Neoadjuvant Chemotherapy with Breast Conservation for Locally Advanced Ductal and Lobular Invasive Carcinomas Combining Multimodality Strategies

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1 Med. J. Cairo Univ., Vol. 82, No., March: 37-42, Neoadjuvant Chemotherapy with Breast Conservation for Locally Advanced Ductal and Lobular Invasive Carcinomas Combining Multimodality Strategies EL-SAYED EL-HENDAWY, M.D.*; SALEH M. TEIMA, M.D.* and MOHAMED A. HEGAZY, M.D.** The Departments of Clinical Oncology & Nuclar Medicine* and Surgical Oncology**, Faculty of Medicine, Mansoura University, Egypt Abstract Background: Breast-Conserving surgery (BCS) has generally been limited to T and T2 lesions because it has been thought impossible to achieve good local control with satisfactory cosmesis in patient with more advanced disease. However, many patients with T3 and T4 lesions will exhibit dramatic tumor down staging with neoadjuvant Chemotherapy. Several studies reports low rates of breast conservation after neoadjuvant chemotherapy for operable breast cancers not amenable to initial breast-conserving surgery. Aim of the Work: This study aims to compare the outcome of lobular vs ductal carcinomas after neoadjuvant chemotherapy and to report their local control after conservation breast surgery or mastectcomy. Material and Methods: Between 2005 and 200, 77 patients with clinical stage II/IIIA (invasive ductal carcinoma (IDC) 56 and invasive lobular carcinoma (ILC) 2 breast carcinomas were treated at the Mansoura University Hospital- Department of Oncology and Nuclear Medicine and Mansoura Concology center with primary anthracycline-based polychemotherapy followed by either breast conservation (surgery and/or radiotherapy) or mastectomy. Median follow-up was 2/5 years. Clinical response to primary chemotherapy was significantly worse for lobular than for ductal carcinomas (46 vs 59%; p=0.04), but only histological grade remained predictive in multivariate analysis. Conclusion: After neoadjuvant chemotherapy breast conservation was high for both ductal and lobular carcinomas the lobular type had no adverse effect on locoregional control or overall survival, even in the group of patients treated with breast conservation. Key Words: Breast-Conserving surgery (BCS) Lobular invasive carcinoma. Introduction THE multi-disciplinary approach, including surgery, chemotherapy, endocrine therapy and radiation therapy, has become the standard treatment Correspondence to: Dr. El-Sayed El-Hendawy, The Department of Clinical Oncology & Nuclar Medicine, Faculty of Medicine, Mansoura University, Egypt for primary breast cancer patient with a high risk of recurrence. Although mortality from breast cancer is decreasing in western countries thanks mainly to early detection of the disease by mammography screening and wide usage of postoperative adjuvant systematic therapy, its incidence and mortality are steadily increasing in the rest of the world, including Japan. The new adjuvant approach has been endorsed by several groups and expert for a wide variety of reason [,2] down staging of the tumour remains one of the most important advantages of the neoadjuvont approach [3]. Neoadjuvant chemotherapy is increasingly used in patients with breast cancer. Initially utilized for inflammatory and locally advanced breast cancer; it is now often used to decrease the size of the primary breast tumor in order to achieve breast conservation. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-8 was the initial pivotal study that showed a change in breast conservation rate from 60% in patients undergoing surgery first compared with 68% in patients receiving neoadjuvant chemotherapy [4]. Whether patients with ILC can achieve successful downsizing that would allow for BCS is an important question since response to neoadjuvant chemotherapy is often less impressive in ILC wen compared with IDC. ILC has been shown to be an independent predictor for ineligibility for BCS [5]. Pathological complete response rates have been reported in multiple studies to be lower in patients with ILC (0-3%) compared with IDC (9-20%) [6]. Another studies also showed breast conservation rate to be lower in patients with ILC (6-5%) compared with IDC (29-79%) [7]. 37

2 38 Neoadjuvant Chemotherapy with Breast Conservation Lobular carcinomas are characterized by a specific morophology with discohesive small cells usually associated with estradiol receptor (ER), progesterone receptor (PR) positivity and with a low proliferation rate [8]. These factors are now well established predictive markers of poor response to neoadjuvant chemotherapy [9]. This study aims to compare the outcome of lobular vs ductual carcinomas under neoadjuvant chemotherapy and to report their locoregional control. Patients and Methods Between January 2005 and 200, a total of 77 patients with operable, clinical stage II/IIIA either ductal or lobular invasive breast carcinoma, not amenable to breast conserving surgery, were treated at Mansoura University Hospital Department of Medical Oncology and Surgical Oncology center with primary chemotherapy. All of them had an initial core needle biopsy before the start of treatment 2 with lobular invasive carcinoma and 56 with ductal invasive carcinomas. Median followup was 24 months (2-65). Histological classification was made according to the WHO criteria. Histological grading was performed according to the Scarff Bloom and Richardson method, Bloom and Richardson, 957. Positively to ER and PR was determined by biochemistry. Hormonal receptors (HR) were considered positive when either ER or PR was positive. All slides of lobular carcinomas were respectively reviewed. Treatment decisions were not adapted to the histological type. The following information regarding the treatment details apply both to lobular and ductal carcinomas. No patient received neoadjuvant hormonal therapy. All patients received a median of four (range: -6) cycles of neoadjuvant chemotherapy. Chemotherapy consisted of FAC with 5-Fluorouracil (5F4 500mg/m 2 ) on days, adriamycin (A) (50mg/m 2 or epirubcin E) on days and cyclophosphamide (500mg/m 2 C) on day every 2 days for six cycles (FAC or FEC). Response to primary chemotherapy was assessed clinically 6. According to the International Union against Cancer Criteria Complete response was defined as the total resolution of the breast mass and regional lymph adenopathy as determined by physical examination; partial response was defined as 50% or greater reduction in the product of the two largest perpendicular dimensions of the breast mass and regional adenopathy; minor response was defined as less than a 50% reduction in the product of the two largest perpendicular dimensions. Stable disease was defined as no mea- surable change in the product of the two largest perpendicular dimensions, and progressive disease was defined as an increase of at least 25% in the product of the two largest perpendicular dimensions. Clinical response was divided in two groups: <50 and 50%. Local treatments consisted in breast surgery and radiotherapy. Whenever feasible, it consisted in tumorectomy followed by radiotherapy. When the tumour did not become amenable to conservative surgery, the decision was usually made to perform a mastectomy, followed in most cases by radiotherapy. Radiotherapy delivered a mean dose of 50Gy in 2Gy fractions to the breast, using either standard or lateral decubitus techniques, or to the chest wall. A mean dose of 45Gy (S.D. 2Gy) in fractions was usually delivered to the internal mammary chain and the superaclvicular area with the addition of an axillary irradiation when there was an important involvement or in the absence of an axillary lymph node dissection. In the case of breast-conserving treatments, a boost was delivered to the tumour or to the tumourectomy bed by external beam radiotherapy. The mean total dose was 65Gy to the tumourectomy bed for postoperative radiotherapy. Patients were followed-up clinically every 2 months. Mammograms and/or ultrasound scans were performed annually. Table (): Tumour and treatment characteristics according to the histological type of the invasive breast carcinoma. Total Dutal N-56 Lobular N-2 N % N % Age (DM=0) 45 (33-7) 49 (37-69) <0 2 Median (min max) in years Menopause (DM=0): 0.88 Yes No Clinical T stage 0.03 (DM= 0): T T Clinical N stage 0.6 (DM= 0): N N Histological grade <0-3 (DM=4) a : Hormonal receptors 0.02 (DM=8): ER = and/or PR ER /PR p

3 El-Sayed El-Hendawy, et al. 39 Table (2): Clinical responses to neoadjuvant chemotherapy. Total Dutal N-56 Lobular N-2 N % N % Clinical response to primary chemotharpy: 50% <50% p 0.04 Local treatment (DM=0): 0.0 Tumorectomy followed by RT Mastectomy followed by RT Mastectomy alone Surgery: Breast surgery was either a lumpectomy or a total mastectomy, patients underwent an axillary nodal dissection. All patients with ILC underwent surgery following chemotherapy (See Table 2), only 52% of ILC patients had conservative surgery. In comparison, initial breast conservative surgery was performed in 64% with IDC. Finally, conservative surgery was significantly more frequent for IDC than for ILC (Table 2). Local recurrences were observed in 3.5% of ILC and 8.3% of IDC (p=0.054). Post operative treatment consisted mainly of external radiotherapy, adjuvant endocrine therapy (in case of hormone receptor positivity) and complementary predetermined adjuvant chemotherapy (68 patients). Statistical analysis: Differences between groups were analyzed by the chi-square test for categorical variables and non parametric tests for continuous variables. Actuarial curves were calculated using the Kapalan Meier method and were compared with the log rank test. A logistic regression model was performed to analyze independent factors associated with breast conserving treatments. Multivariate analysis was carried out to assess the relative influence of prognostic factors on overall survival, using the cox proportional hazards model in a backward stepwise procedure. Results A total of 77 patients with either ILC (n=2) patients) or IDC (n=56 patients), treated with neoadjuvant chemotherapy and surgery, were followed in our center for a mean period of 3 years. Overall, patients with ILC tended to be slightly older, with a larger tumor, lower histological grade (SBR) grade, higher N and HR+, and with less frequent inflammatory signs (see Table ). Clinical response to primary chemotherapy was significantly better for ductal invasive carcinomas than for lobular (50% of clinical response in 59% for ductal vs 46% for lobular; p=0.04; Table 2). The rates of breast conserving treatments for lobular carcinomas was lower than that for ductal carcinomas, but the difference was not statistically significant (54% ( out of 2) vs (65% 36 out of 56); p=0.07). Rates of pathological complete response (for all patients who had undergone surgery) were respectively 9% (6 out of 56) for ductal and 4% ( out of 2) for lobular (p=0.94). In the univariate analysis,age (<50/>50), initial tumor size histological type (IDC/ILC), ER status (ER+/ER ), PR status (PR+/PR ), SBR grading (,2,3),mSBR grading (,2), surgical treatment (conservative/mastectomy) and pathological response (pcr/no pcr) were all highly significant for 5-year disease-free survival. A multivariate analysis on the whole Cases, assessing the relationship between overall survival and various characteristics such as age, pathological type, tumor size, msbr (nuclear) grade, hormone receptor status and lymph node status, was performed as shown in Table (3). The results showed that event free-survival and overall survival were related to tumor size, msbr (nuclear) grade, receptor status and nodal involvement, but not related to age and pathological type. Surgery: Breast surgery was either a lumpectomy or total mastectomy. Conservative surgery was significantly more frequent for IDC than for ILC (see Table 2). Local recurrences were observed in 3.5% of ILC and 8.6% of IDC (p=0.054). Pathological response and survival: Histology following neoadjuvant chemotherapy showed persisting invasive lesions in 96% of the patients with ILC: Only 4% of the patients had a pathological complete response (pcr) in breast and axillary samples, whereas 9% of patients with IDC had a pcr. Residual invaded lymph nodes were more frequent in patients with ILC and the rate of patients with positive lymph nodes greater than three was higher in patients with ILC Table (3). The relationship of pcr to hormone receptor status showed that in patients with IDC there was a higher frequency of pcr in HR+ patients. Results cannot be interpreted in patients with ILC only one patient had a pcr. Despite the fact that response to neoadjuvant chemotherapy and surgical

4 40 Neoadjuvant Chemotherapy with Breast Conservation outcome was globally better in patients with IDC, the follow-up at 60 months showed a better relapsefree survival in patients with ILC (75.6% versus 6.8%, see Fig. ) Results were similarly in favor of ILC for overall survival (9.2% versus 79.3%, see Fig. 2). Difference in relapse-free survival and overall survival were still significant. Relapse-free survival probability Survival probability p=0.006 ILC IDC Months Fig. (): Relapse-free survival by histologic type. p= ILC IDC Months Fig. (2): Overall survival by histologic type. Table (3): Overall survival according to patient and tumor characteristics (cox 's regression model). Overall survival PR (IC 95%) Age: <50 > (0.6-.2) Histological type: Lobular Ductal Tumor size: T-T2 T3-T4 M SBR: 2 ER+ ER PN: 0-3N+ >4N+.4 ( ).8 (.4-2.6) 2.3 (.5-3.4) 3.( ) 2.3 (.8-2.8) 5.2 (3.3-8) p NS NS Discussion Neoadjuvant chemotherapy was largely used when breast conservation appeared compromised due to large tumor size and the patient was suitable for chemotherapy. In our study, we observed the differences in surgery between ILC and IDC were not erased by neoadjuvant chemotherapy. Conservation surgery was performed in 52% of patients with ILC 64% with IDC. Pathological complete respmse to chews therapy has been identified as a reliable strong marker for long term survival [0,] but in our series we can't judge as the PCR numbers are only one in ILC. In terms of survival, neoadjuvant strategy, mostly based on anthracyclines, appeared to be similar to a standard surgery followed by adjuvant chemotherapy [4,0] and the main advantage being more breast-conservation surgery. Histologic type was an independent factor for type of surgery. However it was not an independent factor for survival conversely to nodal status, hormone receptor status and Msbr (nuclear grade). The strong expression of ER (and consequently the treatment by tamoxifen) and low cell proliferation are two factors associated with a better survival rate this results in agreement with the results obtained by [2]. The primary goals of neoadjuvant chemotherapy are to permit rest conservation and to achieve pcr as a surrogate of improved long term outcome. Most of the studies demonstrate that pcr rates in ILC are minimal and our study now shows that BCS rates did not appear to be substantially improved with the use of neoadjuvant chemotherapy. Clinical response to neoadjuvant chemotherapy was seen in 46% for ILC and 59% for IDC in our study, similar to those reported in patients with IDC [4,7,4]. A pcr was seen in only one patient (4%), which is also consistent with other ILC series in the literature [7,3,4,5]. It has been suggested that the lower response rate to neoadjuvant chemotherapy in ILC patients would place them at increased risk of local recurrence following BCS 4. In our series, however, with nearly 5 years of follow-up in the neoadjuvant cohort, LR rates after BCS remain exceedingly small well within 5 years LR rates reported for all cohorts undergoing BCS [6,7]. Thus it appears

5 El-Sayed El-Hendawy, et al. 4 that the use of neoadjuvant chemotherapy is not an independent risk factor for the development of LR in ILC patients who undergo BCS following systemic therapy. Conclusion: Our series confirmed that lobular carcinomas demonstrate a lower response rate to neoadjuvant chemotherapy than ductal carcinomas, but that in multivariate analysis. Has no impact in overall survival the breast conversation in our series was promising than the one expected from both histological types. The lobular type had no adverse on locoregional control even in the group of patients treated with breast conservation. ILC tend to be low grade tumours, which are associated with a minor response to chemotherapy compared with higher grade tumours. ILC are frequently estrogen receptor (ER) and progesterone receptor (PR) positive, and usually Her2 negative. Hormone positive tumours are known to be more endocrine therapy and less responsive to chemotherapy. It is known that large tumours, low grade, and ER positivity are associated with minor response to neoadjuvant chemotherapy. Since the hormonal and biologic profile of ILC suggested that it may be more responsive to hormonal therapy, neoadjuvant endocrine therapy in hormone receptor positive ILC may be a better strategy to downsize tumours and increase breast conservation rates. Acknowledgements: We thank all the members of the Clinical Oncology and Nuclear Medicine Mansoura University and also Cancer center in Mansoura, who have contributed to the completion of this study. We also thank Prof. Gamal Elwehidy, Hanem Sakr, Nawal Elkoly, and Inas Abdelhalim for excellent support to all the staff and for their effort along 20 years of help in the management of patient's data and research development. 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