Assessment of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Systemic Therapy.

OBJECTIVE: To quantify the rate of pathological complete response (PCR) in a tertiary care hospital in Pakistan, and to explore the association of pathological complete response with tumour histology, tumour grade, and histological subtype based on receptors. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Combined Military Hospital, Rawalpindi, Pakistan from January 2016 to December 2018. METHODOLOGY: Data for 110 patients was retrospectively extracted from the medical records for the last three years. Inclusion criteria comprised of patients with non-metastatic breast cancer staged as cT1- 4 N0-1-2 breast cancer who received neoadjuvant systemic therapy, and undergone subsequent surgical procedures and adjuvant treatment as required. Assessment of pathological response was performed on the final (surgical) histopathology specimen. Complete pathological response (PCR) was evaluated according to Austrian Breast and Colorectal Cancer Study Group, and Neo-Breast International Group criteria as no invasive cancer in the breast or nodes; noninvasive breast residuals allowed (ypT0/is ypN0). RESULTS: The mean age of the study group was 47.21±9.5 years with an age range of 27 - 68 years. Among 110 patients undergoing neoadjuvant systemic therapy and surgery, the rate of pathological complete response was found to be 27.2% (30/110). Univariate analysis showed that pathological complete response was significantly associated with age category, tumour grade, cancer subtype, lymphovascular invasion, and Trastuzumab administration. The occurrence of pathological complete response was significantly different among different cancer subtype groups, being highest (42.8%) among triple-negative cancer subtype, followed by HR-ve/Her+ve, HR+ve/Her+ve, and HR+ve/Her-ve (40.0%, 34.4%, and 13.0% respectively, p=0.022). CONCLUSION: Achieving PCR after neoadjuvant chemotherapy is quite promising keeping into consideration that PCR a potential marker for progression-free survival and overall survival. Tumour grade, age of the patient, Her2 positive subtype, anti-Her2 directed therapy, and negative lymphovascular invasion are found to be potential predictors of complete pathological response. KEY WORDS: Breast cancer, Chemotherapy, Neoadjuvant systemic therapy, Pathological complete response, Surgery.

Correlation of MSH2 exonic deletions and protein downregulation with breast cancer biomarkers and outcome in Pakistani women/patients.

Mismatch repair (MMR) pathway is one of the underlying mechanisms of predisposition to breast cancer (BC). The present study explored the association of MSH2 exonic deletions, respective survival analysis, protein structure prediction, transcription profiling, and expression analysis with BC risk. Genotyping analysis of 493 BC cases and 387 controls confirmed the association of two MSH2 exonic deletions, i.e., exon 3 (OR:6.4, CI = 3.4-12.1) and 9 (OR:7.8, CI = 4.1-14.8) with BC risk. In order to confirm the phenotypic-genotypic relationship, we have performed MSH2 transcriptomic (p < 0.05) and protein expression analysis (OR:30, CI = 4-230) which further confirmed its downregulation/loss in BC biopsy samples highlighting potential role in the onset of breast carcinogenesis. Additionally, we have presented that MSH2 mutations can alter the expression profile of other BC associated biomarkers like ER, PR, CK-7, GATA-3, and E-cadherin. Subsequently, the effect of exonic deletions on secondary structure of protein has shown missing of beta and alpha helices in their protein products via in-silico analysis. However, loss of exon 3 results in the altered core protein structure leading to dysfunction protein, possible cause of BC development. No association of MSH2 exonic deletions with survival statistics was observed conceivably due to the shorter follow-up time. Thus, our results at genetic, transcriptomic, and proteomic levels confirmed the downregulated MSH2, emphasizing its potential contribution in MMR mechanisms for breast tumorigenesis. In conclusion, MSH2 deficiency may cause breast cancer development and progression.

XPC as breast cancer susceptibility gene: evidence from genetic profiling, statistical inferences and protein structural analysis.

BACKGROUND: Gene polymorphisms that affect nucleotide excision repair (NER) pathway may link with higher susceptibility of breast cancer (BC); however, the significance of these associations may vary conferring to the individual ethnicity. Xeroderma pigmentosum complementation gene (XPC) plays a substantial role in recognizing damaged DNA during NER process. OBJECTIVE AND METHODS: To estimate the relationship among XPC polymorphisms and breast cancer (BC) risk, we carried out a case-control-association study with 493 BC cases and 387 controls using TETRA-ARMS-PCR. Distributional differences of clinical features, demographic factors and XPC polymorphisms among BC cases and controls were examined by conditional logistic regression model. Kaplan-Meier test was applied to predict survival distributions and protein structure was predicted using computational tools. RESULTS: Obesity, consanguinity, positive marital status and BC family history were associated (P ≤ 0.01) with higher BC risk. Genotyping revealed significant involvement (P ≤ 0.01) of two XPC polymorphisms rs2228001-A > C (OR = 3.8; CI 1.9-7.6) and rs2733532-C > T (OR = 2.6; CI 1.4-5.03) in BC development, asserting them potential risk factors for increased BC incidence. However, no association (P > 0.05) was detected for overall or progression free survival for both XPC polymorphisms possibly due to shorter follow-up time (45 months). As compared to normal XPC structure, pronounced conformational changes have been observed in the C-terminus of XPCQ939K, bearing rs2228001-A > C substitution. In XPCQ939K, two additional α-helices were observed at A292-E297 and Y252-R286, while L623-M630 and L649-L653 helices were converted into loop conformation. CONCLUSION: In conclusion, both XPC polymorphisms confer significant association with increased BC risk. rs2228001 substitution may change the structural and functional preferences of XPC C-terminus, while rs2733532 may have regulatory role thereby leading to potential BC risk.

