POLSKI PRZEGLĄD CHIRURGICZNY 2014, 86, 2, 77–81
10.2478/pjs-2014-0014
Retrospective analysis of local recurrence rate in breast cancer patients treated at the department of surgical oncology in Łódź between 2009 and 2013 Jan Morawiec, Adam Dziki, Zbigniew Morawiec, Agnieszka Kołacińska Department of General and Colorectal Surgery, Medical University in Łódź Kierownik: prof. dr hab. A. Dziki
The aim of the study was to analyze clinicopathological features in breast cancer patients with local recurrence (LR). Material and methods. A retrospective analysis of database of breast cancer patients operated on in the Department of Surgical Oncology in Łódź from 2 January 2009 to 30 June 2013, identified 1080 women with primary breast cancer and 11 patients with LR. Results. LR rate was 0.23% per year. True recurrence (TR) occurred more frequently in patients with luminal B molecular subtype, in HER-2 positive and in triple-negative subgroups. In one patient with luminal -A subtype new primary (triple negative) occurred. TR were noted predominantly in patients with axillary lymph nodes metastases and with luminal B subtype who did not receive adjuvant chemotherapy but were given only endocrine therapy. LR were observed more frequently in patients who did not receive adjuvant radiotherapy or this treatment was delayed. Minimal surgical margins in postoperative specimens measured by pathologist were 4-25 mm, mean 9.5 mm. Conclusions. The LR rate in patients operated on breast cancer in the Department of Surgical Oncology between 2009 and 2013 was low. TR was diagnosed in patients with non- luminal A breast cancer despite wide surgical margins, especially if the patients did not receive optimal adjuvant systemic treatment or radiotherapy was delayed or omitted. Complete cancer excision followed by an immediate implementation of optimal adjuvant treatment seems to be crucial especially in patients with poor tumor biology. Key words: breast cancer, local recurrence
According to the European Society of Mastology (EUSOMA) the opimal treatment of breast cancer patients is carried out in specialist breast units (1). One of the quality indicators is the rate of local recurrence (LR). The guidelines drawn up by the EUSOMA and ESMO (European Society of Medical Oncology) expert panelists accept the rate of LR in breast cancer patients less than 1% per year (2). In highly experienced institutions these figures usually do not exceed 0.5% per year thanks to close cooperation of multidisciplinary team (1, 2). Ipsilateral LR are divided in two different categories: a true recurrence and new primary (3). The differences between both entities are summarized in tab. 1 (3, 4).
The aim of this study was to analyze clinicopathological features in breast cancer patients with LR. Material and methods A retrospective analysis of database of breast cancer patients operated on in the Department of Surgical Oncology, Regional Cancer Center in Łódź from January 2nd 2009 to June 30th 2013, identified 1080 women with primary breast cancer and 11 patients with LR. The database of routine clinicopathological factors for the latter subgroup was created. Descriptive statistical analysis was performed using Excel 2013.
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78
J. Morawiec et al. Table 1. Differentiation between true recurrence and new primary
Definition and localization Distance from the primary tumor Histological features Molecular characteristics
association with dissemination
True recurrence in the breast after breast conserving surgery (BCS) or in the mastectomy scar; defined as re-growth of cancer cells not completely eradicated by initial treatment the same localization or in the vicinity of the primary tumor (definition of „in the vicinity” is vague) the same histological type, grade G, steroid receptor status, however, biomarker or receptor conversion may occur, for instance switch from ER+ to ER pangenomic examinations, clonal analysis, branched evolutionary tumor growth- methods are very expensive, validation is required but it seems that they may be helpful in differentiation may herald
Results Clinicopathological characteristics of the analyzed patients with LR are presented in tab. 2. The cumulative rate of LR in the analyzed group of 1080 patients was 1% (11 out of 1080) which means 0.23% per year. Recurrences were noted in the mastectomy scar, in the residual breast after BCS and in one case in the axilla. Axillary dissection was performed in 477 patients and sentinel node biopsy procedure was carried out in 603 patients. Only one recurrence was classified as the new primary cancer in a patient after BCS as it was located in another breast quadrant with different histological characteristics and grade. Ten recurrences were identified as true ones. Mean age of patients with local recurrence was 61.8 years, range 43-78 years. Recurrence appeared from one to 86 months after primary surgery, mean 25.9 months. Histological characteristics of primary cancers were as follows: ductal carcinoma – in eight patients, lobular in two, mixed in one patient, grading G 1 – one, G2 – two, G3 – six patients. Tumors less than 2 cm (pT1) were resected in three and less than 5 cm (pT2) – in five patients. Three patients with locally advanced breast cancer (cT4) were given preoperative chemotherapy. In postoperative specimens in one patient cancer was classified as ypT2 and in two – as ypT3. Multifocality was described in 3 patients. Metastases to the ax-
New primary in the breast after BCS, distant from the primary tumor, representing de novo cancer away from the primary tumor, e.g. in another breast quadrant, but closer localization also possible may be different from the primary tumor or may be the same (e.g. ductal type) pangenomic examinations, clonal analysis, branched evolutionary tumor growthmethods are very expensive, validation is required but it seems that they may be helpful in differentiation rarely related
illary lymph nodes were found in eight patients, in two of them – micrometastases. In one patient initially with cN+, pathologic complete response in the axillary lymph nodes (ypN0) was confirmed after preoperative chemotherapy. During axillary dissection from 5 to 21 axillary lymph nodes were harvested, mean 11. In one patient sentinel node biopsy was performed. According to the St. Gallen 2011 classification the surrogates of molecular subtypes were: luminal A – in one (new primary), luminal B HER2 negative- in four patients, luminal B HER2 positive – in one patient, non-luminal HER2 positive – in two, triple negative – in three patients. Mastectomy was performed in eight patients, three patients underwent BCS. Minimal surgical margins measured by the pathologist in postoperative specimens ranged between 4 and 25 mm, mean 9.5 mm. In patients with LR who primary underwent BCS, mastectomy was done. LR in the mastectomy scar were widely excised. Recurrence in the axillary region was deemed inoperable. Adjuvant chemotherapy was given to four patients, six patients received adjuvant endocrine treatment. Three patients were given neoadjuvant chemotherapy. One patient treated with tamoxifen interrupted her therapy after 2 months on her own. In one patient taxane was discontinued after one cycle due to unacceptable toxicity. Two patients with HER2 positive tumors received trastuzumab in the adjuvant setting in standard doses. Patient
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79
Local recurrence rate in breast cancer patients
Sentinel lymph node biopsy
Chemotherapy
Trastuzumab
Endocrine therapy
Radtiotherapy
Local recurrence – months after operation
Dissemination of cancer after local recurrence
Lumyes 25 mastectomy BHER2(-)
no
no
no
Tam
no
19
no
Pt2
43 ductal
T2
N2 (macromets in five lymph nodes)
3
HER2
no
5
mastectomy
no
AC (unacceptable toxicity)
yes
no
delay
13
liver
Pt3
59 ductal
T2
N1 (macromets in one lymp node, extracapsular invasion
3
TN
yes
4
BCT
no
AC
no
no
delay
8
no
Pt4
68 ductal
T2
N0
3
LumBHER2(-)
no
8
mastectomy
no
no
no
Tam
no
17
no
Pt5
61 lobular
T1
N1mi (one lymph node)
-
LumBHER2(-)
no
5
mastectomy
no
AC
no
Tam
yes
16
no
Pt6
63 ductal
T1
N0
1
LumA
no
10 BCT
no
no
no
Tam→ AI
delay
64 (new primary TN ductal pT1c)
no
Pt7
51 mixed
cT4 → cN1→ ypN0 ypT2
x
LumBHER2(-)
no
10 mastectomy
no
AC
no
Tam
no consent
86
bone marrow
Pt8
56 ductal
2
LumBHER2(+)
no
6
yes
no
yes
Tam→ AI
yes
41
no
Pt9
69 ductal
2
HER2
no
10 mastectomy
no
AT
to schedule
no
to schedule
1
no
T1
N1mi (one micromet, vascullar emboli)
cT4→ cN1→ypN1 ypT3 (macromets in one lymph node)
Type of surgery
-
Margins (mm)
N1 (macromets in one lymph node)
Mulifocality
pN
T2
Surrogates of molecular subtypes according to St. Gallen 2011 classification
pT
78 lobular
G
Age
Pt1
Histological type
Patient
Table 2. Clinicopathological features in breast cancer patients with local recurrence
BCT
Pt10 60 ductal
T2
N2
3
TN
yes 12 mastectomy
no
AC+T
no
no
no consent
18
no
Pt11 72 ductal
T3
N3
3
TN
no
no
FEC
no
no
yes
2
lungs
10 mastectomy
with cT4N1 and HER2 positive tumor, who did not receive trastuzumab in the neoadjuvant setting, was scheduled to postoperative treatment, however, a rapid and massive local relapse occurred one month after mastectomy. Adjuvant radiotherapy was planned in 9 patients, two patients refused this treatment, in three patients radiotherapy was delayed due to non-medical reasons (non-compliance). In summary: 1. LR rate in breast cancer patients treated in the Department of Surgical Oncology in Lodz was 0.23% per year. 2. True recurrence occurred more frequently in patients with luminal B molecular subtype (5 out of 11 patients), in HER2 positive (3 out of 11) and in triple-negative subgroups (3 out of 11). In one patient with luminal -A subtype new primary (triple negative) occurred. 3. True recurrences were noted predominantly in patients with axillary lymph nodes metastases (9 out of 11 patients).
4. True recurrence occurred in 3 out of 5 patients with luminal B subtype who did not receive adjuvant chemotherapy but were given only endocrine therapy. 5. LR were observed more frequently in patients who did not receive adjuvant radiotherapy (5 out of 9 patients) or this treatment was delayed. 6. Minimal surgical margins in postoperative specimens measured by pathologist were 4-25 mm, mean 9.5 mm Discussion The surgical treatment of breast cancer has evolved over the past 40-50 years from the era of the Halstedian radical mastectomy with wide margins and major pectoral muscle dissection through quadrantectomy with 2-centimeter margins introduced by Veronesi in the seventies of the last century to local excision with margins free from cancer cells on the
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J. Morawiec et al.
inked border of the specimen (St. Gallen 2013) (5, 6, 7). At the same time, rates of LR have declined steadily (6). This phenomenon can be explained by better knowledge of tumor biology, implementation of novel radiation techniques and more effective systemic treatment delivered to patients in experienced and well equipped cancer centers (1, 2). Low recurrence rate at our institution (0.23% per year) is satisfactory. However, careful analysis of our patients indicates that some of them did not receive an optimal adjuvant treatment due to various reasons (see Results section). The importance of adjuvant treatment was shown in many clinical trials. In the NSABP B14 trial, in patients with ER positive breast cancer hormonal therapy with tamoxifen reduced LR rate more than three times in comparison with patients treated with placebo (5). In the NSABP B13 trial, adjuvant chemotherapy administered in ER negative breast cancer patients diminished LR rate five times (8). The addition of trastuzumab to chemotherapy in HER2 positive patients resulted in a 50% decrease of LR rate (9). New targeted therapies (mTOR, PI3K, PARP inhibitors, HER2 dual blockade) should further improve treatment results (10). A precise identification of patients who may benefit from new targeted therapies is mandatory. In this paper we analyzed the relationship between LR rate and surrogates of molecular subtypes according to the St. Gallen 2011 classification (11). We have shown that true recurrence occurred more frequently in patients with luminal B subtype (5 out of 11 patients), in HER2 positive patients (3 out of 11 patients) and in triple negative subtypes (3 out of 11 patients). In patient with luminal A molecular subtype a new primary tumor occurred. Nguyen et al. have demonstrated that LR rate in patients after BCS differed between molecular subtypes, the lowest (0.8% within 5 years) was noted in luminal-A breast cancer, the highest in HER2 positive breast cancer patients especially without trastuzumab (12). In our analysis the highest LR rate was noted in luminal-B subtype patients, followed by HER2 positive and triple negative subgroups. These groups are, however, very small so any conclusions must be drawn with caution. Mazouni et al. have shown that patients with triple negative breast cancer had an increased rate of distant metastases, but LR appeared more frequently in luminal B subtype, as it was revealed in our
analysis (13). Similar results were reported for luminal B patients with low or lack of expression of progesterone receptor (PR) (13). These results suggest that luminal B breast cancer should be carefully monitored as it may have different biology depending on co-expression of steroid and HER2 receptors and higher proliferation indices. Usually luminal B subtype is ranked between low risk luminal A cancers and HER2 positive and triple negative tumors with definitely poor prognosis. Some of our patients with luminal B subtype did not receive adjuvant chemotherapy (3 out of 5) but they were treated with endocrine therapy which in case of more aggressive tumors with higher proliferation rate could be suboptimal and could explain, at least in part, the high LR rate in this subgroup. The question arises whether ER, PR and HER2 status should be taken into account when planning the extent of surgery. The investigators from the Danish Breast Cancer Group denied it showing the similar higher risk of recurrence in patients with ER negative or HER2 positive breast cancer, even if they were submitted to mastectomy (14). A