bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-12-04: Long Term Follow-Up of a Pilot Trial of Pre-Operative (Neoadjuvant) Letrozole in Combination with Bevacizumab in Post-Menopausal Women with Newly Diagnosed Estrogen and/or Progesterone Receptor Positive Breast Cancer
Authors: Forero A , Saleh M , Galleshaw J , Jones C , Nabell L , Carpenter J , Falkson C , Krontiras H , Urist M , Bland K , De Los Santos J , Meredith R , Caterinicchia V , Bernreuter W , O'Malley J , Yufeng L , LoBuglio A.
Published: April 2011

Introduction: Overexpression of vascular endothelial growth factor (VEGF) in breast cancer tumors has been associated with resistance to anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods: Patients were treated with a neoadjuvant regimen of letrozole, 2.5 mg/day (PO) and bevacizumab 15 mg/kg every 3 weeks (IV) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at three week intervals and tumor assessment (physical exam and tumor ultrasound) at six week intervals. Results: Twenty-five evaluable patients were treated. The regimen was well tolerated except for two patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The four patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. Two of the 17 responding patients were lost to follow-up; with a median follow-up of 50 months, no relapses have been seen in the 15 responsive patients, including 10 patients who received no adjuvant chemotherapy. Two patients with progressive disease at 9 and 16 weeks received neoadjuvant chemotherapy, surgery and radiation. One of these patients relapsed at 35 months and the other is NED at 44 months. Four patients had stable disease and all received adjuvant chemotherapy; one patient relapsed at 25 months, and the reminder are NED at 44-52 months. Overall, 2 out of 21 patients with adequate follow-up had disease reoccurrence (9.5%) at a median follow-up of 45 months. Conclusion: Combination neoadjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. Data suggest that patients having an objective response to neoadjuvant therapy had excellent 4 year disease-free survival (100%) while relapsed occurred in 2 out of 6 patients who failed to have an objective response despite additional neoadjuvant or adjuvant chemotherapy. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of letrozole ± bevacizumab in this patient population.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-04.
Abstract P1-12-06: Outcome of Frail Elderly Patients Treated with Letrozole Alone
Authors: Dixon JMJ , Renshaw L , Keys J , Leeper AD , Williams L , Evans DB.
Published: April 2011

Background

There are no data on the rate of progression of infirm or elderly postmenopausal patients unfit for surgery who have been treated with aromatase inhibiors alone. The aim was to determine the rate of disease control in a series of patients treated in the Edinburgh Breast Unit. Patients

79 patients with a median age of 81 years (range 57 to 98) with ER rich breast cancers (Allred score 6-8) have been treated with letrozole alone. The median follow up is 2.06 years, range 0.34 to 7.64. Of 71 patients with HER2 results, 59 (83%) were negative and 12 (17%) were positive.

Results

At two years, 65% were progression-free. By five years, this was 43%. The median time to first progression was 3.1 years (95% CI 1.7 to 4.5). By the Log Rank test, there was evidence of a significant difference between HER2+ve and-ve cancers (p=0.014). Median time to first progression for HER2-ve patients was 3.1 years (95% CI 1.9 to 4.2) and for HER2+ve patients was 1.8 years (95% CI 0.7 to 2.8). By two years, 67% of HER2-ve patients were progression-free, while 34% of the HER2+ve patients remained progression-free. At five years, 32% of the HER2-ve patients were progression free, however HER2+ve patients had insufficient follow up to estimate the 5 year progression-free rate. At two years, 77% of patients were still alive. By five years, that number was 33%. The median survival time was only 3.2 years (95% CI 2.4 to 4.1).

There was no evidence to suggest a difference in mortality rates between HER2+ve and HER2-ve patients (p=0.79). Median survival time for HER2- ve patients was 2.6 years (95% CI 1.6 to 3.7) and for HER2+ve patients it was 3.0 years (95% CI 2.5 to 3.5). Conclusions

In an elderly unfit population with ER rich breast cancer two thirds of these women will have their cancer controlled at 2 years by letrozole alone. HER2+ve cancers have a significantly shorter progression free survival than HER2-ve cancers.

For older or infirm women unfit for surgegy with ER rich breast cancers, letrozole will control their cancer in the majority to the time of their death which was from other causes in all patients in this series.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-06.
Abstract P1-13-03: Is Bone Biopsy of Metastatic Sites Useful in Advanced Breast Cancer Management?
Authors: Aurilio G , Sciandivasci A , Bagnardi V , Della Vigna P , Monfardini L , Preda L , Rizzo S , Padrenostro M , Renne G , Munzone E , Cullurà D , Petrella MC , Bellomi M , Nolè F.
Published: April 2011

Background: Biopsies of metastatic sites are not recommended in clinical practice to evaluate changes in biological features in advanced breast cancer (ABC) women. We assessed discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor 2 (HER2), between primary tumor and bone metastases and its clinical impact on patient management.

Material and Methods: We retrospectively analyzed 109 ABC patients (pts) underwent computed tomography guided bone biopsy at the European Institute of Oncology in Milan, Italy, from 1997 to 2009. Data on ER and PgR status [positive if ≥1% by immunohistochemistry (IHC)] and on HER2 status (positive if IHC3+ and/or FISH amplified), both primary tumor and bone metastases were collected. Fisher and McNemar's test were used for statistical analysis.

