Comparison of tumor clipping and skin projection marking methods in patients undergoing breast conserving surgery after neoadjuvant chemotherapy

Objective: Breast cancer is the most common cancer in women and is also the second most common cause of cancer-related deaths in women. Its frequency and mortality are increasing worldwide (1-3). Breast cancer is highly heterogeneous due to its biological subtypes and identified genetic mutations. Neoadjuvant therapy occupies an important place in the current treatment of breast cancer. Neoadjuvant therapy provides many clinical advantages such as a decrease in the stage of the disease, an increase in breast conserving surgery rates, determination of the response to systemic chemotherapeutics, and a decrease in axillary dissection rates. When the primary tumoral mass in the breast is evaluated by physical examination and imaging methods with neoadjuvant systemic therapy, an unresponsive, partial or complete response may develop, and rarely it may progress. It is known that 30% of patients with complete clinical response do not develop a pathological complete response (4). Patients who receive neoadjuvant therapy should be operated on, even if they have complete responses in physical examination and radiology because of clinical-pathological discordance. In patients scheduled for breast conserving surgery after neoadjuvant chemotherapy, the primary mass is a metallic clip mark, and the skin projection should be marked with permanent paint (tattoo, tatuage) or mapping method. The standard method is marking with metallic clip markers. In patients whose tumors cannot be palpated after neoadjuvant treatment, which is marked with a clip marker, the location of the clip is marked with a wire on the day of surgery with an imaging. The area marked with a wire is excised in accordance with the principles of breast conserving surgery. There are studies reporting the pathological complete response rate to neoadjuvant therapy up to 65% (5, 6). Since the mass becomes non-palpable clinically after neoadjuvant treatment, wire marking is frequently applied after metallic marker marking. In this situation, the treatment costs and complications due to the invasive procedure increase. Complications such as dislocation (migration), implantation of tumor cells, hematoma, ecchymosis, pain, and infection may occur in clip marking technique. In this procedure, additional invasive interventions such as radiologist need, preoperative wire marking are also required. Instead of this invasive intervention, we aimed to prevent complications that may occur in the standard technique and reduce the cost of the treatment by using the non-invasive technique of marking the skin projection method. Patients and Methods: Female patients older than 18 years of age, diagnosed with cT1-T3, cN - / +, M0 breast cancer and scheduled for breast conserving surgery following neoadjuvant therapy between January 2019 and December 2020 at the Breast Diseases and Breast Surgery Clinic, Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University were included in the study. While the complication rate was 20% in the standard method, we hypothesized that this rate would decrease to 0% in the tattoo method, and the sample size was calculated as 68 patients, with the effect size d=0.34, α=0.05 and power (1-β) = 80%. Due to pandemic conditions, the study was completed with a total of 40 patients, 20 patients in each group. The effect size of our study in reducing complications compared to the standard method was found to be d=0.5 and its power was 88%. In the control group, the tumors were marked by metallic clips during neoadjuvant therapy, under the guidance of ultrasonography in the breast radiology department. In the study group, tattoos were applied at th skin projection of the mass with permanent paint. AC + T ± Anti-Her2 protocols were applied to 98% (n = 39) of the patients as neoadjuvant systemic chemotherapy. After neoadjuvant systemic chemotherapy, breast conserving surgery was performed by marking with a sample matching wire before surgery in patients who were nonpalpable in the group marked with a clip; In the tattoo group, breast conserving surgery was performed with the skin containing the tattoo. The volume of the specimen removed during the operation was measured in cm3 of the water overflow vessel. The distance between the tumor and the skin was determined by the frozen section. If necessary, re-excision was performed and the volume of this response was measured. After neoadjuvant treatment, surgical margins were compared between the two groups. While evaluating the findings obtained in the study, SPSS (Statistical Package for the Social Sciences) version 25.0 (IBM Corp., Armonk, NY, USA) program is used. Descriptive methods (number, percentage, mean, standard deviation, etc.) were used while evaluating the study volume. Differences between groups were analyzed using the Chi-Square test, and quantitative differences were analyzed using the Mann-Whitney U test. Significance was determined at p below 0.05. Results: The median age of the 40 patients included in the study was 52.5 (34-76), %32,5(n = 13) were premenopausal, %67,5 (n = 27) were postmenopausal. It was found that %15 of the patients (n = 6) had normal body mass index, %42,5(n = 17) were overweight and %42,5 (n =17) were in the obese category. It was found that there was no statistically significant difference between the demographic characteristics of the patients according to the study groups (tattoo and clip) (p> 0.05). While %7,5 of the patients (n = 3) were cT1, %92,5 (n = 37) were cT2 tumors; %70 (n = 28) of the patients were clinically positive for axillae. 55% (n = 22) of the tumors were invasive ductal carcinoma. %60 (n = 24) of the tumors were located in the upper outer quadrant. Estrogen receptor in %82,5 (n = 33), progesterone receptor in %72,5 (n = 16), HER-2 expression in %35 (n = 14) and %80 (n = 32) Ki67 expression %20 was positive. It was found that there was no statistically significant difference in the clinicopathological characteristics of the patients according to the study groups (tattoo and clip) (p> 0.05). While AC-T ± Anti-Her2 protocols were applied as neoadjuvant systemic chemotherapy to %98 of the patients (n = 39); Pathological complete response was detected in %37,5 (n = 15) of the patients after neoadjuvant treatment. The breast cup size classification of the patients was "B" in 7 patients (%17,5), "C" in 29 patients (%72,5), and "D" in 4 patients (%10). Radiologically, the average distance of the tumor to the breast skin was calculated as 18.19 ± 8.77 mm. In all patients (n = 40) breast conserving surgery, %20 (n = 8) wire marking (breast), 45% (n = 18) intraoperative surgical margin examination (frozen) and %25 (n = 8) 10) re-excision was performed in a single session. The final tumor surgical margin of the patients was between 1-2 mm in 4 (%10) patients and 2 mm and above in 36 patients (%90). The distance of the tumor to the skin was statistically significantly shorter (p = 0.045) in the study group compared to the control (tattoo: 15.74 ± 7.41 vs clips: 20.64 ± 9.51). Although not statistically significant, the rate of reexcision in the same session (tattoo: %3 vs clips: %35) was smaller in the study group (p = 0.273). Although not statistically significant, all of the patients (n = 4) with tumors found to be close to the surgical margin (1-2 mm) were in the clip group (p = 0.106). Complications (hematoma / ecchymosis) were observed in % 15 (n = 6) of the patients, and pain was observed in %12.5 (n = 5). All patients with complications were found to be in the group marked with clips. Clip migration was observed in %15 (n = 3) of the patients marked with clips. In the study, while the unit price per patient was 900 TL and a total cost of 18.000 TL (20*900) per patient in patients with clips applied, the unit price per patient was approximately 4 TL in tattoo marking patients, and a total cost of 80 TL (20*4) was found to be. Although these findings could not be proven with the total cost effectiveness analysis, it was predicted that the tattoo method was more cost-effective. Conclusions: In patients scheduled for breast preserving surgery following neoadjuvant therapy for breast cancer, tattooing the skin projection of the tumor is an alternative method which can be applied easly, cheaper with fewer complications compared to the standart approach of marking with metalic clips application.