multivariate analysis performed by Mamounas et al. has shown that predictive factors of recurrence was young age, high tumor grade and high score in Oncotype DX, but not the extent of surgery – BCS or mastectomy (15). In our analysis the majority of patients (8 out of 11) underwent total mastectomy, only in three patients BCS was done and surgical margins were ample, mean 9.5 mm. The majority of our patients have cancers with histological grade 3, but only one patient was younger than 50 years. Nine patients were qualified for adjuvant radiotherapy, after BCS or mastectomy. In three patients radiotherapy was delayed (two patients did not give their consent to this treatment, one had a rapid relapse one month after mastectomy). Meta-analysis of 17 randomized clinical trials on 10,601 patients has shown that adjuvant radiotherapy after BCS halves the rate of LR (16). Our results and those published in the literature suggest that local control is the result of interactions between tumor burden, feasibility of its radical resection, receptor and molecular subtype, tumor biology and effectiveness of systemic and local treatment (5, 6, 17). Due to a small sample size, we plan a further multicenter trial on LR, and research on biomarker conversion and cancer dormancy molecular signature in this setting (18).
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Local recurrence rate in breast cancer patients
Conclusions The LR rate in patients operated on breast cancer in the Department of Surgical Oncology between 2009 and 2013 was low. True recurrence was diagnosed in patients with non- luminal A breast cancer despite wide surgical margins,
81
especially if the patients did not receive optimal adjuvant systemic treatment or radiotherapy was delayed or omitted. Complete cancer excision followed by an immediate implementation of optimal adjuvant treatment (systemic and local) seems to be crucial especially in patients with poor prognostic tumor biology.
References 1. www.eusoma.org 2. Aebi S, Davidson T, Gruber G et al.: ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi12-24. 3. West NR, Panet-Raymond V, Truong PT et al.: Intratumoral immune response can distinguish new primary and true recurrence types of ipsilateral breast tumor recurrence. Breast Cancer: Basic and Clinical Research 2011; 5: 105-15. 4. Gerlinger M, Rowan AJ, Horswell S et al.: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883-92. 5. Ho A, Morrow M: The evolution of the locoregional therapy of breast cancer. Oncologist 2011; 16: 1367-79. 6. Morrow M, Harris JR, Schnitt SJ: Surgical margins in lumpectomy for breast cancer-bigger is not better. N Engl J Med 2012; 367: 79-82. 7. Andrè Curigliano G, Criscitiello C, Colleoni M et al.: Highlights from the 13th St Gallen International Breast Cancer Conference 2013. Access to innovation for patients with breast cancer: how to speed it up? Ecancermedicalscience 2013; 7: 299. 8. Fisher B, Dignam J, Mamounas EP et al.: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996; 14: 1982-92. 9. Romond EH, Perez EA, Bryant J et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673-84. 10. Bischoff J, Ignatov A: The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer. Breast Care (Basel) 2010; 5: 134-41.
11. Goldhirsch A, Wood WC, Coates AS et al.: Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22: 1736-47. 12. Nguyen PL, Taghian AG, Katz MS et al.: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008; 26: 2373-78. 13. Mazouni C, Rimareix F, Mathieu MC et al.: Outcome in breast molecular subtypes according to nodal status and surgical procedures. Am J Surg 2013; 205: 662-67. 14. Kyndi M, Sørensen FB, Knudsen H et al.: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008; 26: 141926. 15. Mamounas EP, Tang G, Fisher B et al.: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 2010; 28: 1677-83. 16. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, Correa C et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378: 1707-16. 17. Zumsteg ZS, Morrow M, Arnold B et al.: BreastConserving Therapy Achieves Locoregional Outcomes Comparable to Mastectomy in Women with T1-2N0 Triple-Negative Breast Cancer. Ann Surg Oncol 2013 May 19. (Epub ahead of print). 18. Willis L, Graham TA, Alarcón T et al.: What can be learnt about disease progression in breast cancer dormancy from relapse data? PLoS One 2013; 8: e62320.