Results: Median time from primary diagnosis to bone biopsy was 4.2 years (range 0-18.9). Overall discordance rate (ODR) in ER expression was 20.5% (95% CI: 13.4%-29.5%): 3/7 pts (42.9%) shifted from ER negative to positive and 19/100 pts (19%) from ER positive to negative [p=0.0006]. ODR in PgR expression was 43.9% (95% CI: 34.3%-53.8%): 4/21 pts (19%) changed from PgR negative to positive and 43/86 pts (50%) from PgR positive to negative [P<0.0001]. ODR in HER2 status was 6.9% (95% CI: 2.6%-14.6%): 4/78 pts (5.1%) changed from HER2 negative to positive and 2/8 pts (25%) turned from HER2 positive to negative [p=0.41]. Thirteen out of 21 pts (61.9%) with discordant ER status and 23/77 pts (29.8%) with concordant ER status [p=0.01] changed endocrine therapy; there were no differences in chemotherapy [p=0.80]. Four out of 6 pts (66.6%) with discordant HER2 status and 6/72 pts (8.3%) with concordant HER2 status changed immunologic therapy [p=0.002], 3/6 pts (50%) started trastuzumab and 1/6 patient (16.6%) stopped it; there were no differences in chemotherapy [p=0.68]. All pts well tolerated the invasive procedure, requiring only local analgesia. Discussion: Our analysis showed that receptor profile may significantly change between primary breast cancer and bone metastases, with relevant impact on therapy. Bone biopsy might be useful and should be considered in selected cases to optimize therapeutic choices. Large prospective trials are needed to investigate these outcomes.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-03.
Abstract P1-13-05: The Effect of Treatment with Denosumab or Zoledronic Acid on Health-Related Quality of Life in Patients with Metastatic Breast Cancer
Authors: Fallowfield L , Patrick D , Body J-J , Lipton A , Tonkin KS , Qian Y , Zhao Y , Jiang Q , Braun A , Dansey R , Chung K.
Published: April 2011

Background: Patients with breast cancer and bone metastases often experience skeletal-related events (SREs) and pain, which may impact health-related quality of life (HRQoL). Denosumab is a fully human monoclonal antibody against RANKL shown to be superior in delaying/preventing SREs and more effective in delaying moderate or severe pain in patients with advanced breast cancer compared with zoledronic acid (ZA). Previously reported results from this study population showed that both denosumab and ZA patients showed improvement or maintenance in HRQoL relative to baseline (BL), and a greater proportion of denosumab-treated patients had a clinically meaningful improvement in HRQoL. We now describe the effect of denosumab and ZA treatment on HRQoL among patients with varying degrees of pain at BL.

Methods: Enrolled patients received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pain was evaluated using the Brief Pain Inventory — Short Form (BPI). Patients were divided into 2 subgroups based on the level of pain reported at BL: no/mild pain or moderate/severe pain. Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at BL, day 8, and before each monthly visit to assess overall HRQoL. Higher scores (range 0 to 108) represent better HRQoL. Improvement, maintenance, and worsening of HRQoL were assessed through month 18, when 30% of patients had dropped out due to death, disease progression, or withdrawal of consent. A change of ≥5 points (increase or decrease) in the FACT-G total score was considered a meaningful improvement.

Results: Among patients who reported no/mild pain at baseline, more denosumab-treated patients had a ≥5-point increase in their FACT-G score from month 4 onwards. Over the 18 month period, an average of 4.1% more (range: −0.6% to 9.3%) denosumab-treated patients experienced meaningful improvement in HRQoL than ZA-treated patients. There were also fewer denosumab-treated patients experiencing ≥5-point decrease in HRQoL over 18 months (average of 2.4% fewer [range:-4.4% to 6.3% fewer]). Similar patterns were also noted for patients with moderate/severe pain at baseline. An average of 3.0% more (range:-1.7% to 7.9%) denosumab-treated patients had ≥5-point increase in FACT-G scores compared with ZA-treated patients over 18 months. A lower proportion of denosumab-treated patients (3.5% fewer [range: −1.1% to 11.5% fewer]) than ZA-treated patients had a decrease ≥5-points in their FACT-G score over 18 months.

Conclusion: In patients with breast cancer and bone metastases, a greater proportion treated with denosumab than ZA had a meaningful improvement in HRQoL regardless of their pain level at BL.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-05.
Abstract P1-14-04: Clinical Outcomes of Brain Metastasis by Lapatinib (L) and Capecitabine (C) in an Open-Label Expanded Access Study among Korean Patients with HER2 Positive Metastatic Breast Cancer
Authors: Ro J , Park S , Kim S-B , Kim T-Y , Im Y-H , Rha SY , Chung JS , Moon H , Santillana S.
Published: April 2011

Background: The L-Expanded Access Program (LEAP) was designed to provide access to L/C for HER2+ patients (pts) who previously received anthracycline, taxane, and trastuzumab. In earlier registration trial, CNS metastases occurred in fewer women receiving L/C therapy compared with C alone. Although L therapy has shown efficacy in brain metastasis (BM), it has not been well elucidated in relationship with the outcomes of systemic disease.

Patients and methods : Enrollment in LEAP lasted between Jan. 2007 and Apr. 2008 at 6 centers in Korea. Exploratory analysis on clinical outcomes of brain metastasis was performed.

