bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer
Authors: Park IH , Lee KS , Im S-A , Jung KH , Park KH , Im Y-H , Lee S , Kim YJ , Kim H-J , Lee S , Lee MH , Kim T-Y , Lee K-H , Kim S-B , Ahn J-H , Nam B-H , Ro J
Published: August 2014

Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC.

Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.
Abstract P1-01-02: The SentiMag study: Sentinel node biopsy with superparamagnetic iron oxide vs. radioisotope
Authors: Thill M , Kurylcio A , Blechmann R , van Haasteren V , Grosse B , Berclaz G , Polkowski W , Hauser N
Published: August 2014

Background:

The SentiMag study compares the “gold standard” 99mTc with a new technique, which employs superparamagnetic iron oxide particles (SPIO) for localization of sentinel lymph nodes. Aim of this study is to investigate the potential equivalency of the SentiMag® technique in comparison to the gold standard of sentinel lymph node biopsy (SLNB).

Materials and methods:

In a prospective, multicentre and multinational 2-arm study, 150 patients with histologically verified breast carcinoma are examined. For comparison, SLNs are marked initially with radioisotope following a 1- or 2-day protocol. Additionally, SPIO (Sienna+®) is injected in the operation room by the surgeon at least 20 minutes before SLNB into the subareolar interstitial tissue, followed by 5 minutes massage. SLN-detection is carried out using a magnetometer (SentiMag®) and a gamma probe. Preparation and excision of lymph nodes is conducted using both techniques in a parallel manner. All lymph nodes marked with either tracer are excised.

Results:

Interim analysis of 138 patients resulted in a detection rate concordance per patient of 97% (134/138). An average of 1.9 (radioisotope) and 2.0 (SPIO) lymph nodes were collected per patient. Nodal detection rate was 92% (250/273) for the radioisotope vs. 97% (265/273) for the SPIO tracer with magnetometer detection. The proportion of pathologically positive lymph nodes was 38/250 (15%) vs. 39/265 (15%) for the radioisotope and the SPIO tracer respectively. All pathologically positive lymph nodes detected with the conventional technique (radioisotope) were also detected with the new technique (SentiMag®).

Conclusions:

The SentiMag® provides an easy technique which can be rapidly implemented into daily routine. Due to the simple handling, preoperative efforts can be reduced to a minimum. If further and consistent results prove its efficacy, this technique may ultimately replace the standard of care.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-02.
Abstract P1-02-02: Concordance of microarray based determination of ER, PR and HER2 receptor status and local IHC/FISH assessment in the prospective neo-adjuvant breast registry symphony trial (NBRST)
Authors: Beitsch P , Gittleman M , Akbari S , Stork-Sloots L , de Snoo F , Gibson J , Whitworth P
Published: August 2014

Background

The level of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression is predictive for prognosis and/or treatment response in breast cancer patients. However, differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of the results. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2. Previously TargetPrint was shown to be strongly correlated with high quality IHC/FISH assessment, especially for ER and HER2. Concordance rates were 98% (k = 0.90) for ER; 85% (k = 0.62) for PR and 96% for HER2 (k = 0.78) in 619 patients (Viale et al., SABCS 2011).

This study compares results from the microarray-based TargetPrint with IHC and FISH conducted according to local standard procedures in the prospective NBRST study.

Methods

The NBRST study includes women aged 18–90 with histologically proven breast cancer, who are scheduled to start neo-adjuvant chemotherapy (CT) or neo-adjuvant endocrine therapy (ET), and who provide written informed consent. The mRNA level of ER, PR and HER2 (TargetPrint) was assessed at the Agendia laboratory (Agendia Inc, Irvine, CA) in fresh and formalin fixed paraffin embedded tumor samples submitted from 40 institutes in the US. The results of the IHC/FISH assessments conducted according to local standard procedures were compared to the quantitative gene expression readouts.

Results

There were 355 eligible patients enrolled. 67% of patients are IHC ER positive and 25% Her2 IHC/FISH positive. 11 patients were IHC/FISH HER2 equivocal (all TargetPrint HER2 negative). Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 88% (k = 0.75)for ER; 83% (k = 0.66) for PR and 89% (k = 0.70) for HER2. The discordance range for institutes who submitted more than 10 samples was 0-30% for ER, 0-47% for PR and 0-28% for HER2. 16% of all IHC ER+ samples were classified negative by microarray. In contrast, 4% of IHC ER- samples were classified positive by microarray. However for HER2, as many as 33% of IHC/FISH HER2+ samples were classified negative by microarray; 3% of IHC/FISH HER2- samples were classified positive by microarray.

Conclusions

Microarray based readout of ER, PR and HER2 status using TargetPrint is comparable to local IHC and FISH analysis in 355 analyzed samples from 40 US institutes but the discordance range for individual institutes was up to 30% for ER and 28% for Her2.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-02.
Abstract P1-05-01: Characterization of human postpartum breast involution: Implications for young women’s breast cancer
Authors: Borges VF , Jindal S , Gao D , Bell P , Edgerton SM , Ambrosone CB , Thor AD , Schedin P
Published: August 2014

Introduction: Women diagnosed with breast cancer within 5 years postpartum have poor outcomes. In rodents, postpartum mammary gland involution promotes tumor progression and metastasis, implicating breast involution in the poor prognosis of breast cancers diagnosed in postpartum women. Rodent mammary gland involution is characterized by wound healing programs that include epithelial cell death, immune cell infiltrate, and fibrillar collagen deposition; all attributes associated with breast cancer progression. Thus, the gland remodeling of postpartum involution may provide a plausible explanation for how postpartum breast involution promotes breast cancer. Here, we characterize human breast tissue across pregnancy, lactation, and the postpartum time-period to determine if remodeling of the secretory competent breast to a quiescent state involves loss of secretory lobules, and whether involution is mediated by wound healing-like programs.

Methods: Adjacent normal breast tissues from pre-menopausal women (n = 140), aged 20-45 years, were grouped by reproductive categories of never-been-pregnant (NBP), pregnant, lactating, and by time since last delivery, and evaluated histologically and by special stain for epithelial area, lobular subtype composition, apoptosis, immune cell infiltration, and collagen deposition, using computer assisted quantitative methods. Statistical comparisons between multiple categories were done using one way ANOVA.

Results: Dramatic increases in breast epithelial area and lobule differentiation were observed, with 5-8 fold increases for pregnancy and 10-13 fold for lactation, over nulliparous controls. By 12 months postpartum, epithelial content and lobular differentiation were indistinguishable from nulliparous controls, consistent with complete regