Breast Neoplasms: Aziz Z

El Saghir NS, Eniu A, Carlson RW, Aziz Z, Vorobiof D, Hortobagyi GN, Anonymous00023. · Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. nagi.saghir@ aub.edu.lb · Cancer. · Pubmed #18837023 No free full text.

Abstract: The management of locally advanced breast cancer (LABC) is guided by scientific advances but is limited by local resources and expertise. LABC remains very common in low-resource countries. The Systemic Therapy Focus Group met as part of the Breast Health Global Initiative (BHGI) Summit in Budapest, Hungary, in October 2007 to discuss management and implementation of primary systemic therapy (PST) for LABC. PST is standard treatment for large operable breast cancer in enhanced-resource settings and, in all resource settings, should be standard treatment for inoperable breast cancer and for LABC. Standard PST includes anthracycline-based chemotherapy. The addition of sequential taxanes after anthracycline improves pathologic responses and breast-conservation rates and is appropriate at enhanced-resource levels; however, costs and lack of clear survival benefit do not justify their use at limited-resource levels. It remains to define better the role of endocrine therapy as PST, but it is acceptable in elderly women. Aromatase inhibitors have produced better results than tamoxifen in postmenopausal patients and are used in enhanced-resource settings. The less expensive tamoxifen remains useful in low-resource countries. Trastuzumab combined with chemotherapy yields high pathologic response rates in patients with HER2/neu-overexpressing tumors; its use in low-resource countries is limited by high costs. Most studies on PST of LABC were conducted in countries with enhanced resources. BHGI encourages conducting clinical trials in countries with limited resources.

Eniu A, Carlson RW, Aziz Z, Bines J, Hortobágyi GN, Bese NS, Love RR, Vikram B, Kurkure A, Anderson BO, Anonymous00017. · Department of Breast Tumors, Oncology, Cancer Institute I. Chiricuta, Cluj-Napoca, Romania. · Breast J. · Pubmed #16430398 No free full text.

Abstract: Treating breast cancer under the constraints of significantly limited health care resources poses unique challenges that are not well addressed by existing guidelines. We present evidence-based guidelines for systematically prioritizing cancer therapies across the entire spectrum of resource levels. After consideration of factors affecting the value of a given breast cancer therapy (contribution to overall survival, disease-free survival, quality of life, and cost), we assigned each therapy to one of four incremental levels--basic, limited, enhanced, or maximal--that together map out a sequential and flexible approach for planning, establishing, and expanding breast cancer treatment services. For stage I disease, basic-level therapies are modified radical mastectomy and endocrine therapy with ovarian ablation or tamoxifen; therapies added at the limited level are breast-conserving therapy, radiation therapy, and standard-efficacy chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF], or doxorubicin and cyclophosphamide [AC], epirubicin and cyclophosphamide [EC], or 5-fluorouracil, doxorubicin, and cyclophosphamide [FAC]); at the enhanced level, taxane chemotherapy and endocrine therapy with aromatase inhibitors or luteinizing hormone-releasing hormone (LH-RH) agonists; and at the maximal level, reconstructive surgery, dose-dense chemotherapy, and growth factors. For stage II disease, the therapy allocation is the same, with the exception that standard-efficacy chemotherapy is a basic-level therapy. For locally advanced breast cancer, basic-level therapies are modified radical mastectomy, neoadjuvant chemotherapy (CMF, AC, or FAC), and endocrine therapy with ovarian ablation or tamoxifen; the therapy added at the limited level is postmastectomy radiation therapy; at the enhanced level, breast-conserving therapy, breast-conserving whole-breast radiation therapy, taxane chemotherapy, and endocrine therapy with aromatase inhibitors or LH-RH agonists; and at the maximal level, reconstructive surgery and dose-dense chemotherapy and growth factors. For metastatic or recurrent disease, basic-level therapies are total mastectomy for ipsilateral in-breast recurrence, endocrine therapy with ovarian ablation or tamoxifen, and analgesics; therapies added at the limited level are radiation therapy and CMF or anthracycline chemotherapy; at the enhanced level, chemotherapy with taxanes, capecitabine, or trastuzumab, endocrine therapy with aromatase inhibitors, and bisphosphonates; and at the maximal level, chemotherapy with vinorelbine, gemcitabine, or carboplatin, growth factors, and endocrine therapy with fulvestrant. Compared with the treatment of early breast cancer, the treatment of advanced breast cancer is more resource intensive and generally has poorer outcomes, highlighting the potential benefit of earlier detection and diagnosis, both in terms of conserving scarce resources and in terms of reducing morbidity and mortality. Use of the scheme outlined here should help ministers of health, policymakers, administrators, and institutions in limited-resource settings plan, establish, and gradually expand breast cancer treatment services for their populations.

Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF. · Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy 59100. · J Clin Oncol. · Pubmed #18955454 No free full text.

Abstract: PURPOSE: Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC. PATIENTS AND METHODS: Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS). RESULTS: In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2-positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2-negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms. CONCLUSION: Patients with HER-2-negative or HER-2-untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2-positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2-positive breast cancer patients.

Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, Ng C, Franco SX, Chow LW, Arbushites MC, Casey MA, Berger MS, Stein SH, Sledge GW. · Instituto Nacional de Enfermedades Neoplásicas, Hospital Alberto Sabogal, Lima, Peru. · J Clin Oncol. · Pubmed #18458039 No free full text.

Abstract: PURPOSE: This study (EGF20009) assessed the efficacy and tolerability of two lapatinib administration schedules as first-line monotherapy in women with ErbB2-amplified locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients with ErbB2-amplified, locally advanced or metastatic breast cancer previously untreated in the metastatic setting were randomly assigned to one of two lapatinib dose cohorts and received either 1,500 mg once daily or 500 mg twice daily. Clinical response was assessed at weeks 8 and 12 and every 12 weeks thereafter. RESULTS: A total of 138 patients were treated with lapatinib for a median of 17.6 weeks. The overall response rate (complete response [CR] plus partial response [PR]) was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (CR, PR, or stable disease for >or= 24 weeks). The median time to response was 7.9 weeks, and the progression-free survival rates at 4 and 6 months were 63% and 43%, respectively. The most common lapatinib-related adverse events (AEs) were diarrhea, rash, pruritus, and nausea, and these events were primarily grade 1 or 2. There were no significant differences in clinical activity or the AE profile between the dosing schedules. CONCLUSION: Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.

Aziz Z, Sana S, Akram M, Ilyas N. · Department of Oncology, Allama Iqbal Medical College, Lahore. · J Pak Med Assoc. · Pubmed #11840607 No free full text.

Abstract: OBJECTIVE: A Phase 1 trial was conducted in patients with estrogen negative receptors (ER) or hormone refractory metastatic breast cancer to determine the maximum tolerated dose (MTD) of ifosfamide with a fixed dose of doxorubicin. A secondary objective was to determine the efficacy of the combination in metastatic breast cancer. METHODS: Fifteen patients were entered in the study in cohorts of three patients at each dose level of ifosfamide. The dose of doxorubicin was fixed at 45 mg/m2. Five different dose levels of ifosfamide were tested ranging from dose level 1 of 1.5 gms/m2 day 1-3 to level V at 2.5 gms/m2 day 1-3. RESULTS: Dose escalation of ifosfamide was stopped at 2.5 gms/m2. The MTD of ifosfamide was 2.25 gms/m2 day 1-3 in combination with doxorubicin. All patients in the study were assessable for toxicity. Neutropenia and thrombocytopenia were the major dose limiting toxicities. Other toxicities included anemia, confusion and hematuria. Objective responses were documented in 11 of 15 patients (73.3%). Median time to treatment failure (TTF) was 13 months. Median overall survival (OS) was 18 months. CONCLUSION: The combination of ifosfamide and doxorubicin was a practical well tolerated regimen. There was substantial evidence of clinical activity in this phase I trial. This combination should be further evaluated, as an attractive alternative to taxanes for patients in developing countries where cost effectiveness is important.

Aziz Z, Rehman A, Qazi S. · Department of Oncology, Allama Iqbal Medical College, 13/2 V Block, Phase II, LCCHS, Lahore, Pakistan. · Cancer Chemother Pharmacol. · Pubmed #10602903 No free full text.

Abstract: OBJECTIVE: A prospective trial to evaluate the efficacy and toxicity of ifosfamide (IFX) and vinorelbine (VNB) in patients with prior anthracycline therapy for metastatic breast cancer (MBC) was conducted. At the same time, the scheduling of VNB in order to minimize toxicity of the combination was also evaluated. PATIENTS AND METHODS: Twenty-three patients with MBC who had already received initial chemotherapy with doxorubicin-containing regimens either as adjuvant or as first-line treatment in MBC were entered into the study. IFX 3 g/m(2) and mesna 3 g/m(2) were given in divided doses over 2 days. In 4 patients, VNB was given 25 g/m(2) on days 1 and 3 in 3-h infusion. In 8 patients, VNB was given on days 1 and 8 and in 5 patients VNB was given on days 1 and 15. Thirteen patients had received doxorubicin in adjuvant setting, while 10 patients received doxorubicin as first-line treatment in metastatic disease. Dominant disease sites were soft tissues in 7 patients, visceral in 12 patients, and bone in 4 patients. The median age was 47 years. RESULTS: Overall objective response was seen in 12/23 patients (52.2%). Four patients achieved complete remission (CR), 8 patients achieved partial remission (PR). The median duration of response was 9 months in responding patients, and the median overall survival duration was 15 months. The major dose-limiting toxicities were neutropenia grade III and IV in 8/17 patients and asthenia grade III and IV in 4 patients. CONCLUSION: IFX and VNB is an active combination. Neutropenia and asthenia were most significant when VNB was given on days 1 and 3. In the best-tolerated regimen, VNB was given on days 1 and 8.

Aziz Z, Iqbal J, Akram M, Anonymous00296. · Department of Medical Oncology, Jinnah Hospital/Allama Iqbal Medical College, Lahore, Pakistan. · Breast J. · Pubmed #18540953 No free full text.

Abstract: To assess the relationship between social class disparities on disease stage on presentation, quality of treatment, and survival outcome of breast cancer patients in Pakistan and compare our data with SEER (Surveillance, Epidemiology, and End Results) data from US on white and African-American women to evaluate differences in disease stage and survival outcomes. Patients were evaluated for age, tumor size, grade, receptor status, stage, and 5-year survival and were compared with SEER data. Socio-economic status was evaluated with financial income. Patients were divided in poor and middle/high groups. Excellent and comparable 5-year survival with SEER data was observed with localized disease in all groups from different strata. Advanced disease was more common in the disadvantaged group with negligible 5-year survivals. Development and implementation of early detection programs, public awareness, and clinical and breast self examination that are more pragmatic in the settings of countries with limited resources are essential.

Zhang S, Phelan CM, Zhang P, Rousseau F, Ghadirian P, Robidoux A, Foulkes W, Hamel N, McCready D, Trudeau M, Lynch H, Horsman D, De Matsuda ML, Aziz Z, Gomes M, Costa MM, Liede A, Poll A, Sun P, Narod SA. · Women's College Research Institute, University Health Network, University of Toronto, Canada. · Cancer Res. · Pubmed #18381420 links to  free full text

Abstract: A founder allele in the CHEK2 gene (1100delC) has been associated with an elevated risk of breast cancer. This allele is responsible for the majority of CHEK2-associated breast cancers in women from northern European countries; however, within Europe, it seems to be rare in countries that are close to the Mediterranean. The frequency of the 1100delC allele has not been measured in non-White populations. We measured the frequency of the CHEK2 founder allele in 3,882 breast cancer patients and 8,609 controls from various countries. The allele was not seen among Asian patients (from Pakistan or the Philippines) and was present in 1 of 155 cases from Brazil. Among White women, the allele was present in 1.5% of 825 familial cases of breast cancer and in 0.7% of 1,106 patients with nonfamilial breast cancer. The allele was equally frequent in Jewish and non-Jewish patients. We estimate that the CHEK2 1100delC allele is associated with an odds ratio of 2.6 for breast cancer, which corresponds to a lifetime risk of approximately 24% in Ontario.

Aziz Z, Sana S, Akram M, Saeed A. · Department of Medical Oncology, Allama Iqbal Medical College, Lahore. · J Pak Med Assoc. · Pubmed #15518365 No free full text.

