Oncoplastic Breast Surgery after Neoadjuvant Chemotherapy Replacing Mastectomy in Locally Advanced Breast Cancer ( LABC ) : Single Institute Experience

Background: Integration of neoadjuvant chemotherapy (NCT) in early 70s resulted that many LABC tumors become resectable but with total mastectomy especially those with partial response, oncoplastic techniques give better oncological outcome with better cosmetic results. Objective: We evaluate the oncological safety of oncoplastic breast surgery (OS) in LABC showing partial response to NCT. Methods: We prospectively analyzed the data of 32 out of 58 patients with LABC who showed partial response to NCT and could have conservative surgery with advanced oncoplastic techniques rather than total mastectomy. Results: Out of 58 patients with LABC, received neoadjuvant chemotherapy, complete response was observed in 8 patients (13%), partial response reported in 32 (55.1%) cases, 12 patients (20%) had stable disease and 6 patients (10%) showed progressive disease. Data of 32 cases were studied (mean age 44.84 ± 9.10 years; range 26 59 years). Inferior pedicle was performed in 9 cases, mini LD flap in 3 patients, 5 had Grissotti technique, 6 with superomedial pedicle, 4 had V mammoplasty and 3 with J mammoplasty and 2 had vertical mammoplasty. Margins were positive in 5 cases (15.6%) with mean margin width 9.63 ± 5.72 (range 0 22 mm), and the local recurrence was reported in 2 cases (6.2%). Complications were reported in 3 cases (9.3%). The follow up was 1.67 ± 1.03 (range 0 3.3 years). Conclusions: Integration of neoadjuvant chemotherapy together with advanced oncoplastic techniques opens a new way for management of LABC especially those showing partial response with avoidance of total mastectomy, and comparable oncological safety in addition to better aesthetic and psychological outcome.

Total mastectomy was the only surgical management for resectable LABC, till the evolving of the era of down staging by chemotherapy before surgery which termed neoadjuvant chemotherapy (NCT) [4] [5].Furthermore it gives a good control to micrometastasis in early stage thus stopping the unpredictable behavioral changes that occur in the metastatic cells [6] [7].
Unfortunately, some patients give partial response to NCT with only 30% decrease in tumor size according to RECIST (Response Evaluation Criteria in Solid Tumors), created in 90s [8].
Accordingly, there is no substitute other than mastectomy.However in mid 90s Audretsch firstly described the term of oncoplastic breast surgery in which plastic techniques integrated with oncological procedures giving wide resection with more oncological safety and better cosmetic results [9].Different techniques were described ranging from simple glandular reshaping to advanced mammoplasty techniques which were described by Clough et al. as level 2 oncoplasty in which up to 50% of the breast volume could be resected without compromising the aesthetic results [10].
The aim of this study is to evaluate the oncological safety of oncoplastic surgery in LABC patients after neoadjuvant chemotherapy especially those with partial response.

Patients Selection
This planned study was conducted on 58 female patients during the period from January 2012 to February 2013 who presented to our tertiary referral breast unit at Ain Shams University Hospitals with locally advanced breast cancer stage IIIA, IIIB and IIIC according to AJCC staging system and decision was taken to receive neoadjuvant chemotherapy after approval of the ethical committee held in September 2011.
Inclusion criteria were patients with age range between 25 and 60 years old, performance status ≤2, pathologically proven invasive ductal or lobular carcinoma, left ventricular ejection fraction by Echocardiography more than 55%.We excluded pregnant and lactating patients, those with second or previous malig-nancy, patients with multicenteric tumors, those for palliative wide local excision and patients contraindicated for chemotherapy due to comorbidities.We selected those who showed partial response to NCT (32 patients) for oncoplastic techniques for tumor resection and excluded who showed poor response to neoadjuvant chemotherapy, and those with progressive or complete pathological response (26 patients).

Pre-Treatment Evaluation
All patient diagnosed by clinical examination, bilateral breast ultrasound and mammography with assessment of tumor size before and after NCT clinically and radiologically.Pathological diagnosis done by ultrasound guided core biopsy with determining of the hormonal status.The estrogen (ER) and progesterone receptor (PR) status and HER 2 neu expression were assessed by immunohistochemical and FISH or SISH if needed with evaluation of ki67.
Tumors considered hormone positive if more than 10% of cells stain for estrogen and progesterone receptors and Her-2 positive with score +3.
Metastatic work up done routinely for all cases (pelvi-abdomen and chest CT with bone scan).ECHO, electrocardiography and estimation of EF.
All cases were discussed in our (M.D.T) including clinical oncologist, breast surgeons, radiologist and pathologist.The demographic and pathological data of all patients were shown in Table 1.
The histological type of the tumor, the size of the invasive component, the grade of the tumor and the positive number of lymph nodes were all recorded.
In addition to resected specimens weight, margin status and length (Table 2).

Neoadjuvant Chemotherapy
All eligible patients received neoadjuvant chemotherapy before surgery in the form of anthracycline combination (4 cycles AC) i.e. adriamycin 60 mg/m 2 I.V. on day 1 and cyclophosphamide 600 mg/m 2 I.V day 1.Cycles repeated every 21 days for 4 cycles followed by paclitaxel 80 mg/m 2 by I.V. infusion weekly for 12 wks ± Trastuzumab 6 mg/kg every 3 weeks according to the Her 2 stains.CBC and blood chemistry were done before each cycle.
Assessment of tumor response was done routinely after 2 nd cycle and each 2 cycles using by clinical examination and breast imaging according to RECIST criteria.Patient response is shown in Table 3.

Surgical Techniques
All patients in the study had level 2 oncoplasty by the same surgical team.Preoperative marking done in the clinic day before surgery.Five cases had Grissotti technique for centrally located tumors, 3 with mini L.D flap after Upper outer quadrantectomy, 9 patients had inferior pedicle for upper pole tumors, 6 cases with superomedial pedicle for lower pole tumors, vertical mammoplasty done in 2 cases, 4 patients had V mammoplasty for lower inner quadrant tumors and 3

Follow up Protocol
History and physical examination every 3 months with annual mammography (Figure 1).

Discussion
NCT become widely accepted as standard step in management of LABC after the European institute clinical trial in the early 70s to downstage the tumor or to convert irresectable breast cancer to operable one [11], Moreover it has the same 5 year survival and DFS as adjuvant chemotherapy [12].
However not all patients gives good or complete response after NCT, as partial response still reported and consequently wide resections are required with the overlying skin to achieve negative margins.
Standard conservative breast surgery still have limitations especially in difficult quadrants (UIQ, LIQ and central), when >10% of breast volume had to be resected and when skin resection is required [13].
The use of oncoplastic techniques gives more options to have wide resections without compromising the oncological nor cosmetic results.
In this study we evaluate the effectiveness of oncoplastic breast surgery (OS) in patients with LABC showing partial response after NCT as substitute to total We conducted a prospective study on 32 patients had oncoplastic techniques among 58 patients with LABC and received NCT, Specht and Gralow [15] reported 14 patients (25.9%) with LABC had partial response to NCT, Viera et al. [16] published data of 26 had OS from 486 patient had NCT for LABC, In 2015 Emmanuel et al. [17] reported 29 patients with LABC operated by oncoplastic surgery among 119 cases, Also a prospective clinical trial done by Mathes et al.
We determined tumor size in our patients clinically and radiologically, The mean size before NCT 5.23 ± 0.85 cm (range 3.5 -6.8 cm) And after NCT 4.06 ± 0.70 cm (range 2.8 -5.5 cm), In the study conducted by Emmanuel et al. [17] the initial mean size 41.6 mm before and 25.3 mm after NCT in study on 119 patient (29 had oncoplastic surgery), Veira et al. [16] reported initial tumor size 5.26 cm in 26 patients with LABC underwent OS, The term extreme oncoplasty was first described by Silverstein [20] who published data on 66 patients with mean size 77 mm.
One of the predictors for oncological safety is the margin status, we had 5 cases (15.6%) with positive margins with mean width 9.63 ± 5.72 mm, In Brazil Mathes et al. [18] operated 17 patient with LABC utilizing advanced oncoplastic techniques with no positive margins, Similary Viera et al. [16] reported margin length 16.44 mm by oncoplastic surgery with no positive margins, Emiroglu et al. [14] found that the mean surgical margin length was 8.7 mm (range 5 -17 mm) with positive margins in 7.1% of cases, in a study done by Clough et al. [21] patients who received NACT and OS had a positive margins rate 10.9%.Anthracyclin based regimens were used commonly for three to four cycles till the era of Taxanes, till now no optimal duration nor approach has been established, Also the patients response vary widely as some give maximal tumor reduction within one or two cycles, in contrast other patient may require eight cycles or even more [23].
Many trials have studied the role of taxanes in neoadjuvant setting.Regimen selections varied a lot, between combination regimen and sequential, with different schedule and total number of cycles.However, the use of taxanes in neoadju- vant setting seems to be associated with better outcome as regards response rate ranging from 85% to 93% and pathological complete response (PCR) rates from 11% to 31% in the sequential regiments [24] [25].
In our study, we used the sequential regimen 4 cycles of AC followed by paclitaxel weekly for 12 weeks.
Three cases had surgical complications in our study with delay in the adjuvant therapy in 2 cases (6%), Mazouni et al. [26] reported complications rate 16.7% but most of them were minor, Bogusevicius et al. [22] reported complication rate 5%, with delay in adjuvant therapy in one case.

Conclusion
Management of LABC could be done by advanced oncoplastic surgical techniques especially for partial responders to neoadjuvant chemotherapy to avoid total mastectomy meanwhile it can yield comparable oncological results beside the psychological and cosmetic results.

Table 1 .
Demographic and tumor characteristics among the studied group operated by oncoplastic surgery.
SLNB was done in two cases only with negative axilla (clinically and/or radiologically) before starting NCT, while the other cases (n = 30) had formal axillary clearance (level 1, 2).