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Breast conservative surgery and local recurrence
The Breast xxx (2015) e1ee8
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Original article
Breast conservative surgery and local recurrence Mahdi Rezai a, *, Stefan Kraemer b, Rainer Kimmig c, Peter Kern c a
European Breast Center e Dr. Rezai, Hans-Günther-Sohl-Str.6-10, D-40235 Düsseldorf, Germany University Medical Center Cologne, Kerpener Str. 34, D-50931 Cologne, Germany c University Hospital of Essen, Women's Department, Hufelandstr.55, D-45147 Essen, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Introduction: Breast conservation is a legacy of Umberto Veronesi who laid the groundwork for the preservation of the body image of women affected by breast cancer (BC) with the Milan I study in the late 70ies of the last millennium. Breast conservative surgery (BCS) has two aspects: oncological safety of tumour resection with free margins and aesthetic preservation of the breast. Determinants of local control used to be T-size, nodal status and receptor status until biologically driven concepts defined risk of recurrence on the basis of molecular portraits. We explored whether these concepts of intrinsic subtypes prove at a large scale in the context of BCS and which surgical techniques procure best oncological and aesthetic outcomes, avoiding re-excision and necessity of conversion to mastectomy. Patients and methods: We analyzed 1035 BCS patients with primary unilateral breast cancer (2004 e2009) with regards to the local recurrence as a function of tumour location, surgical technique, resection volume, T-size, nodal status, grading, histopathological and intrinsic subtype and margins. Results: Five surgical techniques were applied to 944 eligible patients at a median follow-up of 5.2 years with the following frequency: Glandular rotation mammoplasty (63.8%), tumour-adapted rotation mammoplasty (20.9%), dermoglandular rotation mammoplasty (6.7%), 4.4% (lateral thoracic wall advancement), 0.7% latissimus dorsi flap (0.7%) and others (13.5%). Tumour-free margins were achieved in 88.6% of all patients at first surgery. Recurrence was independent of the surgical technique used, resection volume, T-size (in a T1/T2-cohort), nodal status (in low N-stages: NO/N1) and histopathology (inv.-ductal vs. lobular), however non-invasive subtype (DCIS), high grading (G3 vs. G1), non-luminal Her2 positive BC and triple-negative breast cancer (TNBC) were significantly associated with local recurrence. Conclusions: Five defined oncoplastic principles presented in our nomogramme (targeted breast surgery) allow the reconstruction of major segmental resection defects during breast-conserving therapy with high clinical applicability and result in favorable oncological and aesthetic outcome. Recurrence was not a function of traditional prognostic factors like T-size or nodal status (in a T1/T2, N0/N1 cohort), but of grading, intrinsic subtypes and non-invasive breast cancer components. Lobular histology, multicentricity and DCIS were predictive for breast preservation failure and conversion to mastectomy. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Breast conservative surgery Local recurrence Surgical technique Targeted breast surgery Predictors of breast preservation failure
Definitions and surgical principles Breast-conserving therapy (BCT) consisting of surgical removal of the primary tumour followed by whole breast irradiation is an alternative to mastectomy which results in equivalent long-term survival. Although rates of BCT have increased
* Corresponding author. E-mail addresses: [email protected] (M. Rezai), [email protected] (S. Kraemer), [email protected] (R. Kimmig), [email protected] (P. Kern).
over time worldwide, there is no consensus about what amount of normal breast tissue should be removed as a margin to minimize the risk of local recurrence. The manifest of the SSO (Society of Surgical Oncology) e ASTRO (American Society of Radiation Oncology) Consensus Panel underlined the importance of obtaining negative margins defined as no ink on tumour (invasive cancer or DCIS), to optimize local control. This was based on the finding in the meta-analysis of Houssami et al. that margins of 1, 2, or 5 mm were not associated with significantly different risks of local recurrences [1]. Oncoplastic principles were introduced into breast-conserving surgery 20 years ago to allow oncologically safe breast
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Fig. 1. Glandular rotation mammaplasty.
conservation, by performing a wide excision for tumours and those in difficult locations limiting the risk of postoperative deformities. Numerous surgical techniques with tissue displacement and tissue replacement have been published with different indications, incision lines and suggested rotation techniques, however a systematic and structured approach for oncoplastic breast surgery was missing. During the last years we have defined five reconstruction principles introducing a new concept of breast-conserving surgery e targeted oncoplastic breast-conserving surgery. We analyzed the oncological and aesthetic outcome of targeted oncoplastic breastconserving surgery in the era of multimodal therapy of early breast cancer in more than 1000 patients [2]. Five major principles in targeted breast (-conserving) surgery were prospectively defined based on the localization, size of the segmental resection defect, size of the breast and the necessity for skin resection during breast-conserving therapy. These major principles were: BCT-glandular rotation, BCT-dermoglandular rotation, BCT-tumouradapted reduction mammoplasty, BCTlateral thoracic wall advancement, BCT-thoracoepigastric flap. In the Düsseldorf Oncoplastic study, we analyzed feasibility, oncological outcome and aesthetic results. Systemic adjuvant treatment and radiotherapy was applicated according to international guidelines.
