Determinants of Advanced Stage at Initial Diagnosis of Breast Cancer in Pakistan: Adverse Tumor Biology vs Delay in Diagnosis

Khokher, Samina,Qureshi, Muhammad Usman,Mahmood, Saqib,Sadiq, Sadia Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.2

Background: Breast cancer is the most frequent cancer of women in Pakistan with the majority presenting with stage III or IV lesionsat initial diagnosis. Patient and health system related factors are well known determinants of delay in presentation and diagnosis. Additionally, breast cancer being a heterogeneous disease, the various molecular subtypes featuring different aggressiveness also need to be considered. The present study evaluated the association of stage at initial diagnosis of breast cancer with these two factors in local women at a tertiary level health care facility in Lahore, Pakistan. Materials and Methods: Patient and tumor features were recorded separately during diagnostic workup in Breast Clinics at INMOL and at Services Hospital, Lahore. Data were entered in MS Excel and analyzed by descriptive statistics and Chi-Square test. Results: Among the 261 patients, 64% were staged as late breast cancer (LBC), the mean age was 46.8 with standard deviation of 13 years. Some 92% had invasive ductal carcinoma (IDC), 61% had luminal types (LT) of non-aggressive tumor while 39% had the non-luminal types (NLT) of of HER2-enriched or basal aggressive tumors. While 70% of patients presented within one year of symptomatic disease (early report group "ERG"), 30% reported after a mean delay of 4 years with a standard deviation of 3.75 years. The stage distribution among ERG patients was not statistically different from those reporting late (P=0.123). Statistically larger proportion of patients with NLT presented as LBC as compared to the LT (P =0.034). Among the ERG, statistically different stage distribution of disease was observed for the NLT versus LT (P=0.047). Among those presenting late, this difference was insignificant (P=0.416). Conclusions: Breast cancer is a distinct disease in Pakistan with a high frequency of aggressive molecular types affecting younger women, with the majority presenting as LBC. Association of NLT with higher stage at diagnosis is statistically significant whereas time delay in diagnosis is not. Further research is required to define the risk profile and features in local patients. The burden of LBC can be reduced by promoting breast health awareness and by establishing easily accessible dedicated breast care set ups in the hospitals.

Association of Immunohistochemically Defined Molecular Subtypes with Clinical Response to Presurgical Chemotherapy in Patients with Advanced Breast Cancer

Khokher, Samina,Qureshi, Muhammad Usman,Mahmood, Saqib,Nagi, Abdul Hannan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.5

Gene expression profiling (GEP) has identified several molecular subtypes of breast cancer, with different clinico-pathologic features and exhibiting different responses to chemotherapy. However, GEP is expensive and not available in the developing countries where the majority of patients present at advanced stage. The St Gallen Consensus in 2011 proposed use of a simplified, four immunohistochemical (IHC) biomarker panel (ER, PR, HER2, Ki67/Tumor Grade) for molecular classification. The present study was conducted in 75 newly diagnosed patients of breast cancer with large (>5cm) tumors to evaluate the association of IHC surrogate molecular subtype with the clinical response to presurgical chemotherapy, evaluated by the WHO criteria, 3 weeks after the third cycle of 5 flourouracil, adriamycin, cyclophosphamide (FAC regimen). The subtypes of luminal, basal-like and HER2 enriched were found to account for 36.0 % (27/75), 34.7 % (26/75) and 29.3% (22/75) of patients respectively. Ten were luminal A and 14 luminal B (8 HER2 negative and 6HER2 positive). The triple negative breast cancer (TNBC) was most sensitive to chemotherapy with 19% achieving clinical-complete-response (cCR) followed by HER2 enriched (2/22 (9%) cCR), luminal B (1/6 (7%) cCR) and luminal A (0/10 (0%) cCR). Heterogeneity was observed within each subgroup, being most marked in the TNBC although the most responding tumors, 8% developing clinical-progressive-disease. The study supports association of molecular subtypes with response to chemotherapy in patients with advanced breast cancer and the existence of further heterogeneity within subtypes.

Comparison of WHO and RECIST Criteria for Evaluation of Clinical Response to Chemotherapy in Patients with Advanced Breast Cancer

Khokher, Samina,Qureshi, Muhammad Usman,Chaudhry, Naseer Ahmad Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

When patients with advanced breast cancer (ABC) are treated with neoadjuvant chemotherapy (NACT), efficacy is monitored by the extent of tumor shrinkage. Since their publication in 1981, World Health Organization (WHO) guidelines have been widely practiced in clinical trials and oncologic practice, for standardized tumor response evaluation. With advances in cancer treatment and tumor imaging, a simpler criterion based on one-dimensional rather than bi-dimensional (WHO) tumor measurement, named Response Evaluation Criteria in Solid Tumors (RECIST) was introduced in 2000. Both approaches have four response categories: complete response, partial response, stable disease and progressive disease (PD). Bi-dimensional measurement data of 151 patients with ABC were analysed with WHO and RECIST criteria to compare their response categories and inter criteria reproducibility by Kappa statistics. There was 94% concordance and 9/151 patients were recategorized with RECIST including 6/12 PD cases. RECIST therefore under-estimates and delays diagnosis of PD. This is undesirable because it may delay or negate switch over to alternate therapy. Analysis was repeated with a new criteria named RECIST-Breast (RECIST-B), with a lower threshold for PD (${\geq}10%$ rather than ${\geq}20%$ increase of RECIST). This showed higher concordance of 97% with WHO criteria and re-categorization of only 4/151 patients (1/12 PD cases). RECIST-B criteria therefore have advantages of both ease of measurement and calculations combined with excellent concordance with WHO criteria, providing a practical clinical tool for response evaluation and offering good comparison with past and current clinical trials of NACT using WHO guidelines.

Impact of a Breast Health Awareness Activity on the Knowledge Level of the Participants and its Association with Socio-Demographic Features

Khokher, Samina,Qureshi, Muhammad Usman,Fatima, Warda,Mahmood, Saqib,Saleem, Afaf Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

The developing countries have higher mortality rates for breast cancer. A reason for this is presentation at advanced stages due to low levels of public awareness. Activities are arranged by health authorities of developing countries to increase the knowledge of women but their effectiveness has not been evaluated in detail. A multiple choice questionnaire with questions about socio-demographic profile and questions about breast cancer knowledge was designed in local language Urdu, to evaluate the knowledge of the participants before and after an audio visual educational activity in Lahore, Pakistan. Scores of 0-2, 3-5 and 6-8 were ranked as poor, fair and good, respectively. Among 146 participants these scores were achieved by 1%, 55% and 45% before activity and 0%, 16% and 84% after the activity. Overall 66% of participants increased their knowledge score. Younger age, higher education, reliance on television as source of information and being a housewife were associated with better impact of the awareness activity. For the six knowledge related questions 3%, 5%, 11%, 23%, 33% and 44% more participants gave correct answers after the activity. However 6% and 7% fewer participants answered correctly for 2 questions related to the cause and the best prevention for breast cancer. The study indicated that awareness activities are effective to increase the knowledge of women and better impact is associated with higher education and younger age of women. The component analysis showed that the questions and related presentations using medical terms have a negative impact and should not therefore be used. Analysis of activity therefore leads to identification of deficiencies which can be remedied in future.

Clinicopathologic Profile of Breast Cancer Patients in Pakistan: Ten Years Data of a Local Cancer Hospital

Khokher, Samina,Qureshi, Muhammad Usman,Riaz, Masooma,Akhtar, Naseem,Saleem, Afaf Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.2

Breast cancer is the most frequent cancer of women worldwide, with considerable geographic and racial/ethnic variation. Data are generally derived from population based cancer registries in the developed countries but hospital data are the most reliable source in the developing countries. Ten years data from 1st Jan 2000 to 31st Dec 2009 of a cancer hospital in Pakistan were here analyzed by descriptive statistics to evaluate the clinicopathologic profile of local breast cancer patients. Among 28,740 cancer patients, 6,718 were registered as breast cancer. The female to male ratio was 100:2. Breast cancer accounted for 23% of all and 41% of female cancers. Some 46% were residents of Lahore, with a mean age of $47{\pm}12$ years. Less than 1% were at Stage 0 and 10%, 32%, 35% and 23% were at Stage I, II, III and IV respectively. Histopathology was unknown in 4% while 91%, 2% and 1% had invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) and mucinous carcinoma respectively. Rare carcinomas accounted for the rest. Tumor grade 1, 2 and 3 was 11%, 55% and 34% among the known. Profile of breast cancer patients in Pakistan follows a pattern similar to that of other developing countries with earlier peak age and advanced disease stage at presentation. The male breast cancer accounts for higher proportion in the local population. Local women have higher frequency of IDC and lower frequency of ILC and DCIS, owing probably to a different risk profile. Use of hospital information systems and establishment of population based cancer registry is required to have accurate and detailed local data. Promotion of breast health awareness and better health care system is required to decrease the burden of advanced disease.

Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan

Aziz, Faiza,Fatima, Warda,Mahmood, Saqib,Khokher, Samina Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.4

Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors.