a stimulatory effect of the wound-healing environment on residual cancer cells. Volume-displacement and volume-replacement techniques might also modify the behaviour of residual disease. To our knowledge, no systematic investigation has compared local relapse after various techniques of oncoplastic breast surgery and standard breastconserving surgery. The effect of radiotherapy in blocking the release of stimulatory factors in wound fluid might depend on radiotherapy being delivered at the time of surgery, rather than days or weeks later. Finally, in view of these postulated effects of radiotherapy on tumour-wound interactions, concomitant systemic or local (intraductal) administration of growth-factor inhibitors or anti-inflammatory drugs might enhance its efficacy.
Conclusion Better understanding of the spatial organisation of breastduct anatomy and the intraductal spread of primary invasive breast cancer, offers an explanation for the increased risk of local relapse in younger women treated with breast-conserving surgery and radiotherapy compared with older women. The therapeutic implications are that taking account of patterns of intraduct permeation at primary surgery might decrease the increased risk of local relapse, especially in women under the age of 50 years. Regardless of age, an increase in the radial margins of primary-tumour resection does not seem to offer greater protection against local relapse due to the stimulatory effects of factors released from the surgical wound. If confirmed, this explanation has interesting implications for both surgery and radiotherapy. Contributors The authors contributed equally to the design and writing of the manuscript. Conflicts of interest The authors declared no conflicts of interest. Acknowledgments We wish to acknowledge the contributions of Marc van de Vijver at the Academic Medical Centre, Amsterdam, Holland, and Alain Fourquet at the Institut Curie, Paris, France, for comments and ideas contributing to this Personal View. References 1 Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–32. 2 Fisher B, Anderson S, Bryant J, 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.
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