Oncoplastic techniques Glandular rotation mammaplasty (63.8%) In cases of segmentectomy without skin resection the glandular defect is easily approximated by mobilising glandular flaps. For the standard segmentectomy an incision directly over the area to be removed is performed. For lesions in the upper breast, incisions are following Langer's lines. The skin is undermined in the affected region, detaching the glandula from the skin. Only after resection of a segment, and after approximating the tissue, further skin mobilisation is performed in skin retracted areas. This minimizes extensive mobilization which has an impact on the chances of long term post-surgical surveillance for recurrence (“inner aesthetic aspects”). In some cases, the central portion of the breast needs to be undermined, separating the nippleeareola-complex from the underlying breast tissue. This allows transfer of some of the central volume of the breast towards the defect, facilitating the replacement of tissue and preventing deviation of the nippleeareola-complex towards the tumour bed. After clip-marking of the tumour bed, the two lateral glandular flaps are approximated and sutured into the defect. This approach was used for 63.8% breast cancers and was applied to all tumour locations (Fig. 1).
Fig. 2. Dermoglandular rotation mammaplasty.
Fig. 3. Tumour-adapted mastopexy without nipple-areola-transposition (according to Rezai).
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Fig. 4. Tumour-site adapted reduction mammaplasty with transposition of the nipple-areola-complex (according to Rezai).
Fig. 5. Lateral thoracic wall advancement (according to Rezai).
Dermoglandular rotation mammaplasty (6.7%) A limitation of excisions of the skin of the upper or lower inner breast quadrant is that upward or downward displacement of the nippleeareola complex may result when too much skin is removed above or below the nipple. Skin resection is performed in a radial orientation. To avoid “birds peak deformation” dermoglandular rotation as tumour-adapted mastopexy is an adequate technique to prevent breast deformities in the lower inner breast quadrant and the lower 6 o'clock localization (Fig. 2).
Tumour-adapted reduction mammoplasty (20.9%) Another oncoplastic approach, when breast volume allows it (B cup or larger), is to perform a remodelling mammoplasty. The early use of mammoplasty techniques for breast-conserving surgery involved patients with large tumours located in the lower pole of the breast (superior pedicle mammoplasty). Lower-pole resections cause more deformities than resections in the upper quadrants and these are impossible to prevent with the simple
unilateral techniques just described. Some patients develop a major deformity that presents with a characteristic “bird's peak” appearance, caused by skin retraction of the lower pole with unsufficient filling and downpointing of the nipple. The tumouradapted reduction mammaplasty avoids these bird peak deformation and allows resection of tumors of all locations in the breast (Fig. 3). There are many advantages of this approach, but the main disadvantage is the need to achieve contralateral symmetry, which can be performed simultaneously in order to avoid secondary procedures. There is a large spectrum of published techniques for mammoplasty with limitations in long term aesthetic outcomes, scars and pedicles. We developed a standardized and universal technique with an inferior flap to overcome the limitations of single mammoplasty techniques published before (Fig. 4).
Lateral advancement flap (4.4%) This technique was developed by the author to reconstruct lateral defects of the breast by mobilization of tissue from the
Fig. 6. Thoraco-epigastric flap.
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Fig. 7. Distribution of tumour locations.
lateral part of the M. latissimus dorsi which is attached to the glandular resection interface (Fig. 5). Thoracoepigastric flap and other techniques For patients with breast cancer localised in the lower inner quadrant with a need of a larger skin resection, a small thoracoepigatric flap (Fig. 6) can be used to reconstruct the resection defect adequately. In most patients, a dermoglandular rotation mammaplasty as volume displacement method will be the alternative for the breast-conserving treatment of tumours in this location. Recurrence and breast conservative therapy The risk of breast cancer recurrence is determined by tumour burden, biology and local and systemic therapy [3]. Many variations of local removal of the tumour burden have evolved in the past, often with extensive surgery combined with flap surgery to reconstruct the defect. However, it is the systemic treatment of the tumoure besides a clear resection of the tumour with no ink on margins e which determines the local course of the disease most. As Mannino et al. indicated, risk of local recurrence was cut down to the half by use of tamoxifen and other endocrine agents [4].
In our Düsseldorf Oncoplastic study, we analyzed recurrence and oncological outcome related to surgical techniques, patients characteristics (age …) and tumour characteristics (tumour size, histopathology, grading, intrinsic subtype). Furthermore we explored the aesthetic outcome related to tumour location, surgical technique, resection volume, age, BMI and other factors. For selection of surgical techniques, we applied the following nomogramme (most frequent used technique is displayed in italics): 1. Upper outer quadrant: Glandular rotation mammaplasty, dermoglandular mammaplasty, lateral advancement flap, latissimus dorsi flap 2. Upper inner quadrant: Glandular rotation mammaplasty, latissimus dorsi flap 3. Lower outer quadrant: Tumour-adapted mastopexy, glandular rotation mammaplasty, latissimus dorsi flap 4. Lower inner quadrant: Tumour adapted mastopexy, glandular rotation mammaplasty, latissimus dorsi flap The distribution of tumour locations is shown in Fig. 7. The frequency of surgical techniques is shown in Fig. 8. Intrinsic subtypes in our oncoplastic cohort are distributed as shown in Fig. 9.
Fig. 8. Distribution of surgical techniques.
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Fig. 9. Distribution of intrinsic subtypes.
Fig. 10. Recurrence and histopathology.
Recurrence and histopathology
Clearness of margins
We analyzed which types of histopathology yield the highest recurrence rates and found the non-invasive subtypes to be at highest level, followed by the combination invasive and noninvasive subtype (Fig. 10).
The status of clearness of margins was not determined by T-size, resection volume or intrinsic subtype (p > .05). Influencing factors for clearness of margins were multicentricity, multifocality and DCIS (p < .001).
Fig. 11. Recurrence and T-size.
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Recurrence and T-size We found recurrences were not differing significantly in the T1/ T2 cohort due to tumour size. Of note, 2 recurrences occurred in the T1a-tumours yielding a high recurrence rate of 7.1%. These were due to a TNBC/G3-tumour and a non-luminal-Her2-tumour in the stage T1a. High recurrence rates in T3-tumours were related to low representation of that tumour stage (n ¼ 3) with one recurrence (Fig. 11). Recurrence and grading Fig. 12 shows the representation of grading in our cohort and the corresponding recurrence rates which were incremental with grading. Recurrence and intrinsic subtypes Fig. 13 shows the representation of intrinsic subtypes in our cohort and the corresponding recurrence rates which were depending on the specific subtype. Discussion Breast conservative treatment has become the standard treatment as a legacy of Umberto Veronesi who founded the groundwork for the preservation of the body image with MILAN I study in
the late 1970ies [11,12]. In the EBCTCG-Meta-Analysis 2011,local control achieved by BCS and adjuvant radiotherapy led to a recurrence free survival of 84.4% at 10 years in nodal-negative breast cancer [13]. Breast conservative surgery has two aspects: oncological safety and aesthetic outcome [14]. Various techniques to achieve these goals have been published, and there is a lack of systematic approach when to appropriately use any of these techniques [15e21]. A case cohort study which has been published recently used the McKissock Mammoplasty Technique [22] as surgery for difficult tumor locations (lower-inner or lower-outer quadrant) with unclear margins at 12% of all cases and secondary mastectomy rates at 8% [23]. Our cohort corresponded well with these findings with slightly lower rates at 11.4% for unclear margins and 7.6% for secondary mastectomy. Another recent study [24] used the Lejour technique e which was originally designed as a reduction mammaplasty with a vertical scar [25,26] e as an oncoplastic technique to achieve local control e with a medial pedicle approach for early breast cancer. This study group also achieved a high degree of patient satisfaction (73%) as in our cohort (88%), but e unlike in our study e did not record any loco-regional or distant recurrences. This may be related to the fact that the case-load of their study was small (n ¼ 30) and follow-up was short (20 months). The Lejour technique as a reduction mammoplasty pattern has its limitations in more extensive macromastia, as the amount of removal of breast tissue is limited. Many other techniques for reduction mammoplasty have been described [26e32], however Shestak KC [33],
Fig. 12. Recurrence and grading.
Fig. 13. Recurrence and intrinsic subtype.
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Rezai M et al. [34e35] and Spear SL [36], described the use of mammoplasty techniques in an oncoplastic context to achieve a high level of local control combined with a high level of aesthetic outcome. In this study, we present a nomogramme for surgical treatment of all tumor locations and all breast sizes applying five simple surgical techniques without the necessity of extensive replacement of tissue using flaps from distant donor regions. In the mammoplasty technique applied in our nomogramme, we use inferior-pedicled approach by Ribeiro [31e32] in the modification of Rezai [35]. The nippleeareola complex derives its blood supply solely through the corium from the cranially pedicled skin. No total necrosis of the nipple-areola complex occurred in our whole cohort. As to the influence of the histopathological subtype on local recurrence, we found an overall recurrence rate of 4.0% at a median follow-up of 5.2 years in the whole cohort. Recurrence rates up to 9% are reported in similar cohorts with the same follow-up in literature [37e38]. In our study, non-invasive subtypes had the highest recurrence rates: DCIS 6.5% and CLIS 7.5%. As to recurrence rates in invasive breast cancer, invasive tumor subtypes recurrence rates were not differing significantly between invasive-ductal and invasive-lobular subtype (p > 0.05). This corresponds well with recent findings of Garcia-Fernandez A et al. [39] who found at a median follow-up of 76 months a recurrence rate of 4% vs. 3.2% for invasive-ductal and invasivelobular breast cancer (p ¼ n.s.). Also in their study, lobular histology was more frequently associated with re-excision and/or mastectomy. In our study, necessity of secondary mastectomy to achieve local control was 5.8% with invasive-ductal breast cancer and 13.6% with