Results: Total 187 pts enrolled in LEAP. The median treatment duration of all pts was 19.0 weeks (range, 1.4 — 146.9). The median progression free survival and overall survival (OS) of all pts were 20.0 (95% confidence interval [CI]= 18.6-24.0) and 60.0 (95% CI= 50.3-72.7) weeks, respectively. All patients received prior trastuzumab therapy, and 48.7% received prior capecitabine. Among 58 enrolled pts who had BM diagnosed before start L/C therapy, 55 pts were included for the analysis excluding 3 pts (1-consent withdrawal and 2-<3 weeks trial). Fifteen pts had single BM. Majority were HER2 IHC 3+ or FISH +, and 48% were both ER/PR-. Prior to EAP enrollment, 35 pts underwent whole brain radiation, 10 pts SRS or gamma knife, 3 pts local excision, 1 pt had leptomeningeal disease only receiving intrathecal therapy, and 6 pts did not receive local CNS therapy. Four pts underwent more than one modality of local CNS therapy. Of 50 pts evaluable for response, 9.1%, achieved or remained CR; 45.5% had some degree of shrinkage of BM; 14.5%, no change (SD) ≥6mo; 7.3%, SD <6mo; 14.5% developed PD or recurrence of BM. Median TTP of pts (n=53) with BM on L/C therapy was 30.7 weeks (95% CI=25.0-35.1) and median OS (n=55) was 53.1 weeks (95% CI= 42.3-78.0). From the multivariate analysis, TTP of BM was significantly associated with response of BM (HR, 20.3, 95% CI=7.3-56.0, P<0.001). OS of pts with BM was significantly longer with tumors of ER or PR+ status (HR, 3.10, 95% CI=1.55-6.19, p=0.0014), and who responded in systemic disease and brain (HR, 4.5, 95% CI= 2.2-9.2, P<0.0001). Of remaining 129 pts, 8 pts (6.2%) developed new BM on EAP.

Conclusion: Overall survival of patients with brain metastasis who received lapatinib plus capecitabine was prolonged specifically in responders of both brain and extracranial disease. Patients with hormone receptor positive tumors had longer survival compared with those of hormone receptor negative disease.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-14-04.
Abstract P1-15-02: Impact of Retinoblastoma (RB) Tumor Suppressor Pathway on Ductal Carcinoma In Situ (DCIS) Recurrence
Authors: Witkiewicz AK , Kline J , Freydin B , Apanasovich T , Schwartz G , Knudsen E.
Published: April 2011

The retinoblastoma (RB) tumor suppressor is functionally inactivated at high frequency in human malignancies including breast cancer. By immunohistochemistry loss of RB function is associated with p16ink4a overexpression and high Ki67 proliferation index.We have previously shown that loss of RB results in dramatic upregulation of genes associated with tumorigenesis and is a key determinant of therapeutic response in invasive breast carcinoma. Recently publish data indicate that RB pathway dysregulation plays an important role in DCIS progression to invasive carcinoma. The aim of this study was to evaluate the expression p16ink4a and Ki67 (indicative of RB loss) in a large cohort of DCIS patients treated at one institution with wide-excision and close follow-up. Material and Methods

149 DCIS patients were included in the study. Expression of p16ink4a and Ki67 was assessed by employing a standard immunoperoxidase method with ani-p16ink4a (MTM Laboratories Westborough, MA) and anti-Ki67 (AbCam Cambridge, MA) antibodies. The p16ink4a staining in DCIS epithelium was scored semi-quantitatively as negative (0; no staining), weak (1;staining in less than 25% of cells), moderate (2; defined as staining in 25-75% of cells) and strong (3; >75% of cells staining). For statistical analysis, the original p16ink4a scores (0, 1, 2, 3) were dichotomized as low (0,1) vs. high (2-3) and original ki67 scores were dichotomized as low (<= 10%) vs. high (> 10%). Stromal p16 staining was scored as absent or present.

Association between p16ink4a and Ki67 and nuclear grade, necrosis, hormone receptor and Her2 expression as well as recurrence was assessed using Fisher's exact test. The Cox proportional hazard model was used for analyses of time to recurrence. Results

There was a statistically significant association between high p16ink4a and Ki67 expression in DCIS epithelium and triple negative as well as Her2 positive DCIS subtypes. Significant association was detected between high expression of p16 and Ki67 in DCIS epithelium and DCIS recurrence (p=0.005). Stromal expression of p16 was the strongest predictor of DCIS recurrence (p < 0.0001). In multivariate Cox model DCIS cases with high expression of p16 and Ki67 in epithelium and stromal p16 expression had the shortest time to recurrence.

Conclusion

RB pathway dysregulation in DCIS epithelium as well as stromal expression of p16ink4a indicative of senescence are associated with DCIS recurrence.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-02.
Abstract P1-15-03: Eight-Year Update of a Prospective Study of Wide Excision Alone for Ductal Carcinoma In Situ (DCIS) of the Breast
Authors: Wong JS , Smith BL , Troyan SL , Gadd MA , Gelman R , Lester SC , Schnitt SJ , Sgroi DC , Chen Y-H , Silver BJ , Harris JR.
Published: April 2011

Background: The need for radiation therapy (RT) in conservatively managed DCIS is a source of ongoing debate. This is an updated analysis of a phase II prospective study of wide excision alone for DCIS. The study was activated in May 1995 and closed in July 2002 following accrual of 158 patients because the number of local recurrences (LR) met the predetermined stopping rules. The objective of the analysis is to update the distribution and cumulative incidence of events (LR, contralateral breast cancer [CBC], second malignancy and death from other causes). Materials and Methods: A total of 158 patients had DCIS with predominant nuclear grade 1 or 2, a mammographic extent of ≥2.5 cm, and excision with final microscopic margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The results presented are from the 8-year analysis (8-year minimum potential follow-up time). Twenty-six patients without recurrence who were followed less than 8 years were excluded from the analysis as were 7 first events (4 LR) that occurred beyond 8 years of follow-up; the analysis thus includes 132 patients and 36 first events. Cumulative incidence curves were generated to assess the rates of LR or other events. Median follow up time was 10 years. Results: Overall, 36/132 patients (27%) had a first event as of April 2010. Of these 36 events, 19 were LR, 13 were CBC, 1 was a second malignancy, and 3 were deaths from other causes. Of the 19 LR, 13 (68%) were DCIS only and 6 (32%) were invasive. Fourteen occurred in the same quadrant and 5 were elsewhere in the ipsilateral breast. The 8-year estimated cumulative incidence of LR was 14.4% (95% CI: 8.4-20.4%). For all other events, the 8-year estimated cumulative incidence was 12.9% (95% CI: 3.6-13.1%).

The estimated annual percentage rates of LR, CBC, and other events were 2.1%, 1.5% and 0.4%, respectively.

Discussion: The results of this prospective study demonstrate a substantial and ongoing risk of LR and CBC in patients with small, nuclear grade 1 or 2 DCIS treated with wide excision with margins of ≥1cm in the absence of RT. Most LRs occurred in the same quadrant, rather than elsewhere in the breast, suggesting that excision alone is inadequate even for this highly selected population. Further study is warranted to determine if there is a subgroup of DCIS patients with nuclear grade 1 or 2 disease who are at low enough risk of LR following wide excision that RT can be omitted safely.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-03.
Abstract P1-15-04: Luminal B Lobular Carcinomas In Situ Have a Higher Risk of Relapse Compared to the Other Molecular Types of Lobular Carcinomas In Situ: Results from a Pilot Retrospective Single Institution Study
Authors: Vincent-Salomon A , Hajage D , Cedenot A , Gautier C , Gruel N , Alran S , Sigal-Zafrani B , Fourquet A , Kirova Y.
Published: April 2011

Aims: To determine the molecular subtypes existing in a retrospective series of classical lobular carcinoma in situ (LCIS) and to evaluate the risk of relapse in the different groups. To assess by immunohistochemistry the expression of stem cell markers in LCIS.

Material and methods: A series of 58 LCIS have been retrospectively selected in our files according to the availability of clinical data. The expression of E-cadherin (clone 4A2C7, Invitrogen), ER (clone 6F11, Novocastra), PR (clone 1A6, Novocastra), ERBB2 (clone CB11, Novocastra), EGFR (clone 31G7, Zymed), KI67 (MIB1), CD44 (1563C11, Thermo Fisher Scientific), CD24 (clone SN3b, Thermo Fisher Scientific) and ALDH1 (clone 44/ALDH, BD transduction Laboratories) were determined on whole tissue sections for 47 patients with available paraffin blocks. For ER, PR, EGFR and Ki67, 10% of positive cells were used as cut-off. For ERBB2, the interpretation was performed according to the ASCO guidelines for invasive carcinomas. The molecular subtypes were defined as luminal A: ER+ ERBB2- and Ki67<10%; luminal B: ER+, Ki67 >10% or ERBB2+; ERBB2 ER-and ERBB2 3+; basal-like: ER-PR-ERBB2-and EGFR+. All patients’ charters were reviewed and clinical data was recorded. All of the patients underwent tumorectomy without any radiation therapy.

Results: Median age was 50 yrs (min 31; max 72). The majority of the lesions were diagnosed by microcalcifications on mammography (62% of the cases) and treated by lumpectomy (98%). The majority of the lesions were classical LCIS (97%). The majority of the cases were E-cadherin negative (53%), the other cases presenting a weak staining of 10 to 80% of the cells, ER +ve (91%), PR +ve (68%), ERBB2 -ve (100%), KI67 low (81%), EGFR-ve (89%). A total of 33 cases were defined as luminal A (72%), 9 cases as luminal B (20%) and 4 cases were ER-ve/ERBB2-ve. At five years, all patients were alive, 1/33 luminal A experienced a relapse contrasting with 4 out of 9 luminal B (1 LCIS, 3 invasive carcinomas including 2 ductal and 1 lobular) (p= 0.004). The majority of the cases was CD44 +ve (93%), CD24 -ve (57%) and ALDH1 -ve (74%). No statistically significant link was observed between the stem cell phenotype defined as CD44+/CD24-/ALDH1+ and a risk of relapse.

Conclusions: Classical LCIS are in majority of luminal A type (72%). 20% of LCIS are luminal B and present a risk of relapse higher than luminal A LCIS. In this retrospective pilot study, for the first time to our knowledge, we observed a higher risk of relapse associated with the luminal B phenotype of LCIS. This observation needs to be confirmed in a larger series but could contribute to improve the clinical management of classical LCIS patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-04.
Abstract P2-01-01: Mammography and Patient or Physician Detected Breast Cancer in 21-39 Year Old Women
Authors: Kaplan HG , Malmgren JA , Atwood MK
Published: April 2011

Background: Mammography screening is not recommended for women under age 40. The American Cancer Society recommends clinical breast exam about every 3 years and breast self-exam as an option for women starting in their 20s. It is not clear what method is best for women at high risk.

Methods: We conducted a prospective cohort study of all women presenting with primary breast cancer, aged 21-39, biopsy confirmed Stage 0-IV from 1990-2008 identified and tracked by our registry. Clinical presentation characteristics including age, race, TNM stage converted to AJCC 6, first degree relative, family and pregnancy history, histologic type and method of detection by patient (PtD), physician (PhysD) or mammography (MgD) were chart abstracted at the time of diagnosis. A first degree relative is a mother, father, son, daughter or sibling with a BC diagnosis. Cases with unknown or other method of detection (n=7) were removed (n=602). For analysis purposes patient and physician detected cases were combined into one manually detected category. Forward conditional stepwise regression was used to test association significance with detection method and the Kaplan-Meier method was used for disease free survival (DFS) analysis.

Results: Women aged 21-39 represented 7% of the patients in our community based cancer center registry database. We did not observe any change in detection method over time with 12% MgD, 7% PhysD and 81% PtD. The majority of MgD cases were in the 30-34 (26%) and 35-39 (65%) year old age groups (Pearson chi square = 11.11, p=.011). 81% of the PhysD/PtD breast cancers were visible on subsequent mammography. 31% of the 74 MgD cases were stage 0 vs. 2.5% of the 528 PhysD/PtD cases. In a conditional logistic regression model with MgD BC yes/no as the binary outcome, age at diagnosis and having a first degree relative with breast cancer were significantly associated with mammography detection. DFS was significantly better in the MgD group (log rank test = 6.10, p=.014).

Conclusions: Mammography detection in 20-39 year old breast cancer patients is associated with age > 30 years and presence of a BC affected first degree relative. Disease specific survival is significantly better in the mammography detected group largely due to lower stage at diagnosis. These results indicate mammography may be a reasonable option for screening high risk women aged 30-39.

Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-01-01.
Abstract P2-02-01: Characterization of the Breast Lesions by Biexponential Signal Attenuation Analysis of Diffusion-Weighted Magnetic Resonance Images
Authors: Tamura T , Murakami S , Arihiro K , Usui S , Naito K , Akiyama M.
Published: April 2011

Purpose: Signal attenuation of diffusion-weighted magnetic resonance images (DWI) in vivo with high b-values is sometimes non-linear when plotted with a semilogarithmic function, but it fits well with the biexponential equation, Sb/S0=f1exp(bD1) + (1-f1)(bD2). Others have indicated that the fast and slow component fractions (f1, 1-f1) of the apparent diffusion coefficients (D1, D2) can be derived by biexponential fitting, and that these fractions correspond to actual diffusion components in the extra-and intracellular space. Here, we investigated the clinical value of DWI for breast screening by performing multi b-factor DWI on healthy volunteers and patients. We then analyzed signals by fitting them with the biexponential equation and compared the fitting parameters of breast lesions.

Patients and methods: This study was approved by our center's institutional review board and all patients and volunteers gave their informed consent. We analyzed data from eight healthy females (controls) and 80 female patients with a total of 100 breast tumors (42 benign and 58 malignant). We performed DWI using 12 and 6 b-values for the controls and patients up to a maximum b-value of 3500 sec/mm2.

Results: We identified the DWI signal attenuation features of the normal mammary gland, and of benign and malignant tumors [Figure1]. The DWI signal attenuation was similar between some proliferative benign tumors and malignancies. A comparison of the parameters derived from biexponential fitting revealed a significant difference in f1 between noninvasive and invasive ductal carcinoma [Figure 2]. Conclusion: The biexponential fitting parameters might reflect the features of tumor cellularity. Thus, to distinguish malignant from benign breast tumors only by DWI is difficult due to the pathological diagnosis that rather emphasizes cell configuration or shape rather than cellularity. Nevertheless, our findings will help to understand why malignant tumors present as high signal intensity in DWI.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-01.
Abstract P2-02-02: Uptake and Predictors of Screening Breast MRI in High Risk Women
Authors: Beattie MS , Blumenthal E , Creasman J , Cheung E , Crawford B.
Published: April 2011

BACKGROUND: Screening breast MRI is recommended in: BRCA carriers, their first degree relatives who have yet to test, and women with lifetime breast cancer risks of over 20-25%. It is unclear, however, whether women who receive screening breast MRI meet any of these criteria. As screening breast MRI becomes more available and accepted, it is also important to describe its uptake and identify its predictors. OBJECTIVE: To determine the uptake over time of screening breast MRI, as well as predictors of receiving screening breast MRI, in a cohort of women at high risk of hereditary breast cancer. METHODS: We surveyed all cancer-free women who enrolled in the UCSF Cancer Risk Program to determine their uptake of screening breast MRI, including their frequency of screening and the results of this screening. We also queried these women regarding their their risk perception, cancer worry, knowledge of high-risk screening recommendations, and their satisfaction with clinical care. We linked survey data to clinical and demographic data. Descriptive and comparative statistics, as well as multivariate logistic regression, were used to analyze this data. RESULTS: The survey response rate was 80% (n = 433) and the median follow up time was 2.7 years (range 0.5 — 12 years). The uptake of screening breast MRI doubled between 2005 and 2006, and doubled again between 2006 and 2008, with an overall uptake of 25% for ever receiving a screening breast MRI. Of the 92 BRCA carriers in this cohort, 74% reported every receiving a screening breast MRI compared to 18% of non-BRCA carriers (P<0.01). The mean age of first screening breast MRI in this cohort was 40 (range 25-61) compared to the mean age overall of 47 (p = 0.03). Ten percent of women who received screening breast MRI reported that their study required a “call-back” and/or further imaging. Using the BRCAPRO risk prediction model to calculate lifetime risk, without knowing BRCA resutls, 28% of this population would meet the 20% lifetime risk threshold. When BRCA results are incorporated into this risk model, 20% of this population would meet the 20% lifetime risk threshold. Variables associated with obtaining a screening breasat MRI are in the table 1 below.

Table 1. Variables independently associated with screening breast MRI use in 433 high risk women withou t breast cancer

CONCLUSIONS: Screening breast MRI is growing substantially. Its use to date demonstrates adherence with high-risk recommendations and guidelines. BRCA positive status is the strongest predictor of its uptake, and most BRCA carriers report receiving at least one screening breast MRI. Early trends indicate that variables not associated with risk, such as site of care (public versus university hospital) and race, may play a role in the uptake of screening breast MRI as its use becomes more widespread.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-02.
Abstract P2-02-03: Influence of Pre-Operative MRI on the Eligibility for Accelerated Partial Breast Irradiation (APBI)
Authors: Kühr M , Stölzle M , Leutner C , Schrading S , Kuhl C , Kuhn W , Braun M.
Published: April 2011

Purpose: Accelerated partial breast irradiation (APBI) following breast-conserving therapy is currently under investigation in prospective randomized studies. Multifocality and multicentricity are exclusion criteria for APBI. It is proven that pre-operative breast MRI has the ability to dectect ipsilateral and contralateral invasive tumor foci or DCIS in addition to conventional diagnostic methods (clinical examination, mammography and ultrasonography). The objective of this retrospective study was to evaluate the impact of pre-operative MRI on the patient selection for APBI. Patients and methods: From 2002 until 2007 a total of 579 consecutive, non-selected patients with newly-diagnosed early-stage breast cancer received pre-operative Breast MRI in addition to conventional imaging studies at the Bonn University Breast Cancer Center. In total, 130 patients met the criteria for APBI by conventional imaging studies (pathologic tumor size ≥3 cm, negative axillary node status, unifocal disease, no evidence of distant metastases, no invasive lobular carcinoma, lobular carcinoma in situ or Paget's disease). We analyzed the amount of additional ipsi-and contralateral tumor foci detected by MRI.

Results: MRI detected additional tumor foci in 7,6 % of patients eligible for APBI (11 tumor foci in 10 out of 130 patients), either ipsilateral (n=7/5,4%) or contralateral (n=4/3.1 %). In one patient MRI found an additional tumor focus both ipsi-and contralateral. Conclusions: Pre-operative breast MRI may be useful for patient selection for APBI. Its ability to identify additional tumor foci in a clinically relevant number of cases may help to avoid undertreatment of these patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-03.
Abstract P2-02-05: Combined Ultrasound/MRI for Breast Cancer Screening in Asian Women of Average Cancer Risk
Authors: Cheng GYC , Ko JS , Wu JNY , Cheng CS , Chen CJH.
Published: April 2011

Background and purpose: MRI is not recommended for screening women at average risk because it is associated with substantial numbers of false-positive results and cost. MRI as a screening tool for breast cancer, however, involves a complexity of cancer epidemiology, socio-economic situation, healthcare policy, and awareness and compliance of general population. Breast MRI may be particularly beneficial as a screening tool for Asian women due to their dense breast. In this study we reported the breast MRI screening results in Chinese women in Taiwan. Materials and Methods: In a period of 8 years, 3681 women underwent breast MRI examination in our imaging center. Of them, 95 women were known to have prior histories of cancers and were excluded from this study. The remaining breast MR images from 3,586 asymptomatic healthy women (mean age, 45.3 years) were retrospectively analyzed in this study. All subjects came to our imaging center for screening breast MR studies by self-referral due to high concern of cancer. All subjects were examined at a 1.5T scanner. The imaging interpretation was based on the criteria of ACR BI-RADS lexicon. After the breast MRI examination, complementary US was performed. If suspicious lesions were detected on MRI but showed negative results on US, double check with targeted US were done by the same radiologist immediately. US was also used to guide needle biopsy when in need.

Results: Overall, among 3,586 cases, totally 115 subjects were suspected to have malignant lesions and ultrasound-guided biopsy (N=106) and/or aspiration cytology study (N=122) was performed in all these 115 subjects. 47 were proved to have malignant lesions in pathology (35 invasive cancers — 27 IDC, 7 ILC, and one apocrine carcinoma; and 12 cases of carcinoma in situ). 31 additional cases of pre-cancerous lesions were found. The mean age in cancer group was 49 y/o and 52.2 y/o in CIS group. Subjects at age 41-50 group had the highest incidence of cancer detection, including 6 in situ lesions and 19 invasive cancers. Five cases were found to have breast cancers 1 or 2 years later. The incidence for malignancy in our asymptomatic group was about 1.31% (47/3586) and increased to 2.2% (78/3586) if precancerous lesions were included. The overall sensitivity of combined US/MRI was 94% and specificity was 99%. Conclusions: Breast MRI can be an option for Asian women of average risk, who usually have dense breast, at their own cost. From our results, it was shown that combined ultrasound and MRI can achieve high sensitivity and specificity for women of average risk. The unnecessary biopsy due to the false positive diagnosis of breast MRI can also be reduced remarkably.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-05.
Abstract P2-05-02: Optical Parameters of Breast Cancer before and after Chemotherapy
Authors: Ogura H , Yamashita D , Nasu H , Teruya C , Ohmae E , Yoshimoto K , Suzuki T , Ueda Y , Oda M , Yamashita Y , Sakahara H.
Published: April 2011

Objectives: To analyze optical parameters of cancer before and after chemotherapy in breast cancer patients.Patients and Methods: Absorption coefficient (µa) and reduced scattering coefficient (µs') of cancer and contra-lateral normal region before and after chemotherapy were measured by using TRS-20SH (Hamamatsu Photonics K.K.). A pulsed laser of 760, 800, and 830 nm wave-length was irradiated at multiple sites in both breasts with time-resolved spectroscopy method and scattered light was analyzed by photon diffusion equation. A total of ten breast cancer patients who underwent neoadjuvant chemotherapy participated in the trial. Written informed consent was obtained from all of the patients.Results: Absorption coefficient (µa, 1/cm) of breast cancer was significantly higher than that of contra-lateral normal region before chemotherapy. In 800 nm wave-length, absorption coefficient of breast cancer decreased significantly after chemotherapy (before:0.0927, after;0.0498, p=0.002). Although absorption coefficient of contra-lateral normal region also decreased (before:0.0561, after;0.0437, p=0.006), cancer showed more significant decrease than contra-lateral normal region (cancer:-43.1%, normal region;-19.0%, P<0.01).

Figure 1. Absorption coefficient (pa, cm-1), at 800rim (cancer-normal)

Similar results were observed in 760 and 830 nm wave-length. There was no difference in reduced scattering coefficient (µs') between before and after chemotherapy in both breast cancer and contra-lateral normal region.

Conclusion: The absorption coefficient of cancer was significantly higher than that of contra-lateral normal region before chemotherapy and decreased significantly after chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-05-02.
Abstract P2-06-02: Health Economic Impact of Risk Group Selection According to ASCO-Recommended Biomarkers uPA/PAI-1 in Node-Negative Primary Breast Cancer
Authors: Jacobs VR , Kates R , Kantelhardt EJ , Vetter M , Schmitt M , Jaenicke F , Untch M , Thomssen C , Harbeck N.
Published: April 2011

Background

Invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy (CTX) in primary breast cancer (BC). Methods

Potential savings in direct, per-patient expected costs of two leading CTX regimens (6xFEC or 3xFEC-3xDOC) resulting from uPA/PAI-1 test were calculated from a German health provider's perspective for a hypothetical 55 year old, N0, ER+, HER-patient in otherwise good health. Assumptions: patient always receives adjuvant endocrine therapy; without uPA/PAI-1 test, patient also receives CTX; with test, adjuvant CTX given only for high uPA/PAI-1 (60%); cost of testing all patients is included. Results

Testing costs (with tissue handling) are 385€. Adjuvant CTX costs are saved in 40% of patients by testing; including medications, prophylaxis, diagnostics, additional supporting therapies and procedures, CTX costs about 20000€ for both regimens considered (6xFEC ∼18000€; 3xFEC+3xDOC ∼21000€); relapse medical costs were modeled at 40000€. Consider a low-uPA/PAI-1 patient: Survival curves without CTX were estimated using CHEMO N0 10y-disease-free survival (89%) plus endocrine therapy benefit (hazard ratio (HR)=0.7). Expected lost life years (LY) due to relapse (with versus without test) were estimated from corresponding survival curves using age-adjusted life expectancy (minus 2y post-relapse survival).

Cost per life year gained in low-risk patients treated by adjuvant chemotherapy

The figure shows estimated savings (∼18500€) per low-risk patient (lowest curve), survival impact (decreasing curve) and cost per LY of not giving the uPA/PAI-1 test (increasing curve), as the assumed adjuvant CTX benefit in the low-risk group (no testing) is varied between HR=0.8 and HR=0.99. If the health care provider were willing to pay 50000€ for 1 LY, then a HR of at most 0.85 would be required in the low-risk group. Very low CTX benefit (HR approaching 1) is associated with astronomical costs/LY.

Conclusions

In clinical practice, the fraction of G2 ER+ HER2- patients for whom CTX savings could be realized could be affected by 1. existence of sufficient tissue for the assay; 2. availability of logistics; 3. additional clinicopathological decision criteria. The main driver of cost utility in low-uPA/PAI-1 patients is their benefit (HR) for adjuvant CTX. Our estimates show that the uPA/PAI-1 test is likely to be cost effective even with respect to LY; its cost effectiveness is expected to be even stronger when quality of life or severe chemotherapy risks such as heart damage and leukemia are considered. Our model thus lends health economic support to current guideline recommendations that uPA/PAI-1 testing is beneficial in node-negative BC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-02.
Abstract P2-06-03: A Polymorphic AAAG Repeat in the Estrogen Receptor-Related-Gamma Gene May Represent a Breast Cancer Predisposition Biomarker
Authors: Garner HR , McCormick JF , Li L-S , McIver LJ , Bubb VJ , George AC , Boothman DA , Quinn JP , Galindo C.
Published: April 2011

Background: There is a strong genetic component to breast cancer, which is the most common neoplasm in women; however current risk markers are few, accounting for less than 10% of breast cancer cases. This means that the majority of familial breast cancers remain unexplained. Our laboratory has studied microsatellite polymorphisms for many years, and we developed techniques to assay these understudied regions of the genome en masse and individually via shot-gun methods to rapidly identify those that are likely to be polymorphic and therefore potentially contribute to phenotype.

Material and Methods: Using these novel approaches, we identified a polymorphic AAAG microsatellite repeat in the estrogen-related receptor gamma (ERR-γ) that is expanded in -10% of the general population. We genotyped over 300 individuals and found a longer allelic version (13+ repeat copies) in 14.3% of breast cancer patients, compared to only 4.8% in cancer-free individuals. We computationally identified 22 transcription factors that could bind directly to this AAAG repeat and the surrounding region. We hypothesized that the AAAG-containing region might serve as a promoter for ERR-y.

Results: We found a statistically significant number of breast cancer patients with the expanded AAAG allele, and preliminary experiments confirm that the AAAG-containing region of ERR-γ does indeed drive reporter gene expression in estrogen receptor positive (ER+) MCF-7 breast cancer cells. This was not the case for the ER-breast cancer cells (MDA-MB-231) we also examined. Our initial assessments also revealed that SKBR-3 breast cancer cells are naturally heterozygotic for the long and short allelic versions of the AAAG repeat. Our ongoing studies involve knockdown of transcription factors in MCF-7 cells that abrogate the endogenous expression of ERR-γ.

Discussion: The role of microsatellites in cancer is well defined for colon cancer, but few studies have been conducted to examine the contribution of these simple sequence repeats in breast cancer. We discovered a polymorphic AAAG repeat in the ERR-γ gene, and our studies indicate that a longer version of this repeat is more prevalent in the genomes of breast cancer patients. Based on our assessment, this allele carries a 2.98 relative risk for the development of breast cancer. The higher incidence of this putative biomarker in breast cancer patients may be a result of altered ERR-γ expression, as the AAAG-containing sequence can drive reporter expression. If the frequency of this potentially predictive marker is sustained in a larger population, and the mechanism by which it confers the cancer phenotype can be identified, it may contribute substantially as a biomarker offering surveillance, prophylactic surgery, and chemoprevention options to patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-03.
Abstract P2-06-09: Mucin4 Is Associated with the Loss of Estrogen-Receptor-α in Breast Cancer
Authors: Chen AC , Migliaccio I , Gilcrease M , Osborne CK , Schiff R.
Published: April 2011

Data suggests that breast carcinomas that overexpress the HER2 oncoprotein are more resistant to endocrine treatments such as tamoxifen (Tam) or estrogen deprivation (ED) via aromatase inhibitors. To investigate possible mechanisms of endocrine resistance in vivo, we performed a gene microarray analysis on estrogen receptor-(ER)+, HER2-overexpressing xenograft tumors that are de novo resistant to tamoxifen treatment and acquire resistance to ED therapy. A large number of genes were upregulated, including several members of the mucin family of genes. This corroborated our finding from histological staining of the resistant tumors that indicated striking increases of mucin vacuoles when compared to sensitive tumors. These vacuoles were located mostly intracellularly and stained positive for mucins with mucicarmine. We were particularly interested in one particular mucin, mucin4 (MUC4) because previous studies have suggested its role in stabilizing and enhancing HER2 signaling. Quantitative realtime PCR confirmed the microarray results and showed that there was an approximately 156-fold increase in MUC4 transcript between the ED-sensitive and ED-resistant tumors, with a 65-fold increase between the early Tam and late Tam-resistant tumors. Immunohistochemistry confirmed that this upregulation in these two treatment groups was present also at the protein level. Furthermore, western blot analysis of these tumors demonstrated that resistant tumors have downregulation of ER protein and its downstream effectors with corresponding increase in total HER2 protein levels. These tumors have seemingly shifted away from the ER pathway to signaling via the growth factor signaling pathway. Preliminary experiments where MUC4 protein was stably overexpressed in ER+, HER2-overexpressing cells model these results in vitro with a downregulation of ER protein and downstream effectors, showing that ER expression and activity are affected. Furthermore, immunohistochemical analysis of 73 primary human invasive breast carcinomas suggests that MUC4 is associated with estrogen-receptor negative tumors (P=0.05). This clinical data validates the preclinical studies for investigating a possible mechanism for the loss of ER, and suggest MUC4 as an inviting biomarker for endocrine treatment and a potential therapeutic target for endocrine resistant breast cancer.

Crosstabulation of MUC4 and ER

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-09.