Abstract: OBJECTIVES: No data is available from developing countries correlating socioeconomic status (SES) with survival in female breast cancer patients. We decided to test the hypotheses whether SES is an independent determinant for disease stage, access to minimal expected treatment (MET) and survival. METHODS: Two hundred eighty six patients diagnosed with breast cancer were recruited between April 1996 to May 1998. Patients were divided into three groups according to their SES. Prognostic factors analyzed were age, tumor size, nodal status; stage at presentation, estrogen receptor status, time elapsed before diagnosis and access to MET. Disease free survival (DFS) and overall survival (OS) were determined according to the SES of the patients. RESULTS: Patients were categorized into three socioeconomic groups, high (21%), middle (44%) and low (35%). Mean age of all patients was 46 years, in patients from lower SES mean age was 43 years compared to 50 years in high SES. Mean time elapsed before diagnosis for women from high-income group was 4.3 months versus 10.6 months in low-income group. Early breast cancer was more common in affluent strata, 70% versus 41% in the lower strata. Eighty-nine percent patients received MET from the affluent group compared to only 43% patients in the lower strata. Literacy rate of patients from high SES was 73.7% compared to 15% in the low SES. Five year DFS and OS are 79% and 86% for high income group, 48% and 68% for middle income group and 31%,49% for lower strata which were statistically significant (P=.0001 and P<.0001). CONCLUSION: In our cohort of patients strong association was noted between low SES and advanced disease, delay in diagnosis, limited access to MET and inferior DFS and OS. The outcome of these patients may be improved by patient education and availability of better health care facilities.

Aziz Z, Sana S, Saeed S, Akram M. · Department of Medical Oncology, Allama Iqbal Medical College, Lahore. · J Pak Med Assoc. · Pubmed #14558740 No free full text.

Abstract: INTRODUCTION: There are no population based cancer registries in Pakistan except for Karachi Cancer Registry (KCR). No data from Punjab is available in the last decade. We decided to conduct a data base analysis to see the frequencies of different cancers in Punjab. PATIENTS AND METHODS: A retrospective analysis of 5100 patients presenting to Jinnah Hospital between January 1997 to December 2001 with histological diagnosis of cancer was performed. A tumor registry performa on all patients was filled which included demographic data as age, sex, duration of symptoms and disease stage at presentation. All cancers were coded according to international classification of Disease-oncology (ICD-10) classification. RESULTS: Male cancers accounted for 47.7% and female cancers 52.2% of the total cases. In males the three most frequent cancers were leukemias, non-Hodgkins lymphoma and lung cancer. In females breast cancer was the most common cancer accounting for 38.5% female followed by ovarian cancer 13.6%. CONCLUSIONS: Our institution based cancer registry indicates hematological malignancies are the most common cancers in males in Punjab followed by lung and colorectal cancer. In females breast cancer is the commonest cancer followed by ovarian cancer. Gall bladder cancer is relatively more frequent in women while cervical cancer is less commonly observed in our patient population. Despite biases until population based incidences are available, studies like ours may prove beneficial for future health planning and research.

Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA. · University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada. · Am J Hum Genet. · Pubmed #12181777 links to  free full text

Abstract: The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.

Aziz Z, Sana S. · Department of Oncology, Allama Iqbal Medical College, LCCHS, 13/2 V Block, Phase II, Lahore, Pakistan. · Gan To Kagaku Ryoho. · Pubmed #11890113 No free full text.

Abstract: INTRODUCTION: There is no population based tumor registry in Pakistan except for Karachi. A Department based tumor registry was established to determine the patterns of cancers in Pakistan especially Punjab. Other objectives were to determine socioeconomic status, disease stage, co-morbid conditions. We also tried to determine if patients had received optimal treatment on diagnosis. MATERIALS & METHODS: 3,274 patients presented to the Department of Oncology between 1995-2000. All patients had histopathologically confirmed diagnosis of cancer. Demographic data included age, sex, socioeconomic status, smoking, other co-morbid and occupation. RESULTS: The Oncology Department drains a catchment area of approximately 400 square kms in Punjab. Breast cancer was the most common cancer in females while leukemias and lymphomas were most common in males. Poor socio-economic status was present in 89% of cases. Illiteracy was present in 76%. Comorbid conditions like hepatitis B & C were present in 37% of patients. Advanced disease was documented in 59% patients. Optimal treatment on initial diagnosis was not provided to 45% patients. DISCUSSION: Advanced stage, poor socio-economic status, illiteracy were common. Associated co-morbid conditions were a major cause in delay in treatment. Optimal treatment was not provided to majority of patients. All these factors are contributing to poor cure rates seen in Pakistan.