invasive-lobular breast cancer (p ¼ 0.001). In our cohort, rate of unclear margins was as low as 11.4% at first surgery in our cohort and only in 7.2% a two-step mastectomy had to be performed following breast conservation attempt. DCIS with and without invasive subtype was predictive of mastectomy (p ¼ 0.001). In international literature, unclear margins are published at a frequency of 10.6e38% at first surgery [40e45]. We identified 11.4% (108/944) patients with unclear margins at first surgery, out of which 89.8% opted for re-excision of margins. However, 10.2% (11/108) refused re-excision, resulting in a rate of 1.5% remaining with unclear margins. No recurrence was recorded in these 11 individuals with remaining unclear margins at a median follow-up of 5.2 years after multimodal treatment. Houssami N et al [46] published a meta-analysis of 33 studies with a minimum follow-up of 4 years and in-breast true recurrence rate of 5.3%, and demonstrated that the distance of clear margins e 1, 2 or 5 mm e did not significantly have an impact on local recurrence. Studies of surgical margins in lumpectomy for breast cancer that “bigger is not better” (Morrow) [46]. However, as stated in the recent SSO-ASTRO-Guidelines [47] margins need to be cleared in terms of “no ink on margins”. Contrary to our findings in this cohort, there is evidence in other studies that unclear margins affect local recurrence and disease-free survival [48], especially in high-risk tumor subtypes, as we also found most recently in a cohort of 2037 patients with triple-negative breast cancer [49]. Traditional prognostic factors like T-size [50,51] in a cohort with a typical distribution of national mammography screening from 50 to 69 years with predominantly T1 and T2-tumors did not show a significant increase of recurrence rate from T1 to T2 stage. Whereas these findings of our study differ from older, published reports [52e54] and might not apply to higher tumor stages (T3, T4) having a low representation in our cohort, it corresponds well with the concept of Sorlie et al. [55] of intrinsic subtypes which primarily govern the course of the disease due to their inborn gene pattern. We also validated this concept in a clinical setting of a large cohort
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recently [56]. The strongest indicator for predicting local recurrence and survival was intrinsic subtype (s. Fig. 13). However, grading as a prognostic factors remains a strong predictor of recurrence as it was demonstrated again in large cohorts before [57,58] and this was also confirmed in our cohort with a 5years-local recurrence rate 1.0% of G1, 3.5% in G2 and 7.0% in G3. The HR for disease recurrence was 3.7 for G3 compared with G1. Also the lymph node status is still a valid prognostic factor for disease recurrence [59e61]. However, in low lymphatic disease we did not detect significant differences in recurrence rates (p > 0.05). Conclusion We explored surgery-related factors like resection volume and margins and did not find a correlation with recurrence and survival parameters. Analyzing more than 1000 patients with breast conservative therapy, we found the following principles applying to breast conservation and recurrence in a typical cohort of T1/T2-tumours. Recurrence is independent of
T-size (in T1/T2-cohorts) Nodal status (in low N-stages: N0/N1) Histopathology (inv.-ductal vs. lobular) Surgical technique (segmentectomy/quadrantectomy) Resection volume (11e793 g) Recurrence is dependent of
Grading Intrinsic subtype (highest local recurrence rates: TNBC, Her2positive (non-luminal), DCIS) Further development of the traditional concept of oncoplastic breast surgery to a concept of targeted oncoplastic breast-conserving surgery [5e10] with five defined oncoplastic principles allows the reconstruction of segmental resection defects during breastconserving therapy with highest clinical applicability and results in favourable oncological and aesthetic outcomes [2,10]. This approach might be useful in extending the indications for breastconserving therapy. Targeted (oncoplastic) breast surgery (Rezai) integrates anatomical, pathological and reconstructive aspects of breast cancer to achieve favourable local outcomes for the patients e combining oncological and aesthetic prerequisites. Conflict of interest statement The authors have no conflict of interests. References [1] Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21(3):717e30. [2] Rezai M, Knispel S, Kellersmann S, Lax H, Kimmig R, Kern P. Systematization of oncoplastic surgery e selection of surgical techniques and patient reported outcome in a cohort of 1035 patients. Ann Surg Oncol 2015 Feb 12 [Epub ahead of print]. [3] Morrow M. Does modern surgery reflect tumor biology?. In: Düsseldorf breast cancer conference (DBCC); 2014. [4] Mannino M. Local relapses are falling after breast conserving surgery and systemic therapy of early breast cancer: can radiotherapy ever be safely withheld? Radiother Oncol 2009;90:14e22. [5] Rezai M. Targeted breast surgery. In: Düsseldorf breast cancer conference (DBCC); 2012. [6] Rezai M, Kern P, Kraemer S. Oncoplastic reduction mammoplasty. In: Urban C, Rietjens M, editors. Oncoplastic and reconstructive breast surgery. Italia: Springer; 2013, ISBN 978-88-470-2651-3.