Squamous Cell Carcinoma of the Breast.

OBJECTIVE: To analyse the epidemiological characteristics, clinical presentations, and histopathological as well as immunological characteristics of squamous cell carcinoma (SCC) of breast. STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Combined Military Hospital, Rawalpindi, from January 1997 to January 2017. METHODOLOGY: Data of all patients, diagnosed as squamous cell carcinoma of breast over defined period of time, were collected and analysed with respect to their clinical presentation, histopathology and receptor status. Year-wise cases of SCC of breast were separated. RESULTS: Thirty patients, diagnosed as squamous cell carcinoma of breast, were identified over a period of 20 years. There was an increase in number of cases diagnosed after 2007 as compared to before 2007. Moreover, 12 (40%) cases were hormonereceptor positive while 18 (60%) were of unknown status. Out of the total, 10 (33%) cases were well differentiated, 17 (57%)were moderately differentiated, while 3 (10%) were poorly differentiated. Seventeen (57%) cases presented as breast masses, 10 (33%) had skin ulceration in addition to breast mass, while 3 (10%) cases presented as fungating masses along with chest wall involvement. CONCLUSION: There is an increased incidence of SCC of breast which can be due to better diagnostic facilities and more awareness amongst doctors about different varieties of breast cancers and their impact on the prognosis of disease.

Managing the Axilla in Early Breast Cancer. Impact of ACOSOG Z0011 Trial in Changing Practices in a Low Middle Income Country

Objective: To determine the impact of the trial on surgeon practice patterns at our institution. Methodology: A comparison of patients undergoing surgery for early breast cancer before and after the implementation of the new guidelines was done. We adopted the new guidelines in April 2015. Patients meeting Z0011 inclusion criteria were identified. For group A (Pre Z0011) patients operated between Jan to Dec 2013 were studied. And for Group B (Post Z0011) patients operated between July 2014 to Jun 2015 were included. Clinicopathologic data were compared between the two groups. Results: There were 318 patients with clinical T1-2 tumors planned for breast conservation. 68% patients had T1 tumor and 32% had T2. 92% of the patients had IDCa. There were 150 patients in the pre-Z0011 group and 168 post-Z0011. 68% of the patients in Group A were ER+ve while 70% in group B. 38 (25.7 %) patients were sentinel lymph node (SLN) positive in the pre-Z0011 group versus 34 (21 %) post-Z0011 (p = 0.392). Before Z0011 100 % (38/38) of SLN-positive patients underwent axillary node dissection (ALND) versus 17 % (6/34) after Z0011 (p < 0.01). Median no of SLNs identified in group A were 1.3 and group B were 1.4. There was a decrease in median operative times of the two groups (80 vs. 60 min, p < 0.01). There was a significant decrease in the overall hospital stay of sentinel lymph node positive patients in between the two groups (2.1 days vs 1.3 days p value < 0.01). Conclusions: Implemention of Z0011 guidelines has resulted in significant short term advantages in terms of reduced axiilary dissections, shorter operative times and shoter hospital stays.

Breast cancer treatment in high-risk elderly patients: A challenging situation and difficult decisions.

OBJECTIVE: To assess whether high-risk elderly patients with aggressive tumour biology can be offered standard treatment despite having multiple comorbid conditions. METHODS: This retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data of breast cancer patients aged 65 years or above treated between 2006 and 2012,. Data was collected regarding patients' demographics, baseline clinical characteristics, comorbidities, treatment and outcomes. Stata 12 was used for data analysis. RESULTS: Of the 407 patients in the study, 399(98%) were women and 8(2%) were men. The overall mean age at diagnosis was 70±4.9 years (range: 65-90 years). Overall, 59(14.5%) participants had family history of breast cancer. Bilateral disease was seen in 17(4.2%). Invasive ductal carcinoma was seen in 299(73.5%). Besides, 101(24.8%) patients had no comorbid conditions, while 138(34%) had one, 102(25%) had two and 66(16%) had three or more comorbid conditions. There was no statistically significant difference between those receiving standard treatment including surgery or other modalities. CONCLUSIONS: Elderly patients of breast cancer may be offered treatment according to the tumour biology and their overall functional status.

Breast Lymphoma Treatment Outcomes in a Pakistani Population: 20 Years of Experience at a Single Center.

BACKGROUND: Breast lymphomas constitute a rare disease entity. To date, limited relevant data have been reported. We therefore here present a review of breast lymphoma patients treated at a single center over a 20 year period, focusing on histological types, treatment modalities and outcomes. MATERIALS AND METHODS: We identified patients who were diagnosed and treated for breast lymphoma at a single center from January 1995 to January 2014 and extracted data regarding patient demographics and clinical data. RESULTS: Twenty-seven patients with breast lymphoma were identified, of which 3 were males. The median age at diagnosis was 37 years (range: 22-76 years). Chemotherapy was the main stay of treatment and 55.6% patients also received radiation to the affected breast. At our institute, only 3 patients, all with progressive disease, had surgery performed to achieve local palliation. Complete response after chemotherapy was seen in 63% patients and partial response in 7.4%, while 26% patients demonstrated disease progression. The mean follow up was 46.8 months. Seven patients (33.3%) who were alive at last follow up, as well as 1 patient who died, survived more than 5 years after diagnosis. CONCLUSIONS: Patients with breast lymphoma should receive aggressive treatment, with combination of chemotherapy and radiation therapy. Surgery should be limited for diagnosis and palliation of local symptoms in cases of progressive disease.