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Soley Bayraktar,
Angelica M Gutierrez Barrera,
Diane Liu,
Lajos Pusztai,
Jennifer Litton,
Vicente Valero,
Kelly Hunt,
Gabriel N Hortobagyi,
Yun Wu,
Fraser Symmans, Banu Arun
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ABSTRACT: USP-11, a member of the ubiquitin-specific protease family, has emerged as an essential regulator of double-strand break repair. Few studies have shown that silencing USP-11 led to hypersensitivity to poly(ADP-ribose) polymerase inhibition, ionizing radiation, and DNA-damaging agents. We sought to examine the predictive and prognostic relevance of USP-11 in patients treated with neoadjuvant systemic therapy (NST) for breast cancer.
Fifty-six women who were treated with NST for breast cancer between 1999 and 2004 were included in the study. The Kaplan-Meier product-limit method was used to estimate disease-free survival and overall survival rates. Logistic regression models were fit to determine the associations between USP-11 status, pathological complete response (pCR), and survival.
Sixteen patients (29%) had high-USP-11-expressing tumors, and 40 (71%) patients had low-USP-11-expressing tumors. No significant differences were observed in pCR rates with respect to USP-11 status. At a median follow-up of 7.4 years, 33 patients (59%) experienced a disease recurrence or death. Patients with high-USP-11-expressing tumors had a higher risk of recurrence (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.51-9.93; P = 0.005) and death (OR, 6.03; 95% CI, 2.00-18.17; P = 0.001) than those with low-USP-11-expressing tumors. Patients who did not achieve a pCR had an increased risk of recurrence (OR, 5.16; 95% CI, 1.16-23.07; P = 0.03).
Our data indicate that USP-11 is not a predictor of a pCR after anthracycline-taxane-containing NST for breast cancer. Low USP-11 expression was independently correlated with better survival outcomes.
The Cancer Journal 01/2013; 19(1):10-7. · 3.26 Impact Factor
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Xiuzhen Duan,
Nour Sneige,
Ashley E Gullett,
Victor G Prieto,
Erika Resetkova,
Lizmarie M Andino,
Yun Wu,
Micharl Z Gilcrease,
Isabelle Bedrosian,
Shaheenah Dawood, Banu Arun,
Constance T Albarracin
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ABSTRACT: Mammary Paget disease (MPD) is considered an intraepidermal manifestation of an underlying mammary carcinoma. In contrast to extramammary Paget disease, invasion of mammary Paget cells into the dermis (invMPD) has not been reported, except for 2 cases described in Rosen's textbook. Our study was designed to identify the presence of dermal invasion of mammary Paget cells and characterize the associated clinicopathologic features. Slides from 146 MPD patients were retrieved. Six cases of invMPD were identified. One case of invMPD was not associated with an underlying breast cancer, 1 was associated with invasive ductal carcinoma (IDC), 1 with ductal carcinoma in situ (DCIS) with microinvasion, and 3 with DCIS only. The underlying breast carcinomas was separate from the area of invMPD. The depth of invasion, measured from the dermal-epidermal junction to the focus of deepest invasion, ranged from 0.02 to 0.9 mm. The horizontal extent ranged from 0.01 to 4.0 mm. Lymph node with isolated tumor clusters was present in case 1, which had no underlying carcinoma but had the greatest extent of invasion, and in case 3, which had DCIS with microinvasion. One patient (case 1) died of unrelated causes 2 years later, and the remaining patients were alive without disease at last follow-up. In summary, we describe 6 cases of MPD with invasion of Paget cells into the dermis and provide histopathologic criteria for the diagnosis of this rare and underrecognized entity. Further studies are required to determine whether invasion in MPD has clinical significance.
The American journal of surgical pathology 09/2012; 36(9):1353-8. · 4.06 Impact Factor
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under review. 09/2012;
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ABSTRACT: The concept of dose-dense chemotherapy has emerged and is based on the hypothesis that maximal chemotherapy effectiveness can be achieved by scheduling the interval of chemotherapy to correspond to the period of most rapid tumor growth, as predicted by preclinical models. The granulocyte-colony stimulating factor support has permitted the safe delivery of chemotherapy at shorter ("dose-dense") inter-treatment intervals. Several randomized trials have been conducted to test the feasibility and effectiveness of anthracycline and/or taxanes-based dose-dense strategies. They have been associated with a modest impact on disease recurrence and overall survival of patients with early-stage breast cancer. Subset analyses have suggested increased benefits for specific tumor subtypes such as hormone receptor-negative, highly proliferative or HER2 overexpressing tumors. This review article aims to outline the theoretical framework for dose-dense chemotherapy and summarizes the results of several recent clinical trials addressing this concept within neoadjuvant and adjuvant breast cancer treatment and discuss their implications for clinical practice. Further studies are needed to define the optimal regimen and the patient population that will receive the greatest benefit from dose-dense strategy.