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Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001 Sept 11;98(19):10869e74. [56] Rezai M, Kellersmann S, Knispel S, Lax H, Kimmig R, Kern P. Translating the concept of intrinsic subtypes into an oncoplastic cohort of more than 1000 patients - predictors of recurrence and survival. Breast 2015 Aug;24(4):384e90. [57] Rakha EA, El-Sayed ME, Lee AH, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol 2008 Jul 1;26(19): 3153e8. [58] von Minckwitz, Kaufmann M, Fasching P, et al. Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracyclinetaxane +/- trastuzumab containing chemotherapy. Cancer Res 2009;69(2 Suppl.). Abstr. nr 79. [59] Olivetto IA, Truong PT, Speers CH. Staging reclassification affects breast cancer survival. J Clin Oncol 2003 Dec 1;21(23):4467e8. 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Original article
Breast conservative surgery and local recurrence Mahdi Rezai a, *, Stefan Kraemer b, Rainer Kimmig c, Peter Kern c a
European Breast Center e Dr. Rezai, Hans-Günther-Sohl-Str.6-10, D-40235 Düsseldorf, Germany University Medical Center Cologne, Kerpener Str. 34, D-50931 Cologne, Germany c University Hospital of Essen, Women's Department, Hufelandstr.55, D-45147 Essen, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Introduction: Breast conservation is a legacy of Umberto Veronesi who laid the groundwork for the preservation of the body image of women affected by breast cancer (BC) with the Milan I study in the late 70ies of the last millennium. Breast conservative surgery (BCS) has two aspects: oncological safety of tumour resection with free margins and aesthetic preservation of the breast. Determinants of local control used to be T-size, nodal status and receptor status until biologically driven concepts defined risk of recurrence on the basis of molecular portraits. We explored whether these concepts of intrinsic subtypes prove at a large scale in the context of BCS and which surgical techniques procure best oncological and aesthetic outcomes, avoiding re-excision and necessity of conversion to mastectomy. Patients and methods: We analyzed 1035 BCS patients with primary unilateral breast cancer (2004 e2009) with regards to the local recurrence as a function of tumour location, surgical technique, resection volume, T-size, nodal status, grading, histopathological and intrinsic subtype and margins. Results: Five surgical techniques were applied to 944 eligible patients at a median follow-up of 5.2 years with the following frequency: Glandular rotation mammoplasty (63.8%), tumour-adapted rotation mammoplasty (20.9%), dermoglandular rotation mammoplasty (6.7%), 4.4% (lateral thoracic wall advancement), 0.7% latissimus dorsi flap (0.7%) and others (13.5%). Tumour-free margins were achieved in 88.6% of all patients at first surgery. Recurrence was independent of the surgical technique used, resection volume, T-size (in a T1/T2-cohort), nodal status (in low N-stages: NO/N1) and histopathology (inv.-ductal vs. lobular), however non-invasive subtype (DCIS), high grading (G3 vs. G1), non-luminal Her2 positive BC and triple-negative breast cancer (TNBC) were significantly associated with local recurrence. Conclusions: Five defined oncoplastic principles presented in our nomogramme (targeted breast surgery) allow the reconstruction of major segmental resection defects during breast-conserving therapy with high clinical applicability and result in favorable oncological and aesthetic outcome. Recurrence was not a function of traditional prognostic factors like T-size or nodal status (in a T1/T2, N0/N1 cohort), but of grading, intrinsic subtypes and non-invasive breast cancer components. Lobular histology, multicentricity and DCIS were predictive for breast preservation failure and conversion to mastectomy. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Breast conservative surgery Local recurrence Surgical technique Targeted breast surgery Predictors of breast preservation failure
Definitions and surgical principles Breast-conserving therapy (BCT) consisting of surgical removal of the primary tumour followed by whole breast irradiation is an alternative to mastectomy which results in equivalent long-term survival. Although rates of BCT have increased
* Corresponding author. E-mail addresses: [email protected] (M. Rezai), [email protected] (S. Kraemer), [email protected] (R. Kimmig), [email protected] (P. Kern).
over time worldwide, there is no consensus about what amount of normal breast tissue should be removed as a margin to minimize the risk of local recurrence. The manifest of the SSO (Society of Surgical Oncology) e ASTRO (American Society of Radiation Oncology) Consensus Panel underlined the importance of obtaining negative margins defined as no ink on tumour (invasive cancer or DCIS), to optimize local control. This was based on the finding in the meta-analysis of Houssami et al. that margins of 1, 2, or 5 mm were not associated with significantly different risks of local recurrences [1]. Oncoplastic principles were introduced into breast-conserving surgery 20 years ago to allow oncologically safe breast
http://dx.doi.org/10.1016/j.breast.2015.07.024 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
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Fig. 1. Glandular rotation mammaplasty.
conservation, by performing a wide excision for tumours and those in difficult locations limiting the risk of postoperative deformities. Numerous surgical techniques with tissue displacement and tissue replacement have been published with different indications, incision lines and suggested rotation techniques, however a systematic and structured approach for oncoplastic breast surgery was missing. During the last years we have defined five reconstruction principles introducing a new concept of breast-conserving surgery e targeted oncoplastic breast-conserving surgery. We analyzed the oncological and aesthetic outcome of targeted oncoplastic breastconserving surgery in the era of multimodal therapy of early breast cancer in more than 1000 patients [2]. Five major principles in targeted breast (-conserving) surgery were prospectively defined based on the localization, size of the segmental resection defect, size of the breast and the necessity for skin resection during breast-conserving therapy. These major principles were: BCT-glandular rotation, BCT-dermoglandular rotation, BCT-tumouradapted reduction mammoplasty, BCTlateral thoracic wall advancement, BCT-thoracoepigastric flap. In the Düsseldorf Oncoplastic study, we analyzed feasibility, oncological outcome and aesthetic results. Systemic adjuvant treatment and radiotherapy was applicated according to international guidelines.
Oncoplastic techniques Glandular rotation mammaplasty (63.8%) In cases of segmentectomy without skin resection the glandular defect is easily approximated by mobilising glandular flaps. For the standard segmentectomy an incision directly over the area to be removed is performed. For lesions in the upper breast, incisions are following Langer's lines. The skin is undermined in the affected region, detaching the glandula from the skin. Only after resection of a segment, and after approximating the tissue, further skin mobilisation is performed in skin retracted areas. This minimizes extensive mobilization which has an impact on the chances of long term post-surgical surveillance for recurrence (“inner aesthetic aspects”). In some cases, the central portion of the breast needs to be undermined, separating the nippleeareola-complex from the underlying breast tissue. This allows transfer of some of the central volume of the breast towards the defect, facilitating the replacement of tissue and preventing deviation of the nippleeareola-complex towards the tumour bed. After clip-marking of the tumour bed, the two lateral glandular flaps are approximated and sutured into the defect. This approach was used for 63.8% breast cancers and was applied to all tumour locations (Fig. 1).
Fig. 2. Dermoglandular rotation mammaplasty.
Fig. 3. Tumour-adapted mastopexy without nipple-areola-transposition (according to Rezai).
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Fig. 4. Tumour-site adapted reduction mammaplasty with transposition of the nipple-areola-complex (according to Rezai).
Fig. 5. Lateral thoracic wall advancement (according to Rezai).
Dermoglandular rotation mammaplasty (6.7%) A limitation of excisions of the skin of the upper or lower inner breast quadrant is that upward or downward displacement of the nippleeareola complex may result when too much skin is removed above or below the nipple. Skin resection is performed in a radial orientation. To avoid “birds peak deformation” dermoglandular rotation as tumour-adapted mastopexy is an adequate technique to prevent breast deformities in the lower inner breast quadrant and the lower 6 o'clock localization (Fig. 2).
Tumour-adapted reduction mammoplasty (20.9%) Another oncoplastic approach, when breast volume allows it (B cup or larger), is to perform a remodelling mammoplasty. The early use of mammoplasty techniques for breast-conserving surgery involved patients with large tumours located in the lower pole of the breast (superior pedicle mammoplasty). Lower-pole resections cause more deformities than resections in the upper quadrants and these are impossible to prevent with the simple
unilateral techniques just described. Some patients develop a major deformity that presents with a characteristic “bird's peak” appearance, caused by skin retraction of the lower pole with unsufficient filling and downpointing of the nipple. The tumouradapted reduction mammaplasty avoids these bird peak deformation and allows resection of tumors of all locations in the breast (Fig. 3). There are many advantages of this approach, but the main disadvantage is the need to achieve contralateral symmetry, which can be performed simultaneously in order to avoid secondary procedures. There is a large spectrum of published techniques for mammoplasty with limitations in long term aesthetic outcomes, scars and pedicles. We developed a standardized and universal technique with an inferior flap to overcome the limitations of single mammoplasty techniques published before (Fig. 4).
Lateral advancement flap (4.4%) This technique was developed by the author to reconstruct lateral defects of the breast by mobilization of tissue from the
Fig. 6. Thoraco-epigastric flap.
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Fig. 7. Distribution of tumour locations.
lateral part of the M. latissimus dorsi which is attached to the glandular resection interface (Fig. 5). Thoracoepigastric flap and other techniques For patients with breast cancer localised in the lower inner quadrant with a need of a larger skin resection, a small thoracoepigatric flap (Fig. 6) can be used to reconstruct the resection defect adequately. In most patients, a dermoglandular rotation mammaplasty as volume displacement method will be the alternative for the breast-conserving treatment of tumours in this location. Recurrence and breast conservative therapy The risk of breast cancer recurrence is determined by tumour burden, biology and local and systemic therapy [3]. Many variations of local removal of the tumour burden have evolved in the past, often with extensive surgery combined with flap surgery to reconstruct the defect. However, it is the systemic treatment of the tumoure besides a clear resection of the tumour with no ink on margins e which determines the local course of the disease most. As Mannino et al. indicated, risk of local recurrence was cut down to the half by use of tamoxifen and other endocrine agents [4].
In our Düsseldorf Oncoplastic study, we analyzed recurrence and oncological outcome related to surgical techniques, patients characteristics (age …) and tumour characteristics (tumour size, histopathology, grading, intrinsic subtype). Furthermore we explored the aesthetic outcome related to tumour location, surgical technique, resection volume, age, BMI and other factors. For selection of surgical techniques, we applied the following nomogramme (most frequent used technique is displayed in italics): 1. Upper outer quadrant: Glandular rotation mammaplasty, dermoglandular mammaplasty, lateral advancement flap, latissimus dorsi flap 2. Upper inner quadrant: Glandular rotation mammaplasty, latissimus dorsi flap 3. Lower outer quadrant: Tumour-adapted mastopexy, glandular rotation mammaplasty, latissimus dorsi flap 4. Lower inner quadrant: Tumour adapted mastopexy, glandular rotation mammaplasty, latissimus dorsi flap The distribution of tumour locations is shown in Fig. 7. The frequency of surgical techniques is shown in Fig. 8. Intrinsic subtypes in our oncoplastic cohort are distributed as shown in Fig. 9.
