Abstract

Material & Method

This is a single-center, prospective cohort study, from January 2021 to July 2022. All cases are operated on or supervised by a single surgeon and all clips are parked in breast tumors by a single radiologist.

Inclusion criteria: The inclusion criteria were all patients between the age of 18 and 80 years, who were candidates for NAST and BCT

Exclusion criteria: Patients with early breast cancer needing upfront surgery, patients with the multicentric disease, locally advanced or inflammatory breast cancer, patients opting for mastectomy and patients presented after excision biopsy elsewhere were excluded.

After the institute’s ethical board approval, data of the patients who have fulfilled the inclusion criteria was collected by a standard performa after their consent. This included patient demographics, primary disease, focality of tumor masses, number of clips inserted, radiological and histopathological margin clearance, and any complication; hematoma, clip migration, etc. The data was analyzed using Stata 17.0. We had both continuous and categorical variables in our data. Age, tumor size,   DCIS, and post-NACT tumor size were continuous variables. Categorical variables included the focality of the tumor, presence, and absence of DCIS, margin status, and receptor status. Univariate analysis of age, tumor size, and DCIS was performed. The comparison of the categorical variables is done using bar charts and pie charts.

Pre- NACT Treatment Protocol:

All patients were clinically assessed followed by imaging, biopsy, and a multidisciplinary decision for BCT after neoadjuvant systemic therapy was made and this information is documented.

After the final decision of BCT in MDT the patient was booked for clipping. We used 1-1.5 cm cut pieces of a 5-cc disposable syringe needle; the bevel end of the needle is discarded. These pieces are inserted into the breast tissue via a lumbar puncture (LP) needle under aseptic measures and local anesthesia. It is not only confirmed on ultrasonogram (USG) that the clips are hyperechoic linear structures but also on the post-procedural mammogram (MG) that they are located appropriately. In lesions 2.5cm or > in size, we inserted clips at the widest dimension in the coronal plane.

Post NACT Treatment Protocol: Or Pre-Operative assessment:

Patients were assessed clinically and radiologically after the completion of neoadjuvant therapy to assess the tumor response and pre-operative planning. For patients with complete clinical response (cCR) after NAST, pre surgery mammogram; true lateral and CC views of the concerned  side are taken to see the residual mass as well as the position of the clips. Additionally, ultrasound guided  marking scan was also performed a day before surgery for any residual disease and clips, and the area is marked on the skin, while the patient was lying supine with the concerned arm extended at the right angle (surgical position).

Surgical Protocol: Or Intra-Operative Protocols

A suitable incision was made on the breast and the area of concern was excised with a rim of surrounding normal tissue. Excised specimen was checked under C- arm for clip presence and adequacy of excision. The specimen is oriented with a suture for histopathological evaluation. Histopathologically tumor-free margins remain the gold standard.

We have 80.25% T2 and 18.25% T3 tumors. One patient with a T1 lesion and TPBC included in the study has multifocal lesions. Of 81 patients 73 were on neoadjuvant systemic and 8 on neoadjuvant hormonal treatment. Tumor response to neoadjuvant treatment was categorized into cPR, good, partial and minimal and it was 19.8%, 19.8%, 48.1% and 12.3% respectively. [38] On further analysis we see that cPR  was highest in TNBC, good response in luminal A, partial response again in luminal A, while minimal response ratio was highest in luminal B type of breast cancer in this cohort group (Chart 2). Of interest are 3 patients in our study who have residual microscopic foci of tumour scattered throughout the tumour  bed, 2 of which were seen in luminal A and one in luminal B tumour type.

Out of 81 patients, 72 patients had clear margins on the final histopathology report. Among the remaining 8 patients, 2 patients had positive margins and 6 had unifocal involvement of margins. [22] The uni-focally involved margins don't need re-excision. [23] The one patient with a positive margin was not offered re- excision because according to American Society of Breast Surgeons (ASBrS) 2018 guidelines it may not be necessary for the involved anterior and posterior margins if underlying muscle fascia or overlying skin is removed. [12] In only one patient with ILC, we have positive margins and proceeded with completion mastectomy.

Discussion

In the 1950s Bernard Fisher revolutionized breast cancer management. His concept of breast cancer as a systemic disease changed the entire realm of breast cancer management. [24] Later in 2005, it was proposed that breast cancer is a spectrum of diseases that ranges from locoregional disease to systemic disease. [25] These conceptual advancements in breast cancer understanding opened new horizons not only in systemic management but also in breast conservation therapy (BCT). Many studies demonstrate a significant response of the primary breast lesion to the neoadjuvant therapy with success rates reaching about 80–90%. [26, 27] Even with cCR it is essential to proceed with surgery to see the definitive response of treatment on the tumor. [28]

BCT is a combination of breast-conserving surgery and breast radiation therapy. [29] With every new concept, there are new challenges and with BCT comes the problem of intraoperative localization of tumor bed after the neoadjuvant treatment as well as the oncological margin safety. Metallic clips strategically placed in the tumor bed in the widest dimension not only help the surgeon intra-operatively but also reduce the risks of positive margins and re-excision lumpectomy rates. They help in reducing the ipsilateral breast tumour recurrence (IBTR) and so as overall survival  ( OS) of the patients. Therefore, placement of clips in the lesions before neoadjuvant treatment is currently the standard of care for post-therapy tumor bed localization and adequate margin resection. [10,30-37]

Tumor response to chemotherapy varies in patients, with high-grade tumors of TNBC and HER II enriched types, a complete clinical and pathological response is achieved quite often. [37]

Tumors regression pattern also varies; some tumors has unifocal regression pattern, while some tumors show multiple separate foci of residual tumor cells scattered through out  the tumor bed after NACT. [38]

Different guidelines, tools, and techniques have been in practice to ensure intra-operative tumor bed localization and excision for better oncological margin safety. [39-41] Royal College of Pathologists recommends sampling the entire tumor bed in three dimensions as residual microscopic tumor foci may be scattered throughout it. [38] So, whether the tumor is palpable or not, the goal of the BCT is the complete excision of the tumor bed with clear surgical resection margins, for which our standard is “no ink on tumor”. [14,17,42-46]

As per consensus guidelines on breast cancer lumpectomy margin by the ASBrS histopathological margin status is a surrogate marker of the residual disease in the breast and IBTR. [14,45] Data suggests that histologically positive margins for both invasive or in situ breast carcinoma (ink positive) after a lumpectomy have increased ipsilateral breast tumor recurrence (IBTR) compared to patients with negative margins. [44,47,48] IBTR and LRR after BCT for invasive cancer can impact patient survival. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) concludes that 1 life is saved at a 15-year follow- up for every 4 local recurrences are prevented at 10 years after lumpectomy.[18]

Quality of margin safety can be indirectly measured by re-excision lumpectomy rates (RELR) by institutes and individual surgeons. RELR is being used as a quality measure (QM) by The European Society of Breast Cancer Specialists (EUSOMA), and the National Consortium of Breast Center (NCBC). [49-55] RELR rates vary greatly from 0% to 70% in the United States, and 12% - 13% in England. [49,56] In other centers use of RELR is controversial and as per ASBrS guidelines; RELR shouldn't be used as a single predictor of QM in BCT. [14]

Positive surgical margin rates (PSM) after BCT for breast cancer are variable. PSM have been reported for palpable and nonpalpable lesions as 38%. In a prospective meta-analysis they have 9.4% positive margins and 17.8% close margins, in another study PSM has improved from 6.54 % in 2004 to 3.91 % in 2013. [57-59] Positive margins in BCT is a cause for high LRR and re-excision surgery is a significant  burden on the patient and health care system. [60] Wire localization of the tumor bed is an accepted technique and Lamiaa, et al, has reported clip and wire localization of tumor area with negative margins on a frozen section at 95.5% and negative margins on paraffin blocks at 95%. [12]

Running a breast center in a low-income country isn’t easy. [61] We have higher rates of patients presenting with the T2 and T3 lesions, BCT in T3 lesions is tricky but not impossible. [62,63] In our data 80.25% patients were with T2 lesions followed by 18.52% with T3 lesions.

Most of the patients cannot afford commercially available clips and wire localization of these clips. We observed that multiple clips at the margins of the lesion help to achieve negative margins not only in T2 but T 3 lesions as well. The technique of placing multiple metallic clips at tumor margins has worked effectively in our center. Our study represents the PSM to be 2.46%, focal positives were 7.4% and re-do surgery rates were 1.23%.

Conclusion

In the preview of these results, we can suggest that placing multiple metallic clips strategically in the widest dimension of the tumor in the coronal plane is an approach to ensure oncological safe resection margin intraoperatively. Our study shows that the positive margin percentage is lower than the data around the world and it can provide a base for improvisation in BCT. This is an ongoing study but with current data we can ensure patient safety from the surgical point of view with complete tumor resection even with T3 tumors.

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