Received: 3.12.2013 r. Adress correspondence: 90-647 Łódź, Pl. Hallera 1 e-mail: [email protected]
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10.2478/pjs-2014-0014
Retrospective analysis of local recurrence rate in breast cancer patients treated at the department of surgical oncology in Łódź between 2009 and 2013 Jan Morawiec, Adam Dziki, Zbigniew Morawiec, Agnieszka Kołacińska Department of General and Colorectal Surgery, Medical University in Łódź Kierownik: prof. dr hab. A. Dziki
The aim of the study was to analyze clinicopathological features in breast cancer patients with local recurrence (LR). Material and methods. A retrospective analysis of database of breast cancer patients operated on in the Department of Surgical Oncology in Łódź from 2 January 2009 to 30 June 2013, identified 1080 women with primary breast cancer and 11 patients with LR. Results. LR rate was 0.23% per year. True recurrence (TR) occurred more frequently in patients with luminal B molecular subtype, in HER-2 positive and in triple-negative subgroups. In one patient with luminal -A subtype new primary (triple negative) occurred. TR were noted predominantly in patients with axillary lymph nodes metastases and with luminal B subtype who did not receive adjuvant chemotherapy but were given only endocrine therapy. LR were observed more frequently in patients who did not receive adjuvant radiotherapy or this treatment was delayed. Minimal surgical margins in postoperative specimens measured by pathologist were 4-25 mm, mean 9.5 mm. Conclusions. The LR rate in patients operated on breast cancer in the Department of Surgical Oncology between 2009 and 2013 was low. TR was diagnosed in patients with non- luminal A breast cancer despite wide surgical margins, especially if the patients did not receive optimal adjuvant systemic treatment or radiotherapy was delayed or omitted. Complete cancer excision followed by an immediate implementation of optimal adjuvant treatment seems to be crucial especially in patients with poor tumor biology. Key words: breast cancer, local recurrence
According to the European Society of Mastology (EUSOMA) the opimal treatment of breast cancer patients is carried out in specialist breast units (1). One of the quality indicators is the rate of local recurrence (LR). The guidelines drawn up by the EUSOMA and ESMO (European Society of Medical Oncology) expert panelists accept the rate of LR in breast cancer patients less than 1% per year (2). In highly experienced institutions these figures usually do not exceed 0.5% per year thanks to close cooperation of multidisciplinary team (1, 2). Ipsilateral LR are divided in two different categories: a true recurrence and new primary (3). The differences between both entities are summarized in tab. 1 (3, 4).
The aim of this study was to analyze clinicopathological features in breast cancer patients with LR. Material and methods A retrospective analysis of database of breast cancer patients operated on in the Department of Surgical Oncology, Regional Cancer Center in Łódź from January 2nd 2009 to June 30th 2013, identified 1080 women with primary breast cancer and 11 patients with LR. The database of routine clinicopathological factors for the latter subgroup was created. Descriptive statistical analysis was performed using Excel 2013.
Unauthenticated Download Date | 8/19/15 10:29 AM
78
J. Morawiec et al. Table 1. Differentiation between true recurrence and new primary
Definition and localization Distance from the primary tumor Histological features Molecular characteristics
association with dissemination
True recurrence in the breast after breast conserving surgery (BCS) or in the mastectomy scar; defined as re-growth of cancer cells not completely eradicated by initial treatment the same localization or in the vicinity of the primary tumor (definition of „in the vicinity” is vague) the same histological type, grade G, steroid receptor status, however, biomarker or receptor conversion may occur, for instance switch from ER+ to ER pangenomic examinations, clonal analysis, branched evolutionary tumor growth- methods are very expensive, validation is required but it seems that they may be helpful in differentiation may herald
Results Clinicopathological characteristics of the analyzed patients with LR are presented in tab. 2. The cumulative rate of LR in the analyzed group of 1080 patients was 1% (11 out of 1080) which means 0.23% per year. Recurrences were noted in the mastectomy scar, in the residual breast after BCS and in one case in the axilla. Axillary dissection was performed in 477 patients and sentinel node biopsy procedure was carried out in 603 patients. Only one recurrence was classified as the new primary cancer in a patient after BCS as it was located in another breast quadrant with different histological characteristics and grade. Ten recurrences were identified as true ones. Mean age of patients with local recurrence was 61.8 years, range 43-78 years. Recurrence appeared from one to 86 months after primary surgery, mean 25.9 months. Histological characteristics of primary cancers were as follows: ductal carcinoma – in eight patients, lobular in two, mixed in one patient, grading G 1 – one, G2 – two, G3 – six patients. Tumors less than 2 cm (pT1) were resected in three and less than 5 cm (pT2) – in five patients. Three patients with locally advanced breast cancer (cT4) were given preoperative chemotherapy. In postoperative specimens in one patient cancer was classified as ypT2 and in two – as ypT3. Multifocality was described in 3 patients. Metastases to the ax-
