bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-07-02: Prediction of oncotype DX® recurrence score using pathology generated equations
Authors: Bhargava R , Klein ME , Shuai Y , Brufsky AM , Puhalla SL , Jankowitz R , Dabbs DJ
Published: August 2014

BACKGROUND: Oncotype DX® is a quantitative reverse transcription polymerase chain reaction based assay that has been shown to have prognostic and predictive value in estrogen receptor (ER) positive breast cancers. The result is reported as a recurrence score (RS) ranging from 0–100, divided into low risk (<18), intermediate risk (18–30), and high risk (≥31) categories. Prior studies have shown that RS is influenced by ER and progesterone receptor (PR) expression, HER2 status, proliferation index, and tumor grade. Our pilot study showed that RS can be predicted by an equation incorporating standard morpho-immunohistologic variables (referred to as Original Magee Equation; Mod Pathol. 2008;21:1255–1261).

METHODS: Using a dataset of 817 cases, we formulated three additional equations to predict the RS category for an independent set of 255 cases. Three models were built based on different hypotheses and data availability and are represented below.

New Magee Equation 1 (nME1): RS = 15.31385 + Nottingham score*1.4055+ ER H-score*(−0.01924) + PR H-score*(−0.02925) + (0 for HER2 negative, 0.77681 for equivocal, 11.58134 for HER2 positive) + Tumor size*0.78677 + KI67 index*0.13269.

New Magee Equation 2 (nME2): RS = 18.8042+ Nottingham score*2.34123 + ER H-score*(−0.03749) + PR H-score*(−0.03065) + (0 for HER2 negative, 1.82921 for equivocal, 11.51378 for HER2 positive) + Tumor size*0.04267.

New Magee Equation 3 (nME3): RS = 24.30812+ ER H-score*(−0.02177) + PR H-score*(−0.02884) + (0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive) + KI-67*0.18649.

RESULTS: The concordance between the risk category of oncotype DX® and our equations was 55.8%, 59.4%, and 54.4% for nME1, nME2, and nME3 respectively. With exclusion of the intermediate risk categories for both the actual RS and estimated RS, the concordance for each equation increased to more than 95%, reflecting the very low two step discordance (100% {76/76}, 98.6% {75/76}, and 98.7% {79/80} for nME1, nME2, and nME3 respectively). Even when the estimated RS fell in the intermediate category with any of the equations, the actual RS was either intermediate or low in more than 85% of the cases. The Pearson correlation coefficient between estimated and actual RS was similar for each of the equations (0.61661, 0.60386 and 0.59407 for nME1, nME2 and nME3, respectively).

CONCLUSIONS: Any of the 3 equations can be used to estimate the RS depending on available data. If the estimated RS is clearly high or low, the oncologists should not expect a dramatically different result from oncotype DX®, and the oncotype DX® test may not be needed. Conversely, an oncotype DX® result that is dramatically different from what is expected based on standard morpho-immunohistologic variables should be thoroughly investigated.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-02.
Abstract P6-07-03: Risk classification of Early Stage Breast Cancer as Assessed by MammaPrint and Oncotype DX Genomic Assays
Authors: Clough KB , Poulet B , Jamshidian F , Butler S , Svedman C , Levy E
Published: August 2014

Background: The 21-gene Oncotype DX® Recurrence Score® assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy (CT) in patients (Pts) with estrogen receptor-positive (ER+) early stage breast cancer (ESBC). MammaPrint® is a multi-gene assay that has been validated as a prognosticator in a heterogenous Pt population that includes ER+, ER−, triple negative and HER2+ Pts. While the development and validation cohorts for these genomic assays are significantly different, the tests are frequently believed to provide equivalent information. The aim of the present study was to assess how these tests classify patients when compared side by side in the same Pt specimen.

Materials and methods: Pts with ER+, HER2−, ESBC in which the MammaPrint assay had been sent were identified at the Institut du Sein, Paris, France. Clinical and pathological characteristics and the MammaPrint results (failure, low or high risk) were collected. Oncotype DX quantitative RT-PCR analysis was performed at Genomic Health and was blinded to the clinical and MammaPrint data. Descriptive statistics were calculated for failure rates, cross classification, and tumor characteristics.

Results: Informed consent and sufficient tumor material for analysis was available from 67 Pts who were predominantly low and intermediate risk by clinicopathologic features: Tumor grade- 24 low, 36 intermediate and 7 high; Histology- 49 ductal, 14 lobular and 4 other. MammaPrint analysis had failed to deliver result for 10 of the 67 Pts. Recurrence Score results were generated in all 67 Pts. The risk classification of the MammaPrint and Oncotype DX tests in the 57 patients where both results were available is presented in the Table below. Of note, there were only 2 high Recurrence Score results compared with 22 high risk MammaPrint results. Furthermore, 45% of the Pts with high risk MammaPrint result had a low Recurrence Score result; they also had high quantitative ER expression of more than 9.5 expression units by RT-PCR, which is associated with likely hormonal therapy benefit. There was no clear association between tumor characteristics and MammaPrint failure or differences in risk classification.

Conclusions: This direct comparison demonstrates that the MammaPrint and Oncotype DX tests classify a large proportion of Pts differently. Of note, nearly half of the Pts with high risk MammaPrint result had a low Recurrence Score indicating minimal, if any, benefit from chemotherapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-03.
Abstract P6-07-12: Akt2 expression is associated with good long-term prognosis in estrogen receptor positive breast cancer
Authors: Fohlin H , Pérez-Tenorio G , Fornander T , Skoog L , Nordenskjöld B , Carstensen J , Stål O
Published: August 2014

Introduction: Akt is a signaling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of Akt1 and Akt2 in estrogen receptor positive (ER+) and estrogen receptor negative (ER−) breast cancer with long-term follow-up.

Material and Methods: The expression of Akt in tumor tissue was analyzed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. Hazard ratios and 95% confidence intervals were estimated using the Cox's proportional hazards model.

Results: The risk of distant recurrence was reduced for patients with ER+ tumors expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumor characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. After more than five years since diagnosis the risk reduction was 57% for patients with Akt2 positive tumors. The prognostic value of Akt2 increased with higher estrogen receptor levels from no effect among patients with ER− tumors to 68% risk reduction for the group with high ER-levels (P for trend= 0.042). Akt1 showed no significant prognostic information.

Conclusion: Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumors and that this association remains long-term. The prognostic value of Akt2 increases with higher estrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-12.
Abstract P6-07-23: Proportion of invasive micropapillary carcinoma lesion and primary breast cancer prognosis
Authors: Takei J , Nakayama K , Yagata H , Hayashi N , Yoshida A , Ohde S , Suzuki K , Nakamura S , Yamauchi H
Published: August 2014

Background: Invasive micropapillary carcinoma (IMPC) has been classified as a special type of breast cancer and has a high incidence of lymph node metastases and lymphatic invasion with poor prognosis. IMPC is often mixed with other histological types. This study examined whether the prognosis is correlated with proportion of the IMPC.

Methods: The subjects included 124 patients with IMPC that were surgically resected at St. Luke's International Hospital between February 2000 and January 2011. The resected specimens were reviewed histopathologically to determine the proportion of IMPC lesion. Patients were classified into two groups based on three cut-points of the proportion of IMPC lesion, 25%, 50%, and 75%. For each of these dichotomous classifications, we examined overall survival (OS), recurrence rate (RR) and pathological histology between the two groups. We used the Kaplan-Meier curve method and log-rank test to evaluate overall and disease-free survival time and the chi-squared test for pathological histology.

Results: The subjects were 124 cases, and two of them were male breast cancer.

The patient's age at presentation ranged from 29 to 83 years (mean 54.5 years).

At a median follow-up of 52 months (interquartile range, 7 to 115 months).

For all cut off points, there was no significant difference in survival rate and recurrence rate. We observed high-rates of lymphatic invasion and lymph node metastasis even in patients with a low proportion of IMPC lesion.

Conclusion: Our results provide no evidence to support a relationship between proportion of IMPC lesion and breast cancer prognosis. However, lymphatic invasion and lymph node metastasis was a high frequency with low proportion of the IMPC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-23.
Abstract P6-07-29: Independent prognostic value of age depends on breast cancer subtype
Authors: Brouckaert O , Salihi R , Laenen A , Vanderhaegen J , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Moerman P , Peeters S , Paridaens R , Floris G , Wildiers H , Vergote I , Christiaens M-R , Neven P
Published: August 2014

Background: Whether age is an independent prognostic factor in early breast cancer remains controversial. Different cut-off values have been suggested in different studies and few studies assessed its value in triple negative breast cancer and other phenotypes.

Methods: We included all primary operable breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We excluded male patients, patients treated elsewhere first, patients treated with primary systemic treatment first. We assessed the effect of age as a continuous and categorical variable for distant metastasis free interval (DMFI), locoregional free interval (LRRFI) and breast cancer specific survival (BCSS) in multivariable analysis (correcting for phenotype, tumor size, nodal status, chemo−, endocrine−, radiotherapy, type of breast and axillary surgery). We assessed the effect of age for DMFI, LRRFI and BCSS in basal-like breast cancer and other phenotypes.

Results: We included 4318 patients with a mean/median age of 58/ 57 years (1170 patients were younger than 50 years) and with a median follow-up of 6,0 years. Multivariate analysis confirmed age as an independent prognostic variable for LLRFI (HR1.91; 95% CL:1.33–2.74; p = 0.0005), DMFI (HR:1.77; 95% CL:1.33–2.36; P < 0.0001) and BCSS (HR:2.35; 95% CL:1.66–2.74; P < 0.0001). The optimal cut-off value is 41years for LLRFI and BCSS and 44 years for DMFI. We did not find an independent prognostic value for age in triple negative breast cancer regarding DMFI and LRRFI. Results for other subtypes are subject to currently ongoing analyses.

Conclusions: Overall, young age in primary operable breast cancer patients is an independent prognostic value for DMFI, LRRFI and BCSS after adjusting for known prognostic factors. In triple negative breast cancer, age did not retain independent prognostic value for DMFI and LRRFI.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-29.
Abstract P6-07-34: Disease-related outcomes with adjuvant chemotherapy in HER2 positive or triple negative T1a/bN0 breast cancers
Authors: Shao T , Olszewski AJ , Boolbol SK , Migdady Y , Boachie-Adjei K , Sakr BJ , Klein P , Sikov W
Published: August 2014

Background: Previous studies reported higher relapse rates in T1a/bN0 breast cancers characterized by high-risk biology (HER2 positive or triple negative). The benefits of adjuvant chemotherapy in this group have not been evaluated. The purpose of our study was to determine potential impact of chemotherapy on incidence of relapses and to define the population appropriate for treatment based on observational data.

Methods: We pooled data from two multi-institutional databases spanning the period of 1996–2008 (Beth Israel Medical Center) and 2000–2010 (Brown University). We fitted a propensity score model to adjust for unbalanced confounders between the groups treated or untreated with adjuvant chemotherapy and, in case of HER2+ disease, with trastuzumab. Competing risk analysis was employed to study the effect of chemotherapy on cancer relapses in the matched population.

Results: The study included 321 patients (160 from Beth Israel and 161 from Brown) with a median age of 57 years (range 28–88). 111 (35%) cases were triple negative (TN) and 210 (65%) were HER2+ (of which 64% were ER+). 41% patients received adjuvant chemotherapy and 22% of HER2+ cases received trastuzumab. The treated group differed from untreated with regards to distribution of age, menopausal status, year of diagnosis, histological subtype and grade, tumor size, rates of mastectomy, and adjuvant endocrine therapy. All confounders were successfully balanced with the propensity score analysis. With a median follow-up of 56 months, 20 relapses (12 locoregional and 8 distant) and 10 unrelated deaths occurred. The cumulative incidence of relapse at 5 years was 7.3% (95% CI, 4.3–11.4) and relapse-free survival was 90.2% (95% CI, 85.2–93.6). Age less then 35 years (46.4% vs. 6.1%, p = 0.0004) and TN status (12.9% for TN versus 4.8% for HER2+, p = 0.03) were associated with higher risk of relapse. No significant differences with regards to tumor size (T1a or T1b), surgery type and other variables were observed. There was no significant effect of chemotherapy on incidence of relapse (Hazard ratio 1.2, 95% CI 0.34–4.23, p = 0.78), relapse-free survival or distant recurrence-free interval after propensity score adjustment. Additionally in the HER2+ patients, no benefit of trastuzumab was detected (hazard ratio 0.78, 95% CI 0.06–9.85, p = 0.85). Adjuvant endocrine therapy was associated with lower risk of relapse in the ER+ subgroup (p = 0.04).

Conclusion: Survival outcomes in very early stage breast cancer are excellent with current therapy even in biologically aggressive subtypes. Triple negative status and very young age correlate with higher incidence of relapse. While adjuvant endocrine therapy may be effective in ER positive subset, the risk/benefit ratio of chemotherapy with or without trastuzumab remains uncertain.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-34.
Abstract P6-07-36: A Prognostic Model For Triple-Negative Breast Cancer Patients Based On Node Status, Cathpesin-D And Ki-67
Authors: Huang L , Liu Yb , Chen S , Zhou Rj , Liu Y , Shao Z-M
Published: August 2014

Background: Triple-negative breast cancer (TNBC) had been classified as a breast cancer subgroup that is negative for ER, PR and HER2. The purpose of this study was to identify prognostic factors affecting outcome in women with TNBC and to construct a prognostic model which can predict recurrence.

Material and methods: We retrospectively analyzed the clinicopathologic characteristics and outcome of 284 patients diagnosed with a stage I to III triple negative breast cancer in Shanghai Cancer Hospital, including age, menopausal status, tumor size, node status, grade, ER, PR, HER-2, Cathpesin-D, PS2, Nm23, P53, Bax, Bcl-2, P27, Topo-IIa, GSTn, MDR, Cyclin D1 and Ki67. 196 patients in 2000, 2001 and 2002 belonged to training set. Prognostic significance of factors was assessed using univariate and multivariate analyses, which were combined to build a model. DFS and OS were estimated by the Kaplan-Meier method and compared among groups via the log-rank test. The prognostic value of the model was further validated in separate testing set containing 88 patients in 2003 and 2004. The median age of patients was 50 years (range, 23–85 years). 95.1% patients received cytotoxic chemotherapy after surgery; 216 (76.1%) with anthracycline based, 54 (19.0%) with CMF regimen.

Results: The median follow-up duration was 70.6 months, 102 patients (35.9%) experienced recurrence or metastasis. In Cox regression, ≥4 lymph node metastasis (HR = 3.7, P < 0.001), Cath-D positive (HR = 2.1, p = 0.034), and Ki-67 index≥20%, (HR = 2.0, p = 0.006) were identified as independent factors for DFS, only ≥4 lymph node metastasis (HR = 4.9, P < 0.001) showed prognostic significance for OS. The prognostic model is based on the sum total of factors, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. According to the prognostic score, patients were assigned to low-risk group(0 and 1 point) and high-risk group(2 and 3 point). The 5-year DFS rates in two groups were 82.3% and 47.8%, respectively (p < 0.001). The model provided a high predictive accuracy of recurrence, which showed an AUC of 0.71 in the training set and an AUC of 0.70 in validation set.

Conclusion: Based on nodal status, Ki-67 and Cathpesin-D, we built a model that had considerable clinical value in predicting recurrence in TNBC patients, which help clinicians guide the appropriate level of adjuvant treatment and scheduling of surveillance visits.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-36.
Abstract P6-07-37: Impact of body mass index on recurrence risk in patients with ductal carcinoma in situ.
Authors: Klepczyk LC , Meredith RF , De Los Santos JF , Li Y , Keene KS
Published: August 2014

Background: Body mass index (BMI) has been correlated with risk of recurrence in invasive breast cancer, but the association between BMI and recurrence in ductal carcinoma in situ (DCIS) is less clear. Recent retrospective data indicates that local recurrence is not related to BMI at initial diagnosis. Here we examine the relationship between initial BMI and recurrence in a separate cohort of patients with DCIS.

Methods: One hundred eighty-nine patients with DCIS treated between the years of 1999 and 2005 at the University of Alabama at Birmingham were analyzed. BMI was divided into 4 categories as follows: underweight (BMI <18.5 kg/m (2)), normal weight (BMI 18.5–24.9 kg/m (2)), overweight (BMI 25–29.9 kg/m (2)), and obese (BMI ≥30 kg/m (2)). Fisher's exact test was used to evaluate the association between likelihood of recurrence based on initial BMI and the log rank test was used to evaluate recurrence-free survival. Risk of both overall recurrence and specifically local recurrence were analyzed.

Results: There were 199 cases of DCIS identified in our cohort of 189 patients (10 patients had bilateral disease). Of these 189 patients, 1.1% (2/189) were underweight, 31.2% (59/189) were normal weight, 22.7% (43/189) were overweight, and 21.7% (41/189) were obese. BMI could not be obtained for 23.3% (44/189) of patients. With a median follow-up of 87.2 months, there were 28 total recurrences identified in the 199 cases (14.1%) with 85.7% of these including a local recurrence. No significant associations were found between the likelihood of overall or local recurrence and any of the four BMI categories. Further, analysis of recurrence-free survival did not show any significant associations between BMI and recurrence.

Conclusions: Our data supports recently reported evidence that BMI at diagnosis does not affect the risk of overall or local recurrence in patients with DCIS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-37.
Abstract P6-07-38: The Value of Progesterone Receptor in Predicting the Recurrence Score for Hormone-Receptor–Positive Invasive Breast Cancer Patients
Authors: Onoda T , Yamauchi H , Yagata H , Hayashi N , Yoshida A , Nakamura S
Published: August 2014

Background: Molecular genomic profiling currently plays a major role in treatment decisions for breast cancer patients. The 21-gene signature (Oncotype DX® [ODX]) is one of the most well-validated assays. Herein we evaluated the associations between high Recurrence Score (RS) measured by the ODX and pathological factors.

Methods: From October 2007 to October 2010, the ODX assay was performed for 139 hormone-receptor–positive invasive breast cancer patients at single institution. Correlations between the RS and the following pathological factors were analyzed: tumor size (T), lymph node metastasis (N), nuclear atypia (NA), mitotic counts (MC), nuclear grade (NG), lymphatic and vascular invasion (LI and VI), estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki-67. Expression of ER, PgR, HER2, and Ki-67 was examined by immunohistochemistry. The Ki-67 labeling index was automatically counted with an Ariol-SL50 instrument (APPLIED IMAGING). The other pathological factors were estimated under the supervision of one experienced pathologist. Spearman rank correlation coefficients were calculated for the analyses. When the r was >0.4 or <–0.4 for two factors, they were determined to be well correlated.

Results: Of 139 patients, the ODX assay revealed 68 (49%) low RS cases, 52 (37%) intermediate RS cases, and 19 (14%) high RS cases. Moderate positive or negative correlations were noted between the RS and PgR (r = −0.53), the RS and Ki-67 (r = 0.42), and the RS and NG (r = 0.41). No patients had high RS with PgR (3+) or NG1. The rate of high RS with Ki-67 (<20%) was one patient (2%). The number of cases who did not show PgR (3+) or NG1 or Ki-67 (<20%) was only 34 (25%). Among high RS cases, the correlation between PgR (0) and NG3 was 83%, the correlation between PgR (0) and NG2 was 75%, and the correlation between PgR (1+) and NG3 was 75%.

The rate of high RS with PgR (0) and Ki-67 (≥20%) was 70%, that of PgR (1+) and Ki-67 (≥20%) was 58%, and that of PgR (2+) and Ki-67 (≥20%) was 21%.

Correlations with T, N, NA, MC, LI, VI, ER, and HER2 were smaller (r ranging from −0.33 to 0.38).

Conclusion: This study demonstrated that PgR, NG, and Ki-67 tend to be strongly correlated with the RS. Judging from PgR (3+), NG1, and Ki-67 (≥20%), we could select the patients who were proposed to perform the ODX. Among these factors, the correlation with PgR was particularly robust. PgR expression is a known marker of a functional ER and represents ER activity. In addition, the absence of PgR may reflect hyperactive cross-talk between ER and growth factor signaling pathways. We consider that these mechanisms could enhance the value of PgR in predicting the RS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-38.
Abstract P6-07-40: Initial Neutrophil-to-Lymphocyte ratio in primary breast cancer patients: a simple and useful biomarker as prognostic factor
Authors: Han A , Noh H , Lee J
Published: August 2014

Background: Increasing neutrophil/lymphocyte ratios (NLR) on preoperative blood tests have been associated with worse survival of patients with colorectal, gastric, hepatocellular, pancreatic and lung cancer. However the utility of NLR to predict mortality in breast cancer patients has not been studied. The aim of our study was to determine whether the NLR is predictive of disease specific mortality in breast cancer and subtype-adjusted prognostic effect in breast cancer patients.

Methods: We retrospectively identified all the patients with primary breast cancer diagnosed at Yonsei University Wonju Medical School between January 2000 and June 2011 who underwent primary surgery and completed all phase of their treatment. Breast cancer with infiltrating ductal histology was included and divided into 4 subtypes: Luminal A, Luminal B, Her2-enriched, and basal type. Each immunohistochemical characteristics are as followings: Luminal A: ER and/or PgR positive and negative Her2, Luminal B: ER and/or PgR positive with positive HER2, Her2-enriched: negative ER and PR with positive Her2, and triple negative as basal.

Results: Patients with NLR≥2.5 showed significantly lower 5-year, 10-year breast cancer specific survival than patients with NLR<2.5. (5-year survival; 88.6% vs. 96.4%, p = 0.009, 10-year survival; 84.3% vs. 92.2%, p = 0.006). Cox proportional multivariate hazard model for cancer-specific mortality showed that patients with NLR≥2.5 has hazard ratio 4.71 with 95% confidence interval 1.77–12.53. Further analysis was done according to stratified patients' subgroup with intrinsic subtype. In Luminal A subtype, patients with NLR≥2.5 showed higher mortality rate(p = 0.014), while NLR≥2.5 failed to show statistical significance in the other subtype such as Luminal B, Her2 enriched, and triple negative subtype.

Conclusion: Increased preoperative NLR is a significant prognostic factor in breast cancer specific survival and relevant in Luminal A subtype. This study shows that NLR could be a useful prognostic factor for breast cancer specific survival. And this study suggests that different factors could contribute as prognostic factor to each subtype, such as NLR was significant prognostic factor in Luminal A, while we couldn't find increased NLR is significant in other subtypes.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-40.
Abstract P6-07-41: Sub classification of early stage hormone positive (HP) Her-2 negative breast cancer (BC) by immunohistochemistry (IHC) into intrinsic subtypes (IS) and their correlation with Oncotype Recurrence Score (RS)
Authors: Mahesh S , Lane J , Ravichandran P
Published: August 2014

Background: Early stage HPBC is a heterogenous disease and various models of prognostication are available. Molecular profiling by IS i.e. Luminal A (LA) and Luminal B (LB) is one such attempt but is complex and expensive. Literature suggests a Ki-67 index of ≥14% as a cutoff between LA and LB tumors. LB subtype is associated with worse breast cancer outcomes. Oncotype RS is one of the most robust tools to assess prognosis and predict benefit from chemotherapy in HP Her-2 negative early BC. We sought to investigate the correlation between IHC classification of IS and RS. In addition, we also evaluated incidence of basal immunophenotype in this population.

Methods: Early Stage Her-2 negative HPBC cases that had RS testing from 2007–2011 were found through our database. IHC for Ki-67, CK 5/6 and EGFR was performed if adequate tissue blocks were present. IHC classification of IS was as follows: Ki-67 ≥ 14%: LB; Ki-67 < 14%: LA; CK 5/6 and/or EGFR expression: Basal. An exploratory analysis using Ki-67 cutoff of 19% i.e. LA (<19%); LB (≥19%) was performed to evaluate its effect on correlation with RS.

Results: We found 115 patients. Median age: 62 years. Stage 1: 79/115 (69%) Stage 2: 36/115 (31%). Using Ki-67 cutoff of 14%, LA: 42/115 (36.5%); LB: 72/115 (62.6%); Using Ki-67 cutoff of 19%, LA: 66/115 (57.4%); LB: 48/115 (41.7%); Basal: 1/115(0.9%). Characteristics of LA and LB and their comparison with Oncotype Dx are shown in the Table 1. Compared to LA, LB patients were younger (p = 0.004) and had higher oncotype scores (p = 0.007). However, range of RS in both subtypes was large. Among LB patients, 43% fell in low risk category and only 15% fell into high risk category. Among LA, results seemed to correlate more with expectations; 69% were in low risk category while 5% were in high risk category. When a cutoff of Ki-67 </≥19% was used to classify LA/LB, 42% of LB were still in low risk category of Oncotype Dx. Only 1 patient had basal immunophenotype (Ki-67 25%, RS 42).

Conclusion: Majority (85%) of LB patients were in Low or Intermediate category of RS. This did not change when a higher KI-67 cutoff was used. Thus, relying solely on Ki-67 to classify LA/LB and using it as a surrogate marker for obtaining benefit from chemotherapy would be inappropriate.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-41.
Abstract P6-08-09: Overcoming Breast Cancer: The Importance of Connecting with Fellow Survivors
Authors: Geoghegan C , Whitman B
Published: August 2014

Y-ME National Breast Cancer's Organization, founded in 1978, is not-for-profit organization with a mission to “To assure through information, empowerment, and peer support, that no one faces breast cancer alone.” Each year, Y-ME's 24×7×365 Breast Cancer Hotline receives approximately 40,000 contacts. Callers to Y-ME's toll-free Hotline are referred by clinicians, community groups and global cancer organizations that recognize the importance of providing emotional relief to patients and their loved ones. Trained and certified peer counselors, all breast cancer survivors, staff the hotline. Callers can speak to a Spanish or English speaking peer counselor or have an interpreter in any of over 150 languages added to the line.

An online survey conducted by Whitman Insight Strategies on behalf of the Y-ME National Breast Cancer Organization was conducted to better understand the psychosocial needs of breast cancer patients and survivors. Surveys were conducted on April 3–5, 2012, among 400 breast cancer patients and survivors 18 years of age and older across the United States. The margin of error for total sample is ±4.9% at the 95% confidence interval. Respondents received an email invite to participate in a short online survey; their emails were selected at random among online market research panelists who had previously indicated that they have or had breast cancer.

The results indicate that talking to a breast cancer survivor can be instrumental in overcoming breast cancer: 84% of breast cancer patients and survivors say this is one of the most important ways of coping with breast cancer and 68% wish that they could have been connected to other survivors. Access to a 24×7×365 hotline, where breast cancer survivors provide emotional support and practical advice, is considered important by virtually all women surveyed (95%)–73% think this is “extremely” or “very” important. Unfortunately, although Y-ME provides such a hotline; however, awareness of it is extremely low (14%). We encourage all healthcare providers to encourage patients to reach our to Y-ME by calling 800–221-2141 and time of the day or night.

Those who had another survivor to talk were asked to select among a number of relevant responses to the question: What did talking to another breast cancer patient/survivor provide you with? The following table provides the proportion that selected each response.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-09.
Abstract P6-09-03: Fatigue after breast cancer may be related to conditions other than the cancer. The impact of comorbidity is essential.
Authors: Reidunsdatter RJ , Hjermstad M , Oldervoll L , Lundgren S
Published: August 2014

Purpose: Fatigue after treatment for breast cancer is common, but is also prevalent in people with chronic diseases such as heart failure, diabetes, and depression etc. The primary objective was to compare the level of fatigue between BC patients one year after end of treatment with data from a representative survey of the Norwegian population (GenPop). Secondary aim was to explore the association between chronic conditions and fatigue and in both samples.

Design and Method: 245 patients treated with chemo –and/or radiotherapy after surgery, were assessed one year after treatment. Comorbidity was recorded by clinical examinations in patients and by self-report in the GenPop (N = 652). Fatigue was measured by the 3-item subscale of the EORTC QLQ-C30, with higher scores on the 0–100 scale implying more fatigue. Analysis of covariance was applied to compare age-adjusted mean scores between groups.

Results: Mean age was 58 (9) years in patients and 52 (14) years in GenPop. 23% of patients and 32% of GenPop had one or more of the following conditions; cardiovascular- or pulmonary disease, diabetes or depression. No significant differences were found in fatigue between BC patients and GenPop (mean score 26.7 vs. 29.7). Comorbidity was the greatest determinant of increased fatigue, regardless of BC treatment. Patients with comorbidity were significantly more fatigued than those without comorbidity (mean difference 10.4), as found in the GenPop (mean difference 13.3).

Conclusion: Similar fatigue levels in BC patients and GenPop one year after treatment is promising, but longer follow-up is needed. Comorbidity conditions should always be assessed when evaluating fatigue and other patient related outcomes. Prevention or treatment of common chronic conditions might be considered in rehabilitation programs to reduce fatigue in cancer survivors.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-09-03.
Abstract P6-10-06: Rational combination therapy against triple-negative breast cancer
Authors: Al-Ejeh F , Miranda M , Simpson PT , Chenevix-Trench G , Lakhani SR , Khanna KK
Published: August 2014

Background: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with higher incidence of recurrence, more distant metastasis, and poorer survival. This subtype is also characterized by complex genomes where little of their genomes remain at normal copy number but without high, focal copy number amplifications. At the transciptome level, the majority of TNBC (∼75%) are classified as basal-like breast cancer (BLBC) according to the five intrinsic subtypes. Despite considerable genomic and gene expression characterization of TNBC, proteomic and phospho-proteomic investigations of this disease are limited with no available targeted therapies in clinical use.

Methods & Results: We used the Kinex™ antibody array (http://www.kinexus.ca/) to interrogate protein/phosphoproteins levels in 43 primary breast cancer biopsies (16 TNBC, 16 ER/PR positive and 11 HER2-positive) and 16 breast cancer cell lines. Unsupervised hierarchical clustering of protein/phosphoprotein levels revealed two subgroups of TNBC in comparison to other subtypes. Western blotting and Proteome Profiler™ Arrays (R&D Systems) were used to validate deregulated proteins/phosphoproteins in TNBC. Pathway analysis revealed that one subgroup of TNBC exploits overlapping and cross-talking networks for survival. These signaling networks are downstream from elevated activation of EGFR, integrins and Insulin-like growth factor 1 receptor (IGF1R).

Targeted molecular inhibitors of activated kinases in these pathways showed specificity against basal-like/TNBC cell lines compared to other subtypes in vitro. These activated kinases/networks represent druggable targets for the treatment of TNBC but may be limited by compensatory effect of the complex cross-talking signaling networks.

To overcome compensatory downstream signaling that would limit the inhibition of a given pathway; we developed EGFR-targeted radioimmunotherapy (RIT) strategy to systemically deliver cytotoxic loads of beta particles (177Lu) that would kill targeted cells and surrounding cells by crossfire effect. The combination of EGFR-directed RIT with chemotherapy and PARP inhibition successfully treated orthotopic and metastatic TNBC models established from cell lines and patient-derived xenografts. The superior efficacy of this triple-agent combination therapy is explained by enhanced DNA damage and reduced DNA repair response, higher apoptotic cell death and the elimination of putative breast cancer stem cells.

Conclusion: Proteomic analysis of TNBC provides a powerful tool to elucidate druggable signaling networks with therapeutic potential. TNBC utilizes complex interacting signaling networks and rational combination therapies are required for effective therapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-06.
Abstract P6-11-09: FAK Inhibitor VS-4718 Attenuates Breast Cancer Stem Cell Function In Vitro and In Vivo
Authors: Kolev VN , Vidal CM , Shapiro IM , Pavdal M , Keegan M , Xu Q , Pachter JA
Published: August 2014

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that mediates signal transduction by integrins as well as growth factor receptors. FAK has been implicated in multiple steps of carcinogenesis including tumor initiation, growth and metastasis. Amplification and overexpression of FAK have been observed in aggressive human cancers including breast cancer. We have now observed that VS-4718, a selective FAK kinase inhibitor, exhibits preferential inhibitory effects on breast cancer stem cells.

VS-4718 is a potent and selective FAK kinase inhibitor that blocks fibronectin-stimulated FAK autophosphorylation at Tyr397 at low nanomolar concentrations. To determine if FAK plays a role in the biology of breast cancer stem cells, VS-4718 was evaluated in a multitude of cancer stem cell assays both in vitro and in vivo. In parallel, treatment of SUM159 triple negative breast cancer cells in vitro with FAK shRNA inhibits tumorsphere formation. These data taken together indicate a role of FAK in breast cancer stem cell renewal. Similarly, pre-treatment of SUM159 cells with VS-4718 in matrigel attenuated secondary tumorsphere formation. Furthermore, VS-4718 reduced the side population (SP) and the percentage of ALDEFLUOR+ cancer stem cells in SUM159 breast cancer cells in vitro. In direct contrast, standard-of-care agent paclitaxel increased the percentage of ALDEFLUOR+ cancer stem cells in all three assays.

The in vivo effect of VS-4718 on cancer stem cells was evaluated in SUM159 and MDA-MB-231 human triple negative breast cancer xenograft models. Following systemic administration, VS-4718 induced significant reduction of cancer stem cells in tumors as assessed by a decrease in ALDEFLUOR+ cells and tumorsphere-forming efficiency relative to vehicle-treated tumors.

In summary, our results indicate the importance of FAK in the self-renewal of breast cancer stem cells in vitro and in vivo, and support the clinical development of the selective FAK inhibitor VS-4718 to target cancer stem cells for the treatment of triple negative breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-09.
Abstract P6-11-12: Nanoparticle-enhanced chemotherapeutics delivery in drug-resistant triple-negative breast cancer
Authors: van de Ven AL , Landis MD , Paskett LA , Meyn A , Frieboes HB , Chang JC , Ferrari M
Published: August 2014

Chemotherapeutics delivery is generally poor in tumors characterized by rapid perfusion and low blood volume fraction. Systemically administered nanoparticles can be engineered to overcome abnormal flow conditions to act as intravascular drug depots for the localized delivery of high concentrations of chemotherapeutics. The feasibility of this approach was first demonstrated using melanoma, and is now being further investigated using well-characterized human triple-negative breast cancer biopsies implanted into mice. Intravital microscopy studies of human cancer-in-mice selected for differing vascular morphologies have yielded intriguing preliminary data regarding the role of tumor vascularity in drug and particle delivery. The first-pass perfusion of a 40kDa dextran tracer revealed that BCM-2665 tumors are perfused ∼6x more rapidly than BCM-4195 tumors (11.3 ± 2.3s vs. 67.6 ± 11.0) and contain ∼30% lower volume fraction of blood (0.046 ± 0.011 vs. 0.062 ± 0.015). Interestingly, flow parameters that adversely impact drug accumulation appear to favor plateloid particle accumulation. BCM-2665 xenografts receiving an i.v. injection of 1000×400 nm particles show ∼10x more particle accumulation than BCM-4195 tumors (24.8 ± 3.2 × 103/mm3 vs. 3.5 ± 0.4 × 103/mm3). The ability of these therapeutic particles to reach tumors appears to be primarily driven by flow-related parameters, which we characterize using a combination of intravital microscopy, computed tomography, and mathematical modeling. The total number of particles accumulated within a given tumor appears to be largely driven by the number of particles entering the tumor, since ∼65–70% of entering plateloid particles are retained by the tumor vasculature. This suggests that cytotoxic intravascular drug depots may be a promising strategy for increasing the efficiency of chemotherapeutics delivery to drug-resistant tumors and is the premise of ongoing therapeutic response studies. Clearly if more drugs can be delivered to the tumors, better outcomes can be expected for the patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-12.
Abstract P6-12-02: Use of cytochrome P450 interacting medications in the setting of adjuvant therapy for breast cancer.
Authors: Njiaju UO , Kolesar JM , Johnston SA , Eickhoff JC , Osterby KR , Poggi LE , Tevaarwerk AJ , Millholland RJ , Oliver KA , Heideman JL , Wisinski KB
Published: August 2014

Background: In the current era of personalized medicine, oral targeted therapies are increasingly used in cancer treatment. In breast cancer, oral anti-estrogen agents have historically been part of standard treatment for hormone receptor positive disease. More recently, other targeted agents have been introduced in the metastatic setting, and are being evaluated as adjuvant therapies. Many oral medications, including anticancer therapies, are metabolized by cytochrome P450 (CYP450) enzymes raising possibility of drug-drug interactions that may affect toxicities or breast cancer outcomes. We sought to evaluate concomitant CYP450 medication use among women seeing a medical oncologist to discuss adjuvant systemic therapy for breast cancer.

Methods: We performed an electronic medical record database extraction. Adult women diagnosed with breast cancer from 1/2008-7/2011 were identified from the University of Wisconsin Hospital and Clinics Cancer Registry. Medication lists were extracted from the first encounter with a medical oncologist after the initial breast cancer diagnosis. Non-systemic medications were excluded. Cytochrome P450 (CYP450) enzyme-interacting medications were categorized as inhibitors, inducers, and/or substrates of specific enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers were further characterized as strong, moderate or weak acting.

Results: A total of 455 women with non-metastatic breast cancer were identified. Mean age was 56.6 years (range of 23–90) and 413 (91%) were Caucasian. Polypharmacy, defined as use of 3–5 medications, was seen in 123 (27.0%) women. A total of 236 (51.9%) women were on 0–4; 109 (24.0%) on 5–10; and 13 (2.9%) on > 10 medications at the time of first encounter with a medical oncologist after a breast cancer diagnosis. 23 (5.05%) women were on strong CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers. CYP450 enzymes most commonly affected were CYP3A4, CYP2C9, and CYP2D6. Among medications taken on a fixed schedule, levothyroxine and simvastatin were the most commonly used, while simvastatin and ranitidine were the most common CYP450 interacting medications. Further classification of potential CYP450 interactions is ongoing.

Conclusions: A significant proportion of patients were on one or more CYP450 interacting medications in the setting of adjuvant therapy for breast cancer. Given the number of new oral cancer agents that are also CYP450 interacting, the potential for drug interactions should be recognized and appropriate management strategies implemented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-12-02.
Abstract P6-13-01: Lyso-thermosensitive liposomal doxorubicin + local hyperthermia for radiation-pretreated chest wall recurrence
Authors: Formenti S , Rugo H , Myerson R , Diederich C , Straube W , O'Conner B , Matzkowitz AJ , Goodman RL , Muggia F
Published: August 2014

Background: Chest wall recurrence (CWR) causes much morbidity when not controlled by local measures. Lyso-thermosensitive liposomal doxorubicin (LTLD) provides accelerated release of doxorubicin (Dox) at ≥ 39° C, and is being studied for CWR based on the pioneering thermochemotherapy work of Dewhirst and colleagues at Duke. We now report on its tolerance, pharmacology, and preliminary antitumor effects in a dose-escalation study combined with local hyperthermia (LH) for radiation-refractory CWR. LH selectively increases liposomal permeability in tumor microvasculature, and promotes release of Dox from LTLD, and Dox tumor uptake, in addition to LH anti-tumor effects.

Methods: This phase I study entered patients (pts) with CWRs < 3 cm deep failing all standard Tx including surgery, radiation, and chemotherapy: pts received up to 6 LTLD/LH treatments every 21 days at a starting dose of 40 mg/m2 (cohort 1) and escalated to 50 mg/m2 (cohort 2). LTLD was infused IV over 30 minutes (min); followed within 30 min by microwave or ultrasound LH. The thermal dose goal was 40°C-42°C for 60 min. Pharmacokinetic samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and 24 hours after starting infusion. Left ventricular ejection fraction was monitored every other cycle.

Results: Eleven pts with a median of 4 prior chemotherapy regimens (range 2 — 12) were enrolled; all but one had prior anthracycline (AC). All pts received ≥ 2 cycles. The within subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 1 ratios ranging from 0.99 to 1.06.

Cmax/dose (ng/ml)/(mg/m2) Cycle 1 Cycle 2

Dox 499.82 512.00

Doxol 0.46 0.45

AUClast/dose ((ng*hr/ml)/(mg/m2)

Dox 1338.12 1381.82

Doxol 7.96 8.04

Grade 3 and 4 toxicities included reversible neutropenia in 17 (40.5%) and one case (each) of mucositis (grade 1), chest wall thermal burn, and chest wall cellulitis (both grade 4); these occurred in only ≥ 5% of 42 cycles given. No cardiomyopathy or hand-foot toxicity occurred. The rate of clinically-significant (≥ 6 point) QoL improvement on the FACT-B after 2 cycles was 54.5% (95% CI: 25.1%–83.9%), including 1 lasting > 3 months. The local objective response rate was encouraging: 45.5% (95% CI: 16.1%–74.9%), with 1 complete and 4 partial local responses.

Conclusion: LTLD + LH is safe in CWR after prior radiation and doxorubicin. A phase II study is planned for pharmacologic evaluations and to add pts with less or no anthracycline treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-01.