Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation.

BACKGROUND: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. METHODS: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. RESULTS: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. CONCLUSIONS: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.

Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer.

BACKGROUND: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. METHODS: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy. In vivo efficacy was tested both as a single agent and in combination therapy in TNBC patient-derived xenografts (PDXs). RESULTS: Selinexor demonstrated growth inhibition in all 14 TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44 nM, range 11 to 550 nM) than were estrogen receptor (ER)-positive breast cancer cell lines (median IC50 > 1000 nM, range 40 to >1000 nM; P = 0.017). In multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin, and doxorubicin in vitro. Selinexor as a single agent reduced tumor growth in vivo in four of five different TNBC PDX models, with a median tumor growth inhibition ratio (T/C: treatment/control) of 42% (range 31 to 73%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin (average T/C ratios of 27% and 12%, respectively). CONCLUSIONS: Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy.

Impact of clinical trial on survival outcomes.

The number of patients with breast cancer who participate in therapeutic clinical trials remains low. One reason is a lack of opportunity; another is health care providers who do not recommend trials because they fear poorer outcome from the use of new drugs. Thus, we compared survival outcome in patients with metastatic breast cancer (MBC) who participated in first-line therapeutic clinical trials with outcome in patients who had never enrolled in a clinical trial and received only standard care. We hypothesized that first-line therapeutic clinical trials does not have a negative survival outcome. We reviewed the records of patients with MBC who were treated at MD Anderson Cancer Center between January 2000, and December 2010. The medical records of 5501 patients with MBC were screened, and 652 patients-285 in the trial arm and 367 in the control arm-met our specific eligible criteria. The median follow-up of our cohort was 7.16 years (95 % confidence interval [CI] 6.53-7.64 years). Among the global population, no significant differences in progression-free survival (PFS) or overall survival (OS) were observed between the treatment arms: for the clinical trial cohort, median PFS was 7 months (95 % CI 5.72-8.71 months), and median OS was 28.48 months (95 % CI 22.70-34.60 months). For the control cohort, median PFS was 10.02 months (95 % CI 7.13-11.99 months), and median OS was 28.71 months (95 % CI 24.41-31.31 months) (P = .089 and .335, respectively). Enrollment in first-line MBC therapeutic clinical trials does not result in less favorable survival outcome than that in MBC patients who never enrolled in a clinical trial.

Recurrence and survival among breast cancer patients achieving a pathological complete response to neoadjuvant chemotherapy.

Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy, including chemotherapy with or without trastuzumab (NAT) have better outcomes than patients with residual disease. Despite the excellent prognosis associated with achieving a pCR, tumors still recur. The objective of this study was to evaluate factors associated with tumor recurrence and survival among patients achieving pCR after NAT. We identified 749 patients with primary breast cancer who achieved pCR after NAT between 1988 and 2009. pCR was defined as no evidence of invasive cancer in the breast and ipsilateral axillary lymph nodes on pathological evaluation. The Kaplan-Meier product limit method and multivariate Cox proportional hazards models were used to determine the association between clinical and demographic factors and outcomes. Median follow-up was 35 months (range, 1-258 months). Overall 5-year distant metastasis-free survival was 93% (95% confidence interval [CI], 90-95%) and 5-year overall survival (OS) was 96% (95% CI, 93-97%). In the multivariable model, we observed that patients >50 years had significantly decreased risk of distant metastasis (hazard ratio [HR] 0.47; 95% CI, 0.22-0.98) and that patients with clinical stage at diagnosis IIIB-C cancer had both an increased risk of distant metastasis (HR 3.92; 95% CI, 1.54-10.00) and lower OS (HR 4.75; 95% CI, 1.60-14.08). Patients with pCR after NAT have excellent outcomes. However, our data show that younger patient and those with clinical stage at diagnosis IIIB and IIIC cancers are at increased risk of developing distant metastasis.

A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.

A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.

Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer.

INTRODUCTION: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. METHODS: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. RESULTS: In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ERα protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ERα protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ERα levels in breast cancer cells. CONCLUSIONS: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ERα loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.

Implications of functional proteomics in breast cancer.

Breast cancer is one of the major public health problems of the Western world. Recent advances in genomics and gene expression-profiling approaches have enriched our understanding of this heterogeneous disease. However, progress in functional proteomics in breast cancer research has been relatively slow. Allied with genomics, the functional proteomics approach will be important in improving diagnosis through better classification of breast cancer and in predicting prognosis and response to different therapies, including chemotherapy, hormonal therapy, and targeted therapy. In this review, we will present functional proteomic approaches with a focus on the recent clinical implications of utilizing the reverse-phase protein array platform in breast cancer research.

Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer.

BACKGROUND: A biomarker that predicts bone metastasis based on a protein laboratory assay has not been demonstrated. Reverse-phase protein array (RPPA) enables quantification of total and phosphorylated proteins, providing information about their functional status. The aim of this study was to identify bone-metastasis-related markers in patients with primary breast cancer using RPPA analysis. PATIENTS AND METHODS: Tumor samples were obtained from 169 patients with primary invasive breast carcinoma who underwent surgery. The patients were categorized by whether they developed breast cancer bone metastasis (BCBM) during follow-up. Clinical characteristics and protein expression by RPPA were compared and verified by leave-one-out cross-validation. RESULTS: Lymph node status (p = .023) and expression level of 22 proteins by RPPA were significantly correlated with BCBM in logistic regression analysis. These variables were used to build a logistic regression model. After filtering the variables through a stepwise algorithm, the final model, consisting of 8 proteins and lymph node status, had sensitivity of 30.0%, specificity of 90.5%, positive predictive value of 30.0%, and negative predictive value of 90.5% in the cross-validation. Most of the identified proteins were associated with cell cycle or signal transduction (CDK2, CDKN1A, Rb1, Src, phosphorylated-ribosomal S6 kinase, HER2, BCL11A, and MYH11). CONCLUSION: Our validated model, in which the primary tumor is tested with RPPA, can predict patients who are at low risk of developing BCBM and thus who likely would not benefit from receiving a bisphosphonate in the adjuvant setting. Clinical trials excluding these patients have the potential to clarify the benefit of bisphosphonates in the adjuvant setting.

Prospective evaluation of the conversion rate in the receptor status between primary breast cancer and metastasis: results from the GEICAM 2009-03 ConvertHER study.

The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally. Overall, 196 patients were included and 184 patients were considered evaluable. Reasons for non-evaluability included the inability to perform biopsy (n = 4) or biopsy results showing normal tissue (n = 3), benign disease (n = 3) or a second neoplasia (n = 2). Conversion rates determined at local level were higher than those determined centrally (HER2: 16 vs. 3 %, ER: 21 vs. 13 %, PR: 35 vs. 28 %, respectively). There was substantial agreement regarding the expression of HER2 in primary tumors and metastases, and ER at metastases, between local and central laboratories. PR at any site and ER at primary site showed moderate agreement. Oncologists altered their treatment plans in 31 % of patients whose tumor subtype had changed. These results reinforce the recommendation for performing confirmatory biopsies of metastases, not only to avoid misdiagnosis of breast cancer relapse, but also to optimize treatment (clinicaltrials.gov identifier: NCT01377363).

Advances and future directions in the targeting of HER2-positive breast cancer: implications for the future.

OPINION STATEMENT: The natural history of HER2-positive breast cancer significantly changed in the past 15 years. Form being the most aggressive type of breast cancer, it became treatable with important cure rates. However, with new and successful drugs, resistance emerges. Progress in research and drug development continues to make available effective anti-HER2 therapies. Our challenge today is to use these tools correctly by looking at the data that support the indications of each compound and to continue clinical trial participation.

Residual tumor thickness at the tumor-normal tissue interface predicts the recurrence-free survival in patients with liver metastasis of breast cancer.

Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin-stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy.

A new hypothesis for the cancer mechanism.

Several observations have led us to a new hypothesis for cancer mechanism. First, that cancer appears only on those multicellular organisms with complicated wound-healing capacities. Second, that wounds considered as risk factors can be identified in all cancers in clinics. And finally, that oncogene activation appears not only in cancer, but also in normal physiology and noncancer pathology processes. Our proposed hypothesis is that cancer is a natural wound healing-related process, which includes oncogene activations, cytokine secretions, stem cell recruitment differentiation, and tissue remodeling. Wounds activate oncogenes of some cells and the latter secrete cytokines to recruit stem cells to heal the wounds. However, if the cause of the wound or if the wound persists, such as under the persistent UV and carcinogen exposures, the continuous wound healing process will lead to a clinical cancer mass. There is no system in nature to stop or reverse the wound healing process in the middle stage when the wound exists. The outcome of the cancer mechanism is either healing the wound or exhausting the whole system (death). The logic of this cancer mechanism is consistent with the rationales of the other physiological metabolisms in the body-for survival. This hypothesis helps to understand many cancer mysteries derived from the mutation theory, such as why cancer only exists in a small proportion of multicellular organisms, although they are all under potential mutation risks during DNA replications. The hypothesis can be used to interpret and guide cancer prevention, recurrence, metastasis, in vitro and in vivo studies, and personalized treatments.

Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer.

BACKGROUND: The current study was conducted to determine the frequency and association between recurrence-free survival (RFS) and MET and catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevations in patients with early stage breast cancer. METHODS: Tumor DNA was extracted from 971 formalin-fixed, paraffin-embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single-nucleotide polymorphism (SNP)-FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan-Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS. RESULTS: Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor-negative disease (P = .019 and P < .001, respectively). At a median follow-up of 7.4 years, there were 252 cases of disease recurrence. The 5-year RFS rates were 63.5% and 83.1% for MET high copy number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS. CONCLUSIONS: A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor-negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS.

Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy.

OBJECTIVE: This study was performed to evaluate long-term local-regional control rates after breast-conserving therapy (BCT) for patients undergoing surgery before or after neoadjuvant chemotherapy. METHODS: There were 2983 patients who underwent segmental mastectomy with whole-breast irradiation from 1987 to 2005. Clinicopathological and outcome data were reviewed, and comparisons were made between those undergoing surgery before and those undergoing surgery after neoadjuvant chemotherapy. RESULTS: There were 2331 patients (78%) who underwent surgery first and 652 (22%) received neoadjuvant chemotherapy. Patients receiving neoadjuvant chemotherapy had more advanced disease at baseline and more adverse clinicopathological features. The 5- and 10-year local-regional recurrence (LRR)-free survival rates were 97% [95% confidence interval (CI), 96-98) and 94% (95% CI, 93-95) for surgery first and 93% (95% CI, 91-95) and 90% (95% CI, 87-93) after neoadjuvant chemotherapy (P < 0.001). However, there were no differences in LRR-free survival rates when comparing the presenting clinical stage (P = NS). Of 607 patients presenting with clinical stage II/III disease, chemotherapy downstaged 313 patients (52%) to pathological stage 0/I disease; 294 (48%) had residual stage II/III disease. In multivariate analysis, an age less than 50 years, clinical stage III, grade 3, estrogen receptor (ER)-negative disease, estrogen receptor-positive disease without receipt of endocrine therapy, lymphovascular invasion, multifocal disease on pathology, and close/positive margins were associated with LRR. Use of neoadjuvant chemotherapy was not significant when added to the model. Adjusting for adverse factors, there were no differences in LRR between patients who underwent surgery before and those who underwent neoadjuvant chemotherapy after surgery. CONCLUSIONS: LRR after BCT is driven by tumor biology and disease stage. Appropriately selected patients can achieve high rates of local-regional control with BCT with either upfront surgery or surgery after neoadjuvant chemotherapy.

Progress in the biological understanding and management of breast cancer-associated central nervous system metastases.

Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.

Locoregional interaction of ixabepilone (ixempra) after breast cancer radiation.

BACKGROUND: Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy. METHODS: We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008-2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity. RESULTS: Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99. CONCLUSIONS: Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.

Breast cancer multifocality and multicentricity and locoregional recurrence.

The impact of multifocal (MF) or multicentric (MC) breast cancer on locoregional (LR) control rates is unknown. Methods. MF was defined as two or more separate invasive tumors in the same quadrant of the breast. MC was defined as two or more separate invasive tumors occupying more than one quadrant of the same breast. Patients were categorized by LR treatment: breast conservation therapy (BCT; n = 256), mastectomy (n = 466), or mastectomy plus postmastectomy radiation therapy (PMRT; n = 184). All patients with MC disease had mastectomy (10 patients treated with BCT for MC disease were excluded). The Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were used to determine independent associations of multifocality or multicentricity with LR control. Results. A total of 906 patients had either MF disease (n = 673) or MC disease (n = 233). With median follow-up of 52 months, the 5-year LR control rate was 99% for MF, 96% for MC, and 98% for unifocal tumors (p = .44). Subset analysis revealed no difference in LR control regardless of the LR treatment (p = .67 for BCT, p = .37 for mastectomy, p = .29 for mastectomy plus PMRT). There were five in-breast recurrences after BCT in the MF group. MF and MC did not have an independent impact on LR control rate on multivariate analysis. Conclusion. MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had rates of LR control similar to those of their unifocal counterparts. These data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for PMRT.

Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer.

BACKGROUND: The purpose of this analysis was to compare disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) between pregnant and nonpregnant patients with breast cancer. METHODS: From 1989 to 2009, 75 women were treated with chemotherapy during pregnancy. Each pregnant case was matched on age and cancer stage to two nonpregnant patients with breast cancer (controls). Fisher's exact test, the Kaplan-Meier method, and Cox proportional hazards regression models were used. RESULTS: Median follow-up time for patients who were alive at the end of follow-up (n = 159) was 4.20 years (range: 0.28-19.94 years). DFS at 5 years was 72% (95% confidence interval [CI]: 58.3%-82.1%) for pregnant patients and 57% (95% CI: 46.7%-65.8%) for controls (p = .0115). Five-year PFS was 70% (95% CI: 56.8%-80.3%) for pregnant patients and 59% (95% CI: 49.1%-67.5%) for controls (p = .0252). Five-year OS was 77% (95% CI: 63.9%-86.4%) for pregnant patients and 71% (95% CI: 61.1%-78.3%) for controls (p = .0461). Hazard ratio estimates favored improved survival for pregnant patients in univariate analyses and multivariate analyses, controlling for age, year of diagnosis, stage, and tumor grade. CONCLUSIONS: For patients who received chemotherapy during pregnancy, survival was comparable to-if not better than-that of nonpregnant women. Pregnant patients with breast cancer should receive appropriate local and systemic therapy for breast cancer.

High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients.

Stearoyl-CoA desaturase 1 (SCD1) is an essential regulator of fatty acid synthesis. We have previously shown that overexpression of SCD1 increases the growth of breast cancer cell lines. The purpose of this study was to determine the relationship between SCD1 expression level and clinical-pathologic characteristics and survival of patients with breast cancer. Fine-needle aspirates were collected from the primary tumors of 250 patients with stage I-III breast cancer. Demographic and clinical characteristics including patient age, ethnicity, and menopausal status and tumor clinical stage, grade, and subtype were reviewed. SCD1 expression was analyzed using reverse-phase protein arrays. Samples were divided into high or low SCD1 expression levels based on a cut-off determined from martingale residual plots and regression tree analysis. SCD1 levels were significantly higher in tumors from patients >50-years old compared to patients ≤50-years old and were lower in triple-negative (estrogen/progesterone receptor-negative and human epidermal growth factor receptor-2-negative) breast cancers than other tumor subtypes. After adjusting for patient age, tumor subtype, tumor grade, and clinical stage, we found that patients with primary breast cancers expressing high SCD1 levels had significantly shorter relapse-free survival (RFS) (P = 0.0140) and overall survival (OS) (P = 0.039) in multivariable analysis. We conclude that SCD1 expression varies by breast cancer subtype and that high levels of SCD1 expression are associated with significantly shorter RFS and OS in multivariable analysis. Future studies are needed to define the role of SCD1 in the malignant phenotype of breast cancer and to evaluate the potential for SCD1 as a therapeutic target.

Genotype in BRCA-associated breast cancers.

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3') location for mutations compared to the upstream (5') mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA-associated breast cancers and whether or not there was a genotype-phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty-four patients with BRCA1-associated breast cancer and 109 patients with BRCA2-associated breast cancer were identified. Among patients with BRCA1-associated cancers, 86 (52%) had mutations in the 5' half of the gene. Among patients with BRCA2-associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1-associated tumors were more likely to be ER/PR- than BRCA2-associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2-associated cancers based on mutation location. In this single-institution study, over half of BRCA1-associated and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.