Predicting Response to Neoadjuvant Chemotherapy in Women with Locally Advanced Breast Cancer in Kenya: Utility of Ki67

Edwin Mogere1, Joseph Githaiga1, Francis Owilla1, Mary Mungania2, Daniel Ojuka1

1 Department of surgery, University of Nairobi.

2 Department of Pathology, Kenyatta National Hospital.

Correspondence to: Dr. Mogere Edwin Obiri, Email: edob40@gmail.com 

Received: 15 June 2019; Revised: 02 October 2019; Accepted: 22 December 2019; Available online: 14 March 2020

 

Abstract

Background: Ki67 levels have been shown to have good predictive value in breast cancer treatment. There is paucity of data on Ki67 levels in predicting response to neoadjuvant chemotherapy (NACT) in Kenya. This study evaluated the utility of Ki67 in predicting response to NACT. Methods: This was a prospective observational study carried out at Kenyatta National Hospital between December 2017 and January 2019 on patients with locally advanced breast cancer. We recruited 61 women through consecutive sampling technique.  Data collected included patient demogra-phics, pre-treatment tumor size, Ki67 levels and tumor biology. After 3 cycles of first-line chemotherapy, ultrasonography was used to determine response. Data were analyzed by SPSS for proportion of change in tumor size. The response was correlated with tumor biology and pretreatment levels of Ki67 using chi-square at a 95% confidence interval. A p-value <0.05 was considered statistically significant.  Results: The response rate after 3 cycles of NACT was 39.4%, sensitivity and specificity of Ki67 levels were 70.8% and 43.2% respectively with a cut-off value of 32.5%. Conclusions: Ki67 was found to predict response in our context at a rate of 39.4% at 20% cutoff after 3 cycles.

 

Keywords: Ki67, Breast cancer, Neoadjuvant chemotherapy

Ann Afr Surg. 2021;18(1):23–28

DOI: http://dx.doi.org/10.4314/aas.v18i1.5

Conflicts of Interest: None

Funding: None

© 2021 Author. This work is licensed under the Creative Commons Attribution 4.0 International License.

 

Introduction

Breast cancer contributes a significant proportion of morbidity and mortality globally. Data from GLOBACAN show it is the 2nd in incidence and 5th cause of mortality globally (1). Data from Nairobi Cancer Registry reveal a high burden of breast cancer: it is the leading malignancy with a prevalence of 51.7 per 100,000 of all cancers in women in Kenya (2). Locally advanced breast cancer (LABC) is the commonest stage accounting for  between 50.7% and 60% of breast cancer cases at first presentation (3). Currently in Kenyatta National Hospital, approximately 3­–4 patients receive neoadjuvant chemotherapy weekly, or an average of 12–16 patients per month and 144–192 patients per year (unpublished data). Treatment of LABC involves a multidisciplinary approach with neoadjuvant chemotherapy (NACT), surgery, i.e. breast conserving surgery or modified radical mastectomy for operable patients, plus radiation therapy, depending on patient selection (4). LABC  poses difficulties in achieving tumor-free resection margins and low chance of breast-conserving surgeries, results in higher recurrence rate and poses challenges in wound closure (5). NACT therefore enables the surgeon to achieve the acceptable resection margins, increases operability and increases the chances of wound closure (6). DNA microarrays have shown that some breast cancers are resistant to chemotherapy: this could result in some patients receiving unnecessary chemotherapy. DNA microarrays have been used to predict response to chemotherapy, but they are expensive and their utility is not universally adopted (7). The methods that have been used to monitor treatment are physical examination, imaging studies, pathologic response, NACT and biomarkers (8). Clinical methods have been shown to be inadequate on their own in predicting response to therapy (9).

Ki67 is a nuclear antigen expressed in actively dividing cells. It is a marker of cellular proliferation (10). It is produced in large amounts in all cancerous tissues and therefore can be used to predict response to treatment (11). It is recommended to measure levels of  Ki67 before initiating neoadjuvant therapy in breast cancer (12). Values of Ki67 levels of more than 25% have been shown to have a favorable response to NACT (13). There is however paucity of data on its utility in locally advanced breast cancer in Kenya, and the data available lack uniformity of Ki67 cutoff levels. Ki67 applied with good accuracy has been shown to have good prediction values (13). This study therefore aims at determining the utility of Ki67 in predicting response to neoadjuvant chemotherapy in LABC.

Methods

This was a prospective observational study carried out at Kenyatta National Hospital surgical wards, surgical outpatient clinic, oncology clinics, radiology department and histopathology laboratory. The study was conducted between December 2017 and January 2019. Inclusion criteria were women with locally advanced breast cancer, who had no systemic metastasis, T3 disease on ultrasonography and chemotherapy naïve patients. Staging was done by clinical examination and radiological assessment using CT scan chest or plain chest x-ray, and abdominal ultrasound. Only patients who were negative for systemic metastases and fully staged were included in the study. Ultrasonography was performed by qualified radiologist as per hospital policy.  

Patients were recruited through convenient sampling procedure after informed consent was administered. Data were collected using the data collection sheet.  Data collected included patients’ demographics, pretreatment Ki67 levels, pretreatment tumor size, tumor biology (tumor grade, lymphovascular invasion and immunohistochemistry: ER, PR and HER2). Tumor size was determined by ultrasound prior to therapy and at the end of 3 cycles. Patients were assessed using Ultrasound Machine Aplio 400 with a high frequency linear probe of 12 MHz to measure the longest tumour diameter. Standard neoadjuvant first line chemotherapy was given for 3 cycles. Every third week the regime given was Adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2.

Sample size was calculated using Daniel’s formula with finite population correction for standard distribution with 95% confidence interval and a desired precision of 0.05. A repeat breast ultrasound was performed after the 3 cycles of chemotherapy, and sizes recorded. The evaluation of response to NACT was performed using the response evaluation criteria in solid tumours (RECIST).

Data were entered into MS Excel sheet, cleaned and transferred to SPSS (version 21.0, Chicago-Illinois) for analysis. Analysis was performed for mean and range of age, mean tumor size change from pretreatment to after 3 cycles of NACT, proportions of patient with high or low Ki67 according to St Galen classification, which used 20% as the cutoff, and proportion of patients who had response as per RECIST. Chi-square was used to analyze the association between Ki67 level to response and other aspects of tumor biology: molecular subtype, tumor grade, and perineural and lymphovascular invasion.

Receiver operator curve (ROC) was drawn using the Ki67 levels against response to NACT. This was then used to determine the sensitivity, specificity, cutoffs, and area under the curve of Ki67 for our population.  p values and 95% confidence intervals (CIs) were calculated as applicable, and p value <0.05 was considered statistically significant.

This study commenced after approval from the Department of Surgery and the UoN-KNH ERC, under approval number P247/05/2017.

 

Results

Sixty-one pa