The Breast Journal 05/2012; 18(3):261-6. · 1.64 Impact Factor
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Wei Tse Yang,
Michael T. Lewis,
Kenneth Hess,
Helen Wong,
Anna Tsimelzon,
Nese Karadag,
Michelina Cairo,
Caimaio Wei,
Funda Meric-Bernstam,
Powel Brown, Banu Arun,
Gabriel N. Hortobagyi,
Aysegul Sahin,
Jenny C. Chang
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ABSTRACT: High mammographic density is associated with a increased risk of breast cancer. We hypothesized that specific pathways exist
that are associated with increased mammographic density, and may therefore be used to identify potential targets for chemoprevention.
Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic
data and mammograms for review. Women with low versus high mammographic breast density were compared. Differentially expressed genes using Affymetrix HG U133Plus2 chips were identified
in dense versus non-dense tissue. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, Ki67, and
COX2 expression was performed. About 66 women were identified, 28 (42%) had high, and 38 (58%) had low mammographic density.
About 73 genes had differential expression between normal breast tissue with high and low mammographic density (P<0.001, fold change ≥1.5with a low false discovery rate (<10%). Network and canonical pathway analysis indicated decreased
TGFβ signaling (TGFBR2, SOS, SMAD3, CD44 and TNFRSF11B) in dense breast tissue relative to non-dense breast. By IHC, only
COX2 expression in the stroma was statistically significant on multivariate analysis. TGFβ ligands are currently the only
growth factors known to prevent mammary epithelial cell proliferation. TGFβ signaling has been reported to be inhibited by
COX-2, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These
results strongly suggest that COX2 inhibition should be investigated for breast cancer prevention despite possible increase
in cardiovascular risk.
Breast Cancer Research and Treatment 04/2012; 119(2):305-314. · 4.43 Impact Factor
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Soley Bayraktar,
Nisreen Elsayegh,
Angelica M Gutierrez Barrera,
Heather Lin,
Henry Kuerer,
Tunc Tasbas,
Kimberly I Muse,
Kaylene Ready,
Jennifer Litton,
Funda Meric-Bernstam,
Gabriel N Hortobagyi,
Constance T Albarracin, Banu Arun
[show abstract]
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ABSTRACT: It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high-risk variables. The authors of this report identified predictive factors for mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS.
One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status.
Of 118 high-risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations. Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. In a multivariate logistic model, ≥2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38-56.29; P = .034), and a score ≥10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23-18.22; P = .0005) remained as independent significant predictors for a BRCA mutation. Fifty-seven percent of mutation carriers but only 25% of noncarriers underwent prophylactic mastectomy(P = .0037). This difference remained significant for patients aged ≤40 years (P = .025).
Women who had DCIS and a family history of OC or who had BRCAPRO scores ≥10% had a high rate of BRCA positivity regardless of age at diagnosis. These findings suggest that high-risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer.
Cancer 03/2012; 118(6):1515-22. · 4.77 Impact Factor
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ABSTRACT: The BRCAPRO model estimates carrier probabilities for the BRCA1 and BRCA2 genes, and was recently enhanced to use estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer. No independent assessment of the added value of these markers exists. Moreover, earlier versions of BRCAPRO did not use human epidermal growth factor receptor 2 (Her-2/neu) status of breast cancer. Here, we incorporate Her-2/neu in BRCAPRO and validate all the markers. We trained the enhanced model on 406 germline tested individuals, and validated on a separate clinical cohort of 796 individuals for whom test results and family history are available. For model-building, we estimated joint probabilities of ER, PR, and Her-2/neu status for carriers and non-carriers of BRCA1/2 mutations. For validation, we obtained BRCAPRO predictions with and without markers. We calculated area under the receiver operating characteristic curve (AUC), sensitivity, specificity, predictive values, and correct reclassification rates. The AUC for predicting BRCA1 status among individuals who are carriers of at least one mutation improved when ER and PR were used. The AUC for predicting the presence of either mutation improved when Her-2/neu was added. Use of markers also produced highly significant correct reclassification improvements in both cases. Breast tumor markers are useful for prediction of BRCA1/2 mutation status. ER and PR improve discrimination between BRCA1 and BRCA2 mutation carriers while Her-2/neu helps discriminate between carriers and non-carriers, particularly among women who are ER positive and Her-2/neu negative. These results support the use of the enhanced version of BRCAPRO in clinical settings.
Breast Cancer Research and Treatment 01/2012; 133(1):347-55. · 4.43 Impact Factor
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Banu Arun,
Soley Bayraktar,
Diane D Liu,
Angelica M Gutierrez Barrera,
Deann Atchley,
Lajos Pusztai,
Jennifer Keating Litton,
Vicente Valero,
Funda Meric-Bernstam,
Gabriel N Hortobagyi,
Constance Albarracin
[show abstract]
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ABSTRACT: To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations.
A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival.
Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not.
BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.
Journal of Clinical Oncology 09/2011; 29(28):3739-46. · 18.37 Impact Factor
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Jack Cuzick,
Andrea DeCensi, Banu Arun,
Powel H Brown,
Monica Castiglione,
Barbara Dunn,
John F Forbes,
Agnes Glaus,
Anthony Howell,
Gunter von Minckwitz,
Victor Vogel,
Heinz Zwierzina
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ABSTRACT: In March, 2010, a group of breast cancer experts met to develop a consensus statement on breast cancer prevention, with a focus on medical and therapeutic interventions. We present the conclusions in this Review. First we agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators--tamoxifen and raloxifene--are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.
The lancet oncology 03/2011; 12(5):496-503. · 14.47 Impact Factor
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The Breast Journal 02/2011; 17(2):210-2. · 1.64 Impact Factor
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Lorenzo Cohen,
Zhen Chen, Banu Arun,
Zhimin Shao,
Mark Dryden,
Linhhui Xu,
Carisa Le-Petross,
Basak Dogan,
Brian J McKenna,
Maurie Markman,
Gildy Babiera
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ABSTRACT: The majority of patients with cancer use some form of complementary or alternative medicine. External qigong treatment (EQT), classified as a bioenergy therapy, is one such approach that patients combine with conventional medicine or, in some cases, use in place of conventional medicine. This study aimed to determine whether EQT could shrink breast cancer tumors and improve quality of life (QOL) in women with pathologically confirmed breast cancer awaiting surgery. A total of 9 women with pathologically confirmed breast cancer were recruited from large cancer centers in the United States (n = 5) and China (n = 4). A single-arm pre/post design was used. Each patient underwent 5 consecutive days of EQT, with each treatment lasting from 2 to 5 minutes. All treatments were performed by the same qigong master. Tumor measurements were made before and after the EQT sessions. Tumor assessments were conducted prior to study initiation and following the last EQT. Patients underwent both an ultrasound and mammogram (United States) or an ultrasound and magnetic resonance imaging (China). All patients also underwent physical breast examinations (PBEs) and completed QOL questionnaires before and after the last EQT. No clinical changes in tumor measurements from pre- to post-EQT were noted. There was also no suggestion of change in tumor size by PBE or change in QOL. Using the current STUDY DESIGN: EQT also does not appear to have any effect on patient QOL. Because of the small sample size and working with only one qigong practitioner, to definitively determine the efficacy or lack of efficacy of EQT, a larger study with multiple qigong practitioners would need to be conducted.
Integrative Cancer Therapies 12/2010; 9(4):348-53. · 2.14 Impact Factor
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ABSTRACT: Family history is a key component of breast cancer risk assessment. Family history provides clues as to the likelihood of a hereditary breast cancer syndrome and the need for a cancer genetics referral and can be used in the setting of a breast cancer risk assessment model to estimate a woman's risk. Appropriate breast cancer screening and risk reduction management plans rely on an accurate assessment of a patient's family history. This article reviews the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Risk Reduction and provides insight into the application of the guidelines in clinical practice.
Journal of the National Comprehensive Cancer Network: JNCCN 11/2010; 8(10):1148-55. · 4.41 Impact Factor
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Patricia G Moorman,
Edwin S Iversen,
P Kelly Marcom,
Jeffrey R Marks,
Frances Wang,
Eunjung Lee,
Giske Ursin,
Timothy R Rebbeck,
Susan M Domchek, Banu Arun,
Lisa Susswein,
Claudine Isaacs,
Judy E Garber,
Kala Visvanathan,
Constance A Griffin,
Rebecca Sutphen,
Jennifer Brzosowicz,
Stephen Gruber,
Dianne M Finkelstein,
Joellen M Schildkraut
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ABSTRACT: The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.
Breast Cancer Research and Treatment 11/2010; 124(2):441-51. · 4.43 Impact Factor
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Therese B Bevers,
Deborah K Armstrong, Banu Arun,
Robert W Carlson,
Kenneth H Cowan,
Mary B Daly,
Irvin Fleming,
Judy E Garber,
Mary Gemignani,
William J Gradishar, [......],
Deborah J Macdonald,
Martin C Mahoney,
Sofia D Merajver,
Ingrid Meszoely,
Lisa Newman,
Elizabeth Pritchard,
Victoria Seewaldt,
Rena V Sellin,
Charles L Shapiro,
John H Ward
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ABSTRACT: Breast cancer is the most commonly diagnosed cancer in American women with 209,060 and 54,010 estimated cases of invasive breast cancer and female carcinoma in situ, respectively, in 2010. Approximately 39,840 women will die of breast cancer in the United States in 2010.(1) Risk factors for the development of breast cancer can be grouped into categories, including familial/genetic factors (family history, known or suspected BRCA1/2, TP53, PTEN, or other gene mutation associated with breast cancer risk); factors related to demographics (e.g., age, ethnicity/race); reproductive history (age at menarche, parity, age at first live birth, age at menopause); environmental factors (prior thoracic irradiation before age 30 years [e.g., to treat Hodgkin disease], hormone replacement therapy [HRT], alcohol consumption); and other factors (e.g., number of breast biopsies, atypical hyperplasia or lobular carcinoma in situ [LCIS], breast density, body mass index). Estimating breast cancer risk for the individual woman is difficult, and most breast cancers are not attributable to risk factors other than female gender and increased age. The development of effective strategies for the reduction of breast cancer incidence has also been difficult because few of the existing risk factors are modifiable and some of the potentially modifiable risk factors have social implications extending beyond concerns for breast cancer (e.g., age at first live birth). Nevertheless, effective breast cancer risk reduction agents/strategies, such as tamoxifen, raloxifene, and risk reduction surgery, have been identified. However, women and their physicians who are considering interventions to reduce risk for breast cancer must balance the demonstrated...
Journal of the National Comprehensive Cancer Network: JNCCN 11/2010; 8(10):1112-46. · 4.41 Impact Factor
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ABSTRACT: Every year approximately 25% of women diagnosed with breast cancer are younger than 50 years of age, and almost 10% of them have a BRCA mutation. Not all potential carriers are identified by existing criteria for BRCA testing. We estimated the costs and benefits of different BRCA testing criteria for women with breast cancer younger than 50 years.
We developed a Markov Monte Carlo simulation to compare six criteria for BRCA mutation testing: (1) no testing (reference); (2) medullary breast cancer in patients younger than 50 years; (3) any breast cancer in patients younger than 40 years; (4) triple negative (TN) breast cancer in patients younger than 40 years; (5) TN breast cancer in patients younger than 50 years; (6) any breast cancer in patients younger than 50 years. Net health benefits were life expectancy and quality-adjusted life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new breast and ovarian cancer cases.
BRCA mutation testing for all women with breast cancer who were younger than 50 years could prevent the highest number of breast and ovarian cancer cases, but with unfavorable ICERs. Testing women with TN breast cancers who were younger than 50 years was cost-effective with an ICER of $8,027 per year of life gained ($9,084 per quality-adjusted life-year), and could reduce subsequent breast and ovarian cancer risks by 23% and 41%, respectively, compared with the reference strategy.
Testing women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.
Journal of Clinical Oncology 09/2010; 28(27):4214-20. · 18.37 Impact Factor
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Robert W Carlson,
Richard Theriault,
Christine M Schurman,
Edgardo Rivera,
Cathie T Chung,
See-Chun Phan, Banu Arun,
Kristine Dice,
Vivian Y Chiv,
Marjorie Green,
Vicente Valero
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ABSTRACT: To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor-positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin.
Premenopausal women with estrogen and/or progesterone receptor-positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity.
Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities.
The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor-positive metastatic breast cancer.
Journal of Clinical Oncology 09/2010; 28(25):3917-21. · 18.37 Impact Factor
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ABSTRACT: Breast cancer is the most common cancer among women in the United States, with 192,870 new cases and 40,170 deaths due to this disease estimated to have occurred 2009. An emphasis on prevention has been increasing in view of a persisting high incidence of disease. Seventy percent of breast cancers are estrogen receptor (ER)-positive, and are therefore presumed to be hormone-responsive and potentially treatable or preventable by anti-estrogenic agents. To date, the large, phase III randomized controlled breast cancer prevention trials have tested and are testing only hormonal drugs designed to antagonize the carcinogenic effect of endogenous estrogen; these agents are either selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). The SERMs, tamoxifen and raloxifene, have been shown in these large trials to reduce the risk of ER-positive breast cancers; prevention trials of AIs are ongoing. Interest is now focusing on developing agents with a broader spectrum of preventive activity, particularly with regard to ER-negative subtypes of breast cancer. A number of phase I and II trials using tissue-derived surrogate endpoint biomarkers (SEBs) as outcomes have been implemented. These smaller trials address prevention not only of ER-negative but also ER-positive breast cancers, since approximately 50% of the latter have been shown to be resistant to the estrogen-targeting drugs used in the large trials. Issues of importance in these smaller trials include choice of agent, selection of appropriate trial participants, trial design, method of access to breast tissue in women without cancer, selection and monitoring of SEBs, and monitoring of drug toxicity.
Seminars in Oncology 08/2010; 37(4):367-83. · 3.50 Impact Factor
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Andrew Tutt,
Mark Robson,
Judy E Garber,
Susan M Domchek,
M William Audeh,
Jeffrey N Weitzel,
Michael Friedlander, Banu Arun,
Niklas Loman,
Rita K Schmutzler,
Andrew Wardley,
Gillian Mitchell,
Helena Earl,
Mark Wickens,
James Carmichael
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ABSTRACT: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.
Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234.
Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).
The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.
AstraZeneca.
The Lancet 07/2010; 376(9737):235-44. · 38.28 Impact Factor
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ABSTRACT: Overexpression of p70S6K in breast cancer patients is associated with aggressive disease and poor prognosis. Recent studies showed that patients with breast cancer with increased p70S6K phosphorylation had poor survival and increased metastasis. The purpose of our study was to determine whether knockdown of p70S6K would inhibit cell growth, invasion, and metastasis in breast cancer. We therefore stably knocked down p70S6K expression in MDA-231, a highly metastatic breast cancer cell line, using a lentiviral short hairpin RNA (shRNA) based approach. Inhibition of p70S6K led to inhibition of cell growth, migration, and invasion in vitro. To determine the role of p70S6K in breast cancer tumorigenesis and metastasis, we used an MDA-231 orthotopic and metastatic animal model. In the orthotopic model, mice injected with MDA-231-p70S6K shRNA cells developed significantly smaller tumors than control mice injected with MDA-231 control shRNA cells (P < 0.01). No metastasis was observed in the p70S6K downregulated group, whereas lung metastasis was detected in all mice in the control group. To determine the role of p70S6K on growth and invasion, we tested downstream signaling targets by Western blot analysis. Knockdown of p70S6K inhibited phosphorylation of focal adhesion kinase, tissue transglutaminase 2, and cyclin D1 proteins, which promote cell growth, survival, and invasion. In addition, downregulation of p70S6K induced expression of PDCD4, a tumor-suppressor protein. In conclusion, we showed that p70S6K plays an important role in metastasis by regulating key proteins like cyclin D1, PDCD4, focal adhesion kinase, E-cadherin, beta-catenin, and tissue transglutaminase 2, which are essential for cell attachment, survival, invasion, and metastasis in breast cancer.
Molecular Cancer Therapeutics 05/2010; 9(5):1180-7. · 5.23 Impact Factor
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Alejandra T Perez, Banu Arun,
Debu Tripathy,
Mary A Tagliaferri,
Heather S Shaw,
Gretchen G Kimmick,
Isaac Cohen,
Emma Shtivelman,
Katherine A Caygill,
Deborah Grady,
Mark Schactman,
Charles L Shapiro
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ABSTRACT: The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.
Breast Cancer Research and Treatment 02/2010; 120(1):111-8. · 4.43 Impact Factor