Fig. 8. Distribution of surgical techniques.
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Fig. 9. Distribution of intrinsic subtypes.
Fig. 10. Recurrence and histopathology.
Recurrence and histopathology
Clearness of margins
We analyzed which types of histopathology yield the highest recurrence rates and found the non-invasive subtypes to be at highest level, followed by the combination invasive and noninvasive subtype (Fig. 10).
The status of clearness of margins was not determined by T-size, resection volume or intrinsic subtype (p > .05). Influencing factors for clearness of margins were multicentricity, multifocality and DCIS (p < .001).
Fig. 11. Recurrence and T-size.
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Recurrence and T-size We found recurrences were not differing significantly in the T1/ T2 cohort due to tumour size. Of note, 2 recurrences occurred in the T1a-tumours yielding a high recurrence rate of 7.1%. These were due to a TNBC/G3-tumour and a non-luminal-Her2-tumour in the stage T1a. High recurrence rates in T3-tumours were related to low representation of that tumour stage (n ¼ 3) with one recurrence (Fig. 11). Recurrence and grading Fig. 12 shows the representation of grading in our cohort and the corresponding recurrence rates which were incremental with grading. Recurrence and intrinsic subtypes Fig. 13 shows the representation of intrinsic subtypes in our cohort and the corresponding recurrence rates which were depending on the specific subtype. Discussion Breast conservative treatment has become the standard treatment as a legacy of Umberto Veronesi who founded the groundwork for the preservation of the body image with MILAN I study in
the late 1970ies [11,12]. In the EBCTCG-Meta-Analysis 2011,local control achieved by BCS and adjuvant radiotherapy led to a recurrence free survival of 84.4% at 10 years in nodal-negative breast cancer [13]. Breast conservative surgery has two aspects: oncological safety and aesthetic outcome [14]. Various techniques to achieve these goals have been published, and there is a lack of systematic approach when to appropriately use any of these techniques [15e21]. A case cohort study which has been published recently used the McKissock Mammoplasty Technique [22] as surgery for difficult tumor locations (lower-inner or lower-outer quadrant) with unclear margins at 12% of all cases and secondary mastectomy rates at 8% [23]. Our cohort corresponded well with these findings with slightly lower rates at 11.4% for unclear margins and 7.6% for secondary mastectomy. Another recent study [24] used the Lejour technique e which was originally designed as a reduction mammaplasty with a vertical scar [25,26] e as an oncoplastic technique to achieve local control e with a medial pedicle approach for early breast cancer. This study group also achieved a high degree of patient satisfaction (73%) as in our cohort (88%), but e unlike in our study e did not record any loco-regional or distant recurrences. This may be related to the fact that the case-load of their study was small (n ¼ 30) and follow-up was short (20 months). The Lejour technique as a reduction mammoplasty pattern has its limitations in more extensive macromastia, as the amount of removal of breast tissue is limited. Many other techniques for reduction mammoplasty have been described [26e32], however Shestak KC [33],
Fig. 12. Recurrence and grading.
Fig. 13. Recurrence and intrinsic subtype.
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Rezai M et al. [34e35] and Spear SL [36], described the use of mammoplasty techniques in an oncoplastic context to achieve a high level of local control combined with a high level of aesthetic outcome. In this study, we present a nomogramme for surgical treatment of all tumor locations and all breast sizes applying five simple surgical techniques without the necessity of extensive replacement of tissue using flaps from distant donor regions. In the mammoplasty technique applied in our nomogramme, we use inferior-pedicled approach by Ribeiro [31e32] in the modification of Rezai [35]. The nippleeareola complex derives its blood supply solely through the corium from the cranially pedicled skin. No total necrosis of the nipple-areola complex occurred in our whole cohort. As to the influence of the histopathological subtype on local recurrence, we found an overall recurrence rate of 4.0% at a median follow-up of 5.2 years in the whole cohort. Recurrence rates up to 9% are reported in similar cohorts with the same follow-up in literature [37e38]. In our study, non-invasive subtypes had the highest recurrence rates: DCIS 6.5% and CLIS 7.5%. As to recurrence rates in invasive breast cancer, invasive tumor subtypes recurrence rates were not differing significantly between invasive-ductal and invasive-lobular subtype (p > 0.05). This corresponds well with recent findings of Garcia-Fernandez A et al. [39] who found at a median follow-up of 76 months a recurrence rate of 4% vs. 3.2% for invasive-ductal and invasivelobular breast cancer (p ¼ n.s.). Also in their study, lobular histology was more frequently associated with re-excision and/or mastectomy. In our study, necessity of secondary mastectomy to achieve local control was 5.8% with invasive-ductal breast cancer and 13.6% with invasive-lobular breast cancer (p ¼ 0.001). In our cohort, rate of unclear margins was as low as 11.4% at first surgery in our cohort and only in 7.2% a two-step mastectomy had to be performed following breast conservation attempt. DCIS with and without invasive subtype was predictive of mastectomy (p ¼ 0.001). In international literature, unclear margins are published at a frequency of 10.6e38% at first surgery [40e45]. We identified 11.4% (108/944) patients with unclear margins at first surgery, out of which 89.8% opted for re-excision of margins. However, 10.2% (11/108) refused re-excision, resulting in a rate of 1.5% remaining with unclear margins. No recurrence was recorded in these 11 individuals with remaining unclear margins at a median follow-up of 5.2 years after multimodal treatment. Houssami N et al [46] published a meta-analysis of 33 studies with a minimum follow-up of 4 years and in-breast true recurrence rate of 5.3%, and demonstrated that the distance of clear margins e 1, 2 or 5 mm e did not significantly have an impact on local recurrence. Studies of surgical margins in lumpectomy for breast cancer that “bigger is not better” (Morrow) [46]. However, as stated in the recent SSO-ASTRO-Guidelines [47] margins need to be cleared in terms of “no ink on margins”. Contrary to our findings in this cohort, there is evidence in other studies that unclear margins affect local recurrence and disease-free survival [48], especially in high-risk tumor subtypes, as we also found most recently in a cohort of 2037 patients with triple-negative breast cancer [49]. Traditional prognostic factors like T-size [50,51] in a cohort with a typical distribution of national mammography screening from 50 to 69 years with predominantly T1 and T2-tumors did not show a significant increase of recurrence rate from T1 to T2 stage. Whereas these findings of our study differ from older, published reports [52e54] and might not apply to higher tumor stages (T3, T4) having a low representation in our cohort, it corresponds well with the concept of Sorlie et al. [55] of intrinsic subtypes which primarily govern the course of the disease due to their inborn gene pattern. We also validated this concept in a clinical setting of a large cohort
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recently [56]. The strongest indicator for predicting local recurrence and survival was intrinsic subtype (s. Fig. 13). However, grading as a prognostic factors remains a strong predictor of recurrence as it was demonstrated again in large cohorts before [57,58] and this was also confirmed in our cohort with a 5years-local recurrence rate 1.0% of G1, 3.5% in G2 and 7.0% in G3. The HR for disease recurrence was 3.7 for G3 compared with G1. Also the lymph node status is still a valid prognostic factor for disease recurrence [59e61]. However, in low lymphatic disease we did not detect significant differences in recurrence rates (p > 0.05). Conclusion We explored surgery-related factors like resection volume and margins and did not find a correlation with recurrence and survival parameters. Analyzing more than 1000 patients with breast conservative therapy, we found the following principles applying to breast conservation and recurrence in a typical cohort of T1/T2-tumours. Recurrence is independent of
T-size (in T1/T2-cohorts) Nodal status (in low N-stages: N0/N1) Histopathology (inv.-ductal vs. lobular) Surgical technique (segmentectomy/quadrantectomy) Resection volume (11e793 g) Recurrence is dependent of
Grading Intrinsic subtype (highest local recurrence rates: TNBC, Her2positive (non-luminal), DCIS) Further development of the traditional concept of oncoplastic breast surgery to a concept of targeted oncoplastic breast-conserving surgery [5e10] with five defined oncoplastic principles allows the reconstruction of segmental resection defects during breastconserving therapy with highest clinical applicability and results in favourable oncological and aesthetic outcomes [2,10]. This approach might be useful in extending the indications for breastconserving therapy. Targeted (oncoplastic) breast surgery (Rezai) integrates anatomical, pathological and reconstructive aspects of breast cancer to achieve favourable local outcomes for the patients e combining oncological and aesthetic prerequisites. Conflict of interest statement The authors have no conflict of interests. References [1] Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014;21(3):717e30. [2] Rezai M, Knispel S, Kellersmann S, Lax H, Kimmig R, Kern P. Systematization of oncoplastic surgery e selection of surgical techniques and patient reported outcome in a cohort of 1035 patients. Ann Surg Oncol 2015 Feb 12 [Epub ahead of print]. [3] Morrow M. Does modern surgery reflect tumor biology?. In: Düsseldorf breast cancer conference (DBCC); 2014. [4] Mannino M. Local relapses are falling after breast conserving surgery and systemic therapy of early breast cancer: can radiotherapy ever be safely withheld? Radiother Oncol 2009;90:14e22. [5] Rezai M. Targeted breast surgery. In: Düsseldorf breast cancer conference (DBCC); 2012. [6] Rezai M, Kern P, Kraemer S. Oncoplastic reduction mammoplasty. In: Urban C, Rietjens M, editors. Oncoplastic and reconstructive breast surgery. Italia: Springer; 2013, ISBN 978-88-470-2651-3.
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Please cite this article in press as: Rezai M, et al., Breast conservative surgery and local recurrence, The Breast (2015), http://dx.doi.org/10.1016/ j.breast.2015.07.024