New primary in the breast after BCS, distant from the primary tumor, representing de novo cancer away from the primary tumor, e.g. in another breast quadrant, but closer localization also possible may be different from the primary tumor or may be the same (e.g. ductal type) pangenomic examinations, clonal analysis, branched evolutionary tumor growthmethods are very expensive, validation is required but it seems that they may be helpful in differentiation rarely related
illary lymph nodes were found in eight patients, in two of them – micrometastases. In one patient initially with cN+, pathologic complete response in the axillary lymph nodes (ypN0) was confirmed after preoperative chemotherapy. During axillary dissection from 5 to 21 axillary lymph nodes were harvested, mean 11. In one patient sentinel node biopsy was performed. According to the St. Gallen 2011 classification the surrogates of molecular subtypes were: luminal A – in one (new primary), luminal B HER2 negative- in four patients, luminal B HER2 positive – in one patient, non-luminal HER2 positive – in two, triple negative – in three patients. Mastectomy was performed in eight patients, three patients underwent BCS. Minimal surgical margins measured by the pathologist in postoperative specimens ranged between 4 and 25 mm, mean 9.5 mm. In patients with LR who primary underwent BCS, mastectomy was done. LR in the mastectomy scar were widely excised. Recurrence in the axillary region was deemed inoperable. Adjuvant chemotherapy was given to four patients, six patients received adjuvant endocrine treatment. Three patients were given neoadjuvant chemotherapy. One patient treated with tamoxifen interrupted her therapy after 2 months on her own. In one patient taxane was discontinued after one cycle due to unacceptable toxicity. Two patients with HER2 positive tumors received trastuzumab in the adjuvant setting in standard doses. Patient
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79
Local recurrence rate in breast cancer patients
Sentinel lymph node biopsy
Chemotherapy
Trastuzumab
Endocrine therapy
Radtiotherapy
Local recurrence – months after operation
Dissemination of cancer after local recurrence
Lumyes 25 mastectomy BHER2(-)
no
no
no
Tam
no
19
no
Pt2
43 ductal
T2
N2 (macromets in five lymph nodes)
3
HER2
no
5
mastectomy
no
AC (unacceptable toxicity)
yes
no
delay
13
liver
Pt3
59 ductal
T2
N1 (macromets in one lymp node, extracapsular invasion
3
TN
yes
4
BCT
no
AC
no
no
delay
8
no
Pt4
68 ductal
T2
N0
3
LumBHER2(-)
no
8
mastectomy
no
no
no
Tam
no
17
no
Pt5
61 lobular
T1
N1mi (one lymph node)
-
LumBHER2(-)
no
5
mastectomy
no
AC
no
Tam
yes
16
no
Pt6
63 ductal
T1
N0
1
LumA
no
10 BCT
no
no
no
Tam→ AI
delay
64 (new primary TN ductal pT1c)
no
Pt7
51 mixed
cT4 → cN1→ ypN0 ypT2
x
LumBHER2(-)
no
10 mastectomy
no
AC
no
Tam
no consent
86
bone marrow
Pt8
56 ductal
2
LumBHER2(+)
no
6
yes
no
yes
Tam→ AI
yes
41
no
Pt9
69 ductal
2
HER2
no
10 mastectomy
no
AT
to schedule
no
to schedule
1
no
T1
N1mi (one micromet, vascullar emboli)
cT4→ cN1→ypN1 ypT3 (macromets in one lymph node)
Type of surgery
-
Margins (mm)
N1 (macromets in one lymph node)
Mulifocality
pN
T2
Surrogates of molecular subtypes according to St. Gallen 2011 classification
pT
78 lobular
G
Age
Pt1
Histological type
Patient
Table 2. Clinicopathological features in breast cancer patients with local recurrence
BCT
Pt10 60 ductal
T2
N2
3
TN
yes 12 mastectomy
no
AC+T
no
no
no consent
18
no
Pt11 72 ductal
T3
N3
3
TN
no
no
FEC
no
no
yes
2
lungs
10 mastectomy
with cT4N1 and HER2 positive tumor, who did not receive trastuzumab in the neoadjuvant setting, was scheduled to postoperative treatment, however, a rapid and massive local relapse occurred one month after mastectomy. Adjuvant radiotherapy was planned in 9 patients, two patients refused this treatment, in three patients radiotherapy was delayed due to non-medical reasons (non-compliance). In summary: 1. LR rate in breast cancer patients treated in the Department of Surgical Oncology in Lodz was 0.23% per year. 2. True recurrence occurred more frequently in patients with luminal B molecular subtype (5 out of 11 patients), in HER2 positive (3 out of 11) and in triple-negative subgroups (3 out of 11). In one patient with luminal -A subtype new primary (triple negative) occurred. 3. True recurrences were noted predominantly in patients with axillary lymph nodes metastases (9 out of 11 patients).
4. True recurrence occurred in 3 out of 5 patients with luminal B subtype who did not receive adjuvant chemotherapy but were given only endocrine therapy. 5. LR were observed more frequently in patients who did not receive adjuvant radiotherapy (5 out of 9 patients) or this treatment was delayed. 6. Minimal surgical margins in postoperative specimens measured by pathologist were 4-25 mm, mean 9.5 mm Discussion The surgical treatment of breast cancer has evolved over the past 40-50 years from the era of the Halstedian radical mastectomy with wide margins and major pectoral muscle dissection through quadrantectomy with 2-centimeter margins introduced by Veronesi in the seventies of the last century to local excision with margins free from cancer cells on the
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J. Morawiec et al.
inked border of the specimen (St. Gallen 2013) (5, 6, 7). At the same time, rates of LR have declined steadily (6). This phenomenon can be explained by better knowledge of tumor biology, implementation of novel radiation techniques and more effective systemic treatment delivered to patients in experienced and well equipped cancer centers (1, 2). Low recurrence rate at our institution (0.23% per year) is satisfactory. However, careful analysis of our patients indicates that some of them did not receive an optimal adjuvant treatment due to various reasons (see Results section). The importance of adjuvant treatment was shown in many clinical trials. In the NSABP B14 trial, in patients with ER positive breast cancer hormonal therapy with tamoxifen reduced LR rate more than three times in comparison with patients treated with placebo (5). In the NSABP B13 trial, adjuvant chemotherapy administered in ER negative breast cancer patients diminished LR rate five times (8). The addition of trastuzumab to chemotherapy in HER2 positive patients resulted in a 50% decrease of LR rate (9). New targeted therapies (mTOR, PI3K, PARP inhibitors, HER2 dual blockade) should further improve treatment results (10). A precise identification of patients who may benefit from new targeted therapies is mandatory. In this paper we analyzed the relationship between LR rate and surrogates of molecular subtypes according to the St. Gallen 2011 classification (11). We have shown that true recurrence occurred more frequently in patients with luminal B subtype (5 out of 11 patients), in HER2 positive patients (3 out of 11 patients) and in triple negative subtypes (3 out of 11 patients). In patient with luminal A molecular subtype a new primary tumor occurred. Nguyen et al. have demonstrated that LR rate in patients after BCS differed between molecular subtypes, the lowest (0.8% within 5 years) was noted in luminal-A breast cancer, the highest in HER2 positive breast cancer patients especially without trastuzumab (12). In our analysis the highest LR rate was noted in luminal-B subtype patients, followed by HER2 positive and triple negative subgroups. These groups are, however, very small so any conclusions must be drawn with caution. Mazouni et al. have shown that patients with triple negative breast cancer had an increased rate of distant metastases, but LR appeared more frequently in luminal B subtype, as it was revealed in our
analysis (13). Similar results were reported for luminal B patients with low or lack of expression of progesterone receptor (PR) (13). These results suggest that luminal B breast cancer should be carefully monitored as it may have different biology depending on co-expression of steroid and HER2 receptors and higher proliferation indices. Usually luminal B subtype is ranked between low risk luminal A cancers and HER2 positive and triple negative tumors with definitely poor prognosis. Some of our patients with luminal B subtype did not receive adjuvant chemotherapy (3 out of 5) but they were treated with endocrine therapy which in case of more aggressive tumors with higher proliferation rate could be suboptimal and could explain, at least in part, the high LR rate in this subgroup. The question arises whether ER, PR and HER2 status should be taken into account when planning the extent of surgery. The investigators from the Danish Breast Cancer Group denied it showing the similar higher risk of recurrence in patients with ER negative or HER2 positive breast cancer, even if they were submitted to mastectomy (14). A multivariate analysis performed by Mamounas et al. has shown that predictive factors of recurrence was young age, high tumor grade and high score in Oncotype DX, but not the extent of surgery – BCS or mastectomy (15). In our analysis the majority of patients (8 out of 11) underwent total mastectomy, only in three patients BCS was done and surgical margins were ample, mean 9.5 mm. The majority of our patients have cancers with histological grade 3, but only one patient was younger than 50 years. Nine patients were qualified for adjuvant radiotherapy, after BCS or mastectomy. In three patients radiotherapy was delayed (two patients did not give their consent to this treatment, one had a rapid relapse one month after mastectomy). Meta-analysis of 17 randomized clinical trials on 10,601 patients has shown that adjuvant radiotherapy after BCS halves the rate of LR (16). Our results and those published in the literature suggest that local control is the result of interactions between tumor burden, feasibility of its radical resection, receptor and molecular subtype, tumor biology and effectiveness of systemic and local treatment (5, 6, 17). Due to a small sample size, we plan a further multicenter trial on LR, and research on biomarker conversion and cancer dormancy molecular signature in this setting (18).
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Local recurrence rate in breast cancer patients
Conclusions The LR rate in patients operated on breast cancer in the Department of Surgical Oncology between 2009 and 2013 was low. True recurrence was diagnosed in patients with non- luminal A breast cancer despite wide surgical margins,
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especially if the patients did not receive optimal adjuvant systemic treatment or radiotherapy was delayed or omitted. Complete cancer excision followed by an immediate implementation of optimal adjuvant treatment (systemic and local) seems to be crucial especially in patients with poor prognostic tumor biology.
References 1. www.eusoma.org 2. Aebi S, Davidson T, Gruber G et al.: ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi12-24. 3. West NR, Panet-Raymond V, Truong PT et al.: Intratumoral immune response can distinguish new primary and true recurrence types of ipsilateral breast tumor recurrence. Breast Cancer: Basic and Clinical Research 2011; 5: 105-15. 4. Gerlinger M, Rowan AJ, Horswell S et al.: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883-92. 5. Ho A, Morrow M: The evolution of the locoregional therapy of breast cancer. Oncologist 2011; 16: 1367-79. 6. Morrow M, Harris JR, Schnitt SJ: Surgical margins in lumpectomy for breast cancer-bigger is not better. N Engl J Med 2012; 367: 79-82. 7. Andrè Curigliano G, Criscitiello C, Colleoni M et al.: Highlights from the 13th St Gallen International Breast Cancer Conference 2013. Access to innovation for patients with breast cancer: how to speed it up? Ecancermedicalscience 2013; 7: 299. 8. Fisher B, Dignam J, Mamounas EP et al.: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996; 14: 1982-92. 9. Romond EH, Perez EA, Bryant J et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673-84. 10. Bischoff J, Ignatov A: The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer. Breast Care (Basel) 2010; 5: 134-41.
11. Goldhirsch A, Wood WC, Coates AS et al.: Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22: 1736-47. 12. Nguyen PL, Taghian AG, Katz MS et al.: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008; 26: 2373-78. 13. Mazouni C, Rimareix F, Mathieu MC et al.: Outcome in breast molecular subtypes according to nodal status and surgical procedures. Am J Surg 2013; 205: 662-67. 14. Kyndi M, Sørensen FB, Knudsen H et al.: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol 2008; 26: 141926. 15. Mamounas EP, Tang G, Fisher B et al.: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 2010; 28: 1677-83. 16. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, Correa C et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378: 1707-16. 17. Zumsteg ZS, Morrow M, Arnold B et al.: BreastConserving Therapy Achieves Locoregional Outcomes Comparable to Mastectomy in Women with T1-2N0 Triple-Negative Breast Cancer. Ann Surg Oncol 2013 May 19. (Epub ahead of print). 18. Willis L, Graham TA, Alarcón T et al.: What can be learnt about disease progression in breast cancer dormancy from relapse data? PLoS One 2013; 8: e62320.
Received: 3.12.2013 r. Adress correspondence: 90-647 Łódź, Pl. Hallera 1 e-mail: [email protected]
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