Hormone Receptor-positive Cancer Research Articles

Total energy intake and breast cancer risk in sisters: the Breast Cancer Family Registry

Energy restriction inhibits mammary tumor development in animal models. Epidemiologic studies in humans generally do not support an association between dietary energy intake and breast cancer risk, although some studies suggest a more complex interplay between measures of energy intake, physical activity, and body size. We examined the association between total energy intake jointly with physical activity and body mass index (BMI) and the risk of breast cancer among 1,775 women diagnosed with breast cancer between 1995 and 2006 and 2,529 of their unaffected sisters, enrolled in the Breast Cancer Family Registry. We collected dietary data using the Hawaii-Los Angeles Multiethnic Cohort food frequency questionnaire. Using conditional logistic regression to estimate the odds ratios (OR) and 95 % confidence intervals (CI) associated with total energy intake, we observed an overall 60-70 % increased risk of breast cancer among women in the highest quartile of total energy intake compared to those in the lowest quartile (Q4 vs. Q1: OR = 1.6, 95 % CI: 1.3-2.0; P (trend) < 0.0001); these associations were limited to pre-menopausal women or women with hormone receptor-positive cancers. Although the associations were slightly stronger among women with a higher BMI or lower level of average lifetime physical activity, we observed a positive association between total energy intake and breast cancer risk across different strata of physical activity and BMI. Our results suggest that within sisters, high energy intake may increase the risk of breast cancer independent of physical activity and body size. If replicated in prospective studies, then these findings suggest that reductions in total energy intake may help in modifying breast cancer risk.

The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer.

Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15–20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.

Abstract 3654: Prognostic role of androgen receptor in bladder cancer

Abstract Aims: Hormone receptors are the prototype predictive marker in breast and prostate cancer. Hormone receptor positive cancers have a better prognosis, increased tropism to metastasize into the bones and respond to endocrine treatment options. The prognostic value of hormone receptor in urothelial carcinoma of the bladder (UCB) is less established. This may in part result from technical limitations of immunhistochemical detection methods. Interestingly, female gender has recently been identified as strong adverse factor in advanced UCB (May et al., 2011). By analyzing whole genome expression data from non-muscle invasive bladder cancer patients, we have evaluated the potential of top candidate genes (ESR1, PGR, AR, CYP19, HER2, RACGAP1) commonly used to stratify breast cancer patients to predict bladder cancer progression. In view of the gender specific effects, we have focused on the prognostic role of androgen receptor expression on tumor invasion, disease progression and survival. Methods: Affymetrix microarray data from 41 non-metastatic bladder cancer patients undergoing curative surgery were analyzed. Prognostic value of androgen receptor mRNA expression was analyzed by unsupervised Cluster analysis, partitioning tests, Mann Whitney tests and Kaplan Meier estimates of cancer specific survival. Results: Cluster analysis in the microarray date of the superficial UCB cohort identified a hormone receptor positive subtype and a proliferation dominated subtype of equal size. Androgen receptor expression was negatively associated with cancer specific death (r=−0,42; p=0,005), while proliferation correlated with increased risk of cancer specific death (r=0,46; p=0,003). In addition, low androgen receptor expression was associated with higher tumor stage (pTa vs pT1-4; p=0,017). In Kaplan Meier analysis, the cancer specific survival was significantly better in tumors exhibiting high androgen receptor levels (80% vs. 20 %; p&amp;lt;0,0001). Discussion: Resembling to some extent the situation in other cancer types, hormone receptors are prognostic factors in early stage bladder cancer. These results may also explain the recently described gender specific effects in bladder cancer. Moreover, these results raise the possibility, that UCB patients may be stratified according to their androgen receptor status in view of prognosis and putative endocrine therapy options. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3654. doi:1538-7445.AM2012-3654

Prone Accelerated Partial Breast Irradiation After Breast-Conserving Surgery: Five-year Results of 100 Patients

To report the 5-year results of a prospective trial of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation in the prone position. Postmenopausal patients with Stage I breast cancer with nonpalpable tumors <2 cm, negative margins and negative nodes, positive hormone receptors, and no extensive intraductal component were eligible. The trial was offered only after eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were simulated and treated on a dedicated table for prone setup. 3D-CRT was delivered at a dose of 30 Gy in five 6-Gy/day fractions over 10 days with port film verification at each treatment. Rates of ipsilateral breast failure, ipsilateral nodal failure, contralateral breast failure, and distant failure were estimated using the cumulative incidence method. Rates of disease-free, overall, and cancer-specific survival were recorded. One hundred patients were enrolled in this institutional review board-approved prospective trial, one with bilateral breast cancer. One patient withdrew consent after simulation, and another patient elected to interrupt radiotherapy after receiving two treatments. Ninety-eight patients were evaluable for toxicity, and, in 1 case, both breasts were treated with partial breast irradiation. Median patient age was 68 years (range, 53-88 years); in 55% of patients the tumor size was <1 cm. All patients had hormone receptor-positive cancers: 87% of patients underwent adjuvant antihormone therapy. At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% ipsilateral breast failure) and one contralateral breast cancer (1% contralateral breast failure). There were no deaths due to breast cancer by 5 years. Grade 3 late toxicities occurred in 2 patients (one breast edema, one transient breast pain). Cosmesis was rated good/excellent in 89% of patients with at least 36 months follow-up. Five-year efficacy and toxicity of 3D-CRT delivered in prone partial breast irradiation are comparable to other experiences with similar follow-up.

Using neoadjuvant therapy for breast cancer in clinical practice: when and how?

The roles of neoadjuvant therapy both as a standard thera-peutic approach and a research tool are very closely tied andhave yielded insights into both breast cancer biology andnew drug development [1, 2]. From a clinician’s standpoint,however, the key questions that arise revolve around theclinical advantages of neo-adjuvant therapy in terms ofsurgical outcomes, long-term recurrence/mortality anddecision-making. At the current time, the main advantage ofneoadjuvant therapy is to improve the odds of adequatesurgical resection, particularly breast-conserving surgery[3, 4]. Beyond that, long-term outcomes or clinical deci-sion-making do not appear to be affected by the sequence ofsystemic therapy in relation to definitive surgery. It isbecoming clear that breast cancer is heterogeneous. Ge-nomically defined subsets, which map to some extent withhormone and HER2 receptor subtypes, exhibit differentialrecurrence hazard reductions with systemic therapies—andthis concept also applies to neoadjuvant therapy response aswell [5]. But there is also clinical diversity, for example,contrasting rapid onset inflammatory cancer to a moreindolent cancer that has been clinically present for severalyears. Therefore, current neoadjuvant treatment paradigmsmust incorporate the base of evidence from large scaleclinical trials as well as the biological context of the disease.The reports contained in this special issue of Breast CancerResearch and Treatment highlight current trends and resultsthat are shaping both patient care and research in this area.The report by Lin et al.[6] demonstrate biological dif-ferences between interval and screen-detected cancerstreated on a prospective trial, even though the number ofscreening-detected cancers was small, as would be typicalin a neoadjuvant trial where the majority of patients werenot undergoing screening. As expected, interval cancershad a tendency to be hormone receptor-negative and ofhigher grade, whereas screen-detected cancers were all ofthe luminal intrinsic subtypes by gene expression array.Nevertheless, this report points to the need to stratifypatients by known characteristics associated with responsein clinical trials and to use established factors in routineclinical practice. For example, it is now clear that patientswith hormone receptor-positive cancer have less responseto neoadjuvant therapy and lower pathologic completeresponse (pCR) rates. Receptor status might thereforeaffect the decision regarding the timing of chemotherapy,especially if breast-conserving surgery is driving thedecision. Several phenotypes that are also related to hor-mone receptor content, but appear to have independentprognostic factors for response, such as proliferation indexand risk score by gene profile assays are the next markerson the horizon that could enter into this decision-making iftumor size reduction is a main goal of therapy [7, 8].Is there an optimum neoadjuvant regimen? Should non-standard adjuvant regimens that yield high pCR rates beadopted into routine practice? Until neoadjuvant trials arepowered for long-term outcome, at the current time, it isimportant to remember that the most important benefit ofneoadjuvant therapy is its ‘‘adjuvant’’ effect on long-termrecurrence and mortality. Therefore, an evidence-basedapproach would dictate the use of proven standard adjuvantregimens in the neoadjuvant setting. However, trials thatbridge pCR rates in relevant subsets to long-term outcomecould serve as the basis for approvals of new drugs andregimens and eventually shorten regulatory approval times[9]. Some long-standing standards may need to be

Expression of Notch Receptors in Primary Breast Cancer and Correlation with Pathological Features

Introduction: Notch signaling evolves as an important mediator of stem cell biology, tumor formation, angiogenesis and cell fate decisions. Four Notch receptors and five ligands have been identified in human, and they regulate a complex signal transduction pathway that interacts with other stem cell-related pathways as Sonic Hedgehog and Wnt. Recently, dysregulation of Notch pathway has been found to play a crucial role in breast cancer oncogenesis and it could serve as a target for treatment. Methods: We estimated the expression of Notch receptors’ at the mRNA level, in 200 human breast cancer samples from a single institution in Northern Greece. Notch 1-4 mRNA was estimated by using Real-time PCR and we correlated the level of Notch expression with breast cancer pathology (TNM, grade oestrogen and progesterone receptors and HER2). Results: We found that Notch receptors (at the mRNA level) are differentially expressed in breast cancer subgroups. Hormone receptor positive cancers express Notch-4 whilst Notch-1 and Notch-3 receptors are involved in the development of triple-negative breast cancer. HER2-positive cancers express lower levels of Notch-1, a finding that is in concert with other reports as well. Conclusion: Notch receptors are expressed differentially and could serve as potential targets for treatment in different molecular subtypes of breast cancer.

PD06-04: Uptake and Economic Impact of First-Cycle Colony Stimulating Factor Use during the Adjuvant Treatment of Breast Cancer.

Abstract Background: In 2002, pegfilgrastim was approved by the FDA and the benefits of dose-dense breast cancer(BC) chemotherapy were reported. A meta-analysis revealed these benefits were limited to hormone receptor negative tumors (20% risk reduction), where hormone receptor positive cancers had a minimal 2% risk reduction. We examined first-cycle growth factor use(FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy by hormone receptor status. Methods: We identified subjects in SEER-Medicare&amp;gt;65 years oldwith stage I-III BC between 1998 and 2005who had≥1 chemotherapy claim within one year of diagnosis. We classified those with an average cycle length &amp;lt;21 days as having had dose-dense therapy. The associations of patient, tumor, and physician-related factors with receipt of any CSF and FC-CSF use were analyzed using GEE. Costs and event-free life-years saved were estimated for patients by HR status. Results: Among the 11,143 patients identified, 5,356(48.1%) hada CSF claim during therapy and 2095(18.8%) had FC-CSF. CSF use increased from 25.4% to 70.9%, FC-CSF increased from 6.4% to 46.9% and pegfilgrastim increased from 5% to 85%. During this time receipt of the combination of an anthracycline and a taxane increased from 12% to 47%. In a multivariable analysis, any CSF use was associated with age, treatment by an oncologist, and chemotherapy type; and negatively associated with black/Hispanic race, rural residence and shorter chemotherapy duration. FC-CSF use was associated also with higher SES. For hormone receptor negative patients, the cost per event-free life year saved was $5,512, with annual costs of $19.5 million. For hormone receptor positive patients, however, there was no savings in life years (and therefore no relevant cost per event-free life year saved) with annual costs of $38.8 million for those over 65. The annual costs were estimated at $86.1 million for the hormone receptor positive patient population incorporating all ages. Conclusions: Our study demonstrated a widespread increase in the use of CSF's and specifically first cycle pegfilgrastim in elderly women receiving adjuvant chemotherapy for breast cancer. This 4-fold increase came shortly after published reports of the benefits of dose-dense therapy. While this approach is very cost-effective in women with hormone receptor negative tumors, it has come at great financial cost in women with hormone receptor positive tumors who are less likely to have a meaningful benefit. In order to reduce the total costs of cancer-care, efforts should be made to ensure that these treatments are reserved for only those who benefit substantially from their use. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD06-04.

Breast Cancer: Evaluation of Response to Neoadjuvant Chemotherapy with 3.0-T MR Imaging

To assess how the molecular biomarker status of a breast cancer, including human epidermal growth factor receptor 2 (HER2), hormone receptors, and the proliferation marker Ki-67 status, affects the diagnosis at 3.0-T magnetic resonance (MR) imaging. This study was approved by the institutional review board and was HIPAA compliant. Fifty patients (age range, 28-82 years; mean age, 49 years) receiving neoadjuvant chemotherapy were monitored with 3.0-T MR imaging. The longest dimension of the residual cancer was measured at MR imaging and correlated with pathologic findings. Patients were further divided into subgroups on the basis of HER2, hormone receptor, and Ki-67 status. Pathologic complete response (pCR) was defined as when there were no residual invasive cancer cells. The Pearson correlation was used to correlate MR imaging-determined and pathologic tumor size, and the unpaired t test was used to compare MR imaging-pathologic size discrepancies. Of the 50 women, 14 achieved pCR. There were seven false-negative diagnoses at MR imaging. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease at MR imaging were 81%, 93%, and 84%, respectively. The mean MR imaging-pathologic size discrepancy was 0.5 cm ± 0.9 (standard deviation) for HER2-positive cancer and 2.3 cm ± 3.5 for HER2-negative cancer (P = .009). In the HER2-negative group, the size discrepancy was smaller for hormone receptor-negative than for hormone receptor-positive cancers (1.0 cm ± 1.1 vs 3.0 cm ± 4.0, P = .04). The size discrepancy was smaller in patients with 40% or greater Ki-67 expression (0.8 cm ± 1.1) than in patients with 10% or less Ki-67 expression (3.9 cm ± 5.1, P = .06). The diagnostic accuracy of breast MR imaging is better in more aggressive than in less aggressive cancers. When MR imaging is used for surgical planning, caution should be taken with HER2-negative hormone receptor-positive cancers.

Long-term follow-up of dose-dense neoadjuvant chemotherapy in patients with stage II/III breast cancer.

e11048 Background: Prior studies have shown that women with operable breast cancer had no improvement in disease free survival (DFS) or overall survival (OS) having received chemotherapy (AC) either pre or postoperatively. However, they were able to delineate a subset of women who had improvement in DFS and OS. Achieving a pathological complete remission (pCR) was directly proportional to DFS and OS. Dose dense adjuvant chemotherapy (ATC) has shown a statistically significant improvement in DFS and OS. Methods: We performed a single institution review of patients (pts) enrolled in a neoadjuvant trial who received dose dense neoadjuvant chemotherapy (doxorubicin 60mg/m2 IV Q2wks x4, paclitaxel 175mg/m2IV Q2wks x4 and cyclophosphamide 600 mg/m2 IV Q2wks x4) to asses response rates, safety and DFS. Women with newly diagnosed breast cancer T > 3cm, any N, and M0 were enrolled. Results: Since 2/2003, 48 pts were enrolled in a trial at UAB (mean age 48.7, range 28-64) and received dose dense chemotherapy. The median follow up is 67.9 months (range 8-88 months). Forty one pts completed dose dense chemotherapy and underwent surgery. Seventeen (41.4%) pts achieved a pCR in the breast and of those 14 (34%) pts were also pathologically negative in axillary lymph nodes. Ten of the 17 pts with pCR in the breast were triple negative. Nine pts have had disease relapse including one pt (HER2+) who had achieved a pCR. Two pts had febrile neutropenia, 2 pts had grade 3 anemia and none with grade 4 thrombocytopenia or anemia. Non hematological grade 3 or 4 toxicity included: venous thrombosis 3 pts, hyperglycemia 2 pts, syncope 1 pt, varicella zoster 1 pt and neuropathy in 2 pts. Conclusions: Our results show that dose dense neoadjuvant chemotherapy is effective, achieving high number of pCRs (breast and node) in triple negative and HER2+ breast cancer subtypes as opposed to hormone receptor positive cancers, with tolerable toxicity. Achieving a pCR is an important factor predicting the subsequent risk of relapse across all tumor types. Triple-negative HER2+ ER+ Total Number of cases (%) 17 (41) 6 (15) 18 (44) 41 (100) Breast pCR 10 (59) 5 (29) 2 (12) 17 (100) Breast/node pCR 8 (57) 4 (29) 2 (14) 14 (100) Relapses 4 2* 3 9 pCR in relapses None 1 None 1

Abstract P3-10-24: Fibroblast Growth Factor Receptor 1 Amplification and Overexpression in Breast Cancer Tissue Microarrays Using Chromogenic In Situ Hybridization and Immunohistochemistry

Abstract Fibroblast growth factor receptors 1 (FGFR1) belongs to a subfamily of receptor tyrosine kinases (RTKs), which are involved in proliferation and apoptosis. FGFR1 amplification and mRNA overexpression occurs in ∼10% of breast cancers and has been associated with poor outcome. However, studies assessing FGFR1 amplification and protein overexpression in a large collection of breast tumors are lacking. In this prospective, we examined a series of primary breast cancers samples derived from the BCIRG trials assembled into 15 tissue microarrays. FGFR1 gene amplification was studied using chromogenic in situ hybridization (CISH) and evaluated with respect to association with level of protein expression and clinicopathological parameters. FGFR1 gene amplification was significantly associated with high protein levels as determined by immunohistochemistry (P&amp;lt;0.0001, 3294 pts with available matched CISH and IHC records). Overall, the incidence of FGFR1 amplification found was 9.7% (160 out of 1646 pts. with available clinicopathological records) without a statistically significant difference between Her2- (78 out 720 pts., 11%) and Her2+ (82 out of 926 pts., 9%) cancers. In both cohorts, the hormone receptor-positive (ER+/PR+) cancers showed statistically significant higher levels of FGFR1 amplification compared to hormone receptor-negative tumors. In the analysis of the association of FGFR1 and the presence of PIK3CA mutations, the incidence of FGFR1 amplificationwas greatly reduced in mutant vs. wt PI3KCA tumors. In these cohorts, a clear relationship between FGFR1 amplification status and clinical outcome was not detected. Data from this large study confirms recently reported incidences of FGFR1 amplification in breast cancer and shows for the first time an association between FGFR1 gene amplification and protein overexpression. Moreover, the lower incidence of FGFR1 amplification in PIK3CA mutated cancers suggests that these are largely exclusive molecular events that could benefit from different targeted therapies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-24.

Gene-expression profiling in breast cancer: bespoke cancer therapy or more fiction than science?

Breast cancer is the most common life threatening malignancy in women. Despite advances in molecular therapeutics, many patients with apparently early stage and curable disease still develop progressive and fatal systemic disease. Haffty et al. [1] demonstrated that despite conservative surgery and radiation followed by administration of chemotherapy in early-stage (T1 tumours) breast cancer patients, the distant metastasis-free survival rate was 71% at 5 years in patients with triple negative disease and 83% at 5 years in non-triple negative. These patients have potentially been under-staged by conventional staging, and therefore may not have received optimum therapy due to their misleading clinical disease profile. Conversely, patients receiving systemic therapy may not derive any additional benefit. Breast cancer is an intricate genetic milieu characterised by numerous molecular alterations that prevents standardising therapeutic strategies to all patients. Until recently, it has been difficult to accurately profile and predict the biological properties and clinical behaviour of breast tumours, however, with the development of DNA microarray technology, it is now possible to analyse the RNA expression of several thousands of genes simultaneously. The clinical application of this technology has the potential to signal a paradigm shift in patient selection for systemic therapy. First, it provided a new molecular classification of breast cancer. This classification was proposed by Perou et al. [2], and subdivided breast cancers into four classes. Luminal-A cancers are ER-positive and mostly low grade. Luminal-B cancers are also ER-positive but tend to be high grade. Basal-like cancers are triple negative and Her-2-like cancers are Her-2 positive and usually ER negative. Currently, there are a number of validated commercially available multigene assays that identify expression of distinct sets of genes in breast cancer: Mammaprint (Agendia), Oncotype DX (Genomic Health), MapQuant and H/I (AvariaDX) (see Table 1 for comparison of assays). Mammaprint uses DNA microarray technology, whereas Oncotype DX and H/I use real time PCR based assays. These assays accurately predict the potential for disease recurrence and enhance patient selection for chemotherapeutic strategies. Mammaprint uses a 70-gene predictor and is involved in the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial [3]. The objective is to administer chemotherapy to patients deemed at high risk of recurrence, and hormonal therapy only to low risk patients, as determined by the Mammaprint gene profile. Having recruited large numbers of patients who are stratified based on the clinical and pathological risks, it is hoped that this study will provide important information regarding the prognostic capabilities of the Mammaprint test and also validate its use in identifying women associated with improved survival. Previously, Buyse et al. [4] demonstrated that Mammaprint outperformed Adjuvant Online in predicting survival in an independent group of patients. Unfortunately, however, a major disadvantage of Mammaprint is that it requires fresh tissue for analysis, which may make its clinical integration difficult. The Oncotype DX and H/I assay, however, can use archival tissue (tissue from original biopsy) and may be more readily applied to the clinical setting. By analysing the expression of 21 known genes, Oncotype DX accurately determined the prognostic outcome in hormone receptor positive cancers post adjuvant tamoxifen in a retrospective cohort of 668 M. Barry M. R. Kell (&) Eccles Breast Screening Unit, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland e-mail: malcolm.kell@breastcheck.ie

Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: The Women's Health Initiative Observational Study

Alcohol consumption is a well-established risk factor for breast cancer. This association is thought to be largely hormonally driven, so alcohol use may be more strongly associated with hormonally sensitive breast cancers. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype. We assessed the relationship between self-reported alcohol consumption and postmenopausal breast cancer risk among 87 724 women in the Women's Health Initiative Observational Study prospective cohort from 1993 through 1998. Multivariable adjusted Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. A total of 2944 invasive breast cancer patients were diagnosed during follow-up through September 15, 2005. In multivariable adjusted analyses, alcohol consumption was positively related to risk of invasive breast cancer overall, invasive lobular carcinoma, and hormone receptor-positive tumors (all P(trend) ≤ .022). However, alcohol consumption was more strongly related to risk of certain types of invasive breast cancer compared with others. Compared with never drinkers, women who consumed seven or more alcoholic beverages per week had an almost twofold increased risk of hormone receptor-positive invasive lobular carcinoma (HR = 1.82; 95% CI = 1.18 to 2.81) but not a statistically significant increased risk of hormone receptor-positive invasive ductal carcinoma (HR = 1.14; 95% CI = 0.87 to 1.50; difference in HRs per drink per day among current drinkers = 1.15; 95% CI = 1.01 to 1.32, P = .042). The absolute rates of hormone receptor-positive lobular cancer among never drinkers and current drinkers were, 5.2 and 8.5 per 10 000 person-years, respectively, whereas for hormne receptor-positive ductal cancer they were 15.2 and 17.9 per 10 000 person-years, respectively. Alcohol use may be more strongly associated with risk of hormone-sensitive breast cancers than hormone-insensitive subtypes, suggesting distinct etiologic pathways for these two breast cancer subtypes.

Using Lifetime Risk Estimates to Recommend Magnetic Resonance Imaging Screening for Breast Cancer Survivors

There are millions of breast cancer survivors in the United States currently, and expectations are that the number will continue to increase in the years to come. Survivors of early-stage breast cancer are at increased risk for developing second primary breast cancers. Data regarding the effectiveness of surveillance mammography among survivors of early-stage breast cancer are limited, but suggest that mammography may reduce breast cancer mortality for this cohort as it does when used to screen the general population. Although national guidelines recommend annual mammographic surveillance for survivors of early-stage breast cancer, studies suggest surveillance mammography is underutilized. Mammography is not a perfect test. In fact, it may be particularly insensitive at detecting breast cancer among selected high-risk populations, such as BRCA carriers, young women, and women with dense breast tissue. Magnetic resonance imaging (MRI) has consistently demonstratedgreatersensitivityversusmammographyinthesepopulations. However, MRI screening is more costly and time consuming, requires the injection of intravenous contrast, generates more false-positive results, and has not been shown to impact breast cancer mortality. Debate regarding the role of MRI as a screening test led the American Cancer Society to convene an expert panel to develop guidelines in 2007. The panel recommended breast MRI screening as an adjunct to mammography for: BRCA mutation carriers and their first-degree relatives; women with a lifetime breast cancer risk 20% to 25%; women with a history of chest radiation between ages of 10 and 30 years; and women with predisposing genetic syndromes (eg, Li-Fraumeni, Cowden). The group felt there was insufficient evidence to recommend for or against MRI screening among women with a personal history of invasive breast cancer or ductal carcinoma in situ. On one hand, MRI surveillance may seem appropriate for breast cancer survivors. Compared to women with a higher than 20% lifetime risk of primary breast cancer as defined by BRCAPRO or other family history–based models, many survivors of early-stage breast cancer could experience an even greater risk of second primary breast cancer. In addition, the sensitivity of mammography among survivors could be impaired by changes in the breast caused by previous treatments. In contrast, no studies have explored the utility of surveillance MRI among survivors. Moreover, this cohort also faces a competing risk of mortality from the primary breast cancer diagnosis. Based on personal observations, use of surveillance MRI among women with a personal history of early-stage breast cancer appears to be increasing. These issues raise serious questions regarding the appropriate use of surveillance breast MRI among survivors of early-stage breast cancer. To explore the implications of applying the American Cancer Society risk threshold to women with a personal history of breast cancer who are not BRCA carriers, we constructed an analytic model to calculate lifetime risk of developing a second breast cancer after diagnosis of an initial breast cancer. Specifically, we sought to determine which subsets of breast cancer survivors met a 20% or 25% lifetime risk threshold of having a new cancer, taking into account the competing risk of cancer mortality from the first diagnosis and agedependent noncancer mortality. The model was designed to provide customized values for lifetime risk of developing breast cancer for each year after diagnosis, as a function of the initial cancer (hormone receptor–positive v –negative, mortality risk), its treatment (breastconserving surgery v mastectomy, and tamoxifen v not for hormone receptor–positive cancers), and age at initial diagnosis. Our model assumed the risk of developing a second breast cancer was constant over time, not related to a patient’s age, and the same for the ipsilateral versus contralateral breast—as demonstrated in multiple prospective and retrospective studies. Adjuvant tamoxifen therapy was associated with a 47% reduction in the risk of developing a new breast cancer over the 10-year period after the primary cancer diagnosis. Therefore, the risk of developing a second breast cancer was only a function of the number of intact breasts and use of tamoxifen. No assumptions were made regarding the sensitivity or specificity of MRI screening in women with a personal history of breast cancer. Mortality risk from the initial diagnosis was assumed to be constant and completed within 7 years for hormone receptor–negative cancers and 15 years for hormone receptor–positive cancers. Patients with an initial diagnosis of ductal carcinoma in situ were assumed to have no mortality risk associated with their primary breast cancer diagnosis. Nonbreast cancer mortality was determined using 2004 United States female life-tables. The annual likelihood of a survivor developing a second breast cancer was determined by multiplying the per year probability of developing a new breast cancer with the per year probability of being alive (ie, not dying from the primary breast cancer or a nonbreast cancer cause). The lifetime risk of developing a JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 27 SEPTEMBER 2

Predictors of pathologic response and correlation with long-term outcomes in a trial of neoadjuvant concurrent paclitaxel radiation in locally advanced breast cancer (LABC).

589 Background: The association of hormone receptor (HR) status of the original tumor with pathologic response and correlation with DFS and OS from a multi-institutional trial of concurrent paclitaxel (P) and radiation (RT) are reported. Methods: 105 LABC patients were treated with neoadjuvant concurrent P and RT (P: 30 mg/m2 2x/week for 10-12 weeks; RT: 1.8 Gy daily to breast, axillary and supraclavicular LN weeks 2-7 to total of 45 Gy followed by a tumor boost of 14 Gy at 2 Gy/fraction). Pathologic response was defined as absence of invasive cancer in breast and LN (pCR) or persistence of less than 10 microscopic foci of invasive cancer in breast or LN (pPR). Logistic regression methods were used to predict response status, logrank tests and Cox proportional hazards methods to evaluate DFS and OS in relation to HR status and pathologic response. Results: Pathologic response (pCR+pPR) for the entire cohort was achieved in 36/105 patients (34%, 95% CI: 25-44%). For all patients, lack of a pathologic response conveyed 4.4 times greater death rate than for pathologic responders (95% CI 1.5-12.7). Nonresponders have a median survival time of 84 months; median not reached for responders. A significantly greater rate of pathologic response occurred in patients with HR negative cancers compared with HR positive cancers (p < 0.001): 54% (95% CI 39-69%) compared to 18% (95% CI of 9-30%). HR status was the only predictor of pathologic response after concurrent P-RT. As expected, HR negative tumors had a worse prognosis than HR positive ones; this feature remained despite the achievement of a pathologic response. However, pathologic response and HR status jointly predicted DFS (likelihood ratio p < 0.001). The clinical benefit from achieving a pathologic response was most pronounced in patients with HR negative tumors with a reduction in recurrence or death rate of 75% as compared with HR negative nonresponders. Conclusions: Conclusions: HR status is highly predictive of response to neoadjuvant concurrent paclitaxel and radiation; more than half of the patients with HR negative tumors achieved a pathologic response, which translates into superior DFS and OS. No significant financial relationships to disclose.

Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer

Aromatase inhibition (AI) is the most effective endocrine treatment for breast cancer in post-menopausal patients, but a percentage of hormone receptor-positive cancers do not benefit from such therapy: for example, about 20% of patients treated with anastrozole do not respond and it is still impossible to accurately predict sensitivity. Our main goal was to identify a robust expression signature predictive of response to neoadjuvant treatment with anastrozole in patients with ER+ breast cancer. At the same time, we addressed the question of delineating treatment effects and possible mechanisms of intrinsic resistance occurring in non-responder patients. We analyzed the transcriptome of 17 tru-cut biopsies before treatment and 13 matched surgical samples after 3 months treatment with anastrozole taken from ER+ breast tumors. Molecular profiles were related to clinical response data. Treatment with anastrozole was associated with a decreased expression of genes relating to cell proliferation and an increased expression of genes relating to inflammatory processes. There was also an enrichment of induction of T-cell anergy, positive regulation of androgen signalling, synaptic transmission and vesicle trafficking in non-responders, and of cell cycle inhibition and induction of immune response in responders. We identified an expression signature of 77 probes (54 genes) that predicted response in 100% of our cases. Five of them were able to accurately predict response on an independent dataset (P = 0.0056) of 52 ER+ breast cancers treated with letrozole. Ten fixed independent samples from the anastrozole study were also used for RT-qPCR validations. This study suggests that a relative small number of genes analysed in a pre-treatment biopsy may identify patients likely to respond to AI neoadjuvant treatment. This may have practical utility translatable to the clinics. Furthermore, it delineates novel mechanisms of intrinsic resistance to AI therapy that could be further investigated in order to explore circumventing treatments.

Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

Advances in Adjuvant Endocrine Therapy for Postmenopausal Women

Hormone receptor-positive cancers are the most common tumor subtype among postmenopausal women with breast cancer. Despite substantial improvements in disease-free survival and overall survival with tamoxifen and chemotherapy, recurrences still occur, and may ultimately lead to death from breast cancer. Importantly, disease recurrence includes both early and late events, with over half of all recurrences detected more than 5 years from initial breast cancer diagnosis. In recent years, a number of large, randomized trials have evaluated the role of the aromatase inhibitors (AIs) in postmenopausal women with hormone receptor-positive breast cancer. These studies have tested one of three approaches: (1) an upfront AI, (2) a sequential approach after 2-3 years of tamoxifen, and (3) extended endocrine therapy beyond 5 years. Results of these studies have challenged the previous standard of a 5-year course of tamoxifen alone. While the AIs have become a standard component of treatment for most postmenopausal women, many questions remain as to how best tailor endocrine treatment to individual patients. In addition, despite the gains achieved with the AIs, many recurrences are not prevented, and novel strategies are urgently needed, particularly for those women at high risk of recurrence. In this article, we review the efficacy and toxicity data from the available trials of endocrine therapy in the postmenopausal setting. We outline controversies in choosing the optimal endocrine approach, and we discuss selected ongoing studies. Finally, we highlight future research directions, such as the need to understand host and tumor heterogeneity.

Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers

To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER alpha. In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade <or= 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) -positive but not in human epidermal growth factor receptor 2 (HER-2) -positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ER alpha in hormone receptor-positive cancers. A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2-positive or triple-negative breast cancers.

Greater Survival After Breast Cancer in Physically Active Women With High Vegetable-Fruit Intake Regardless of Obesity

Single-variable analyses have associated physical activity, diet, and obesity with survival after breast cancer. This report investigates interactions among these variables. A prospective study was performed of 1,490 women diagnosed and treated for early-stage breast cancer between 1991 and 2000. Enrollment was an average of 2 years postdiagnosis. Only seven women were lost to follow-up through December 2005. In univariate analysis, reduced mortality was weakly associated with higher vegetable-fruit consumption, increased physical activity, and a body mass index that was neither low weight nor obese. In a multivariate Cox model, only the combination of consuming five or more daily servings of vegetables-fruits, and accumulating 540+ metabolic equivalent tasks-min/wk (equivalent to walking 30 minutes 6 d/wk), was associated with a significant survival advantage (hazard ratio, 0.56; 95% CI, 0.31 to 0.98). The approximate 50% reduction in risk associated with these healthy lifestyle behaviors was observed in both obese and nonobese women, although fewer obese women were physically active with a healthy dietary pattern (16% v 30%). Among those who adhered to this healthy lifestyle, there was no apparent effect of obesity on survival. The effect was stronger in women who had hormone receptor-positive cancers. A minority of breast cancer survivors follow a healthy lifestyle that includes both recommended intakes of vegetables-fruits and moderate levels of physical activity. The strong protective effect observed suggests a need for additional investigation of the effect of the combined influence of diet and physical activity on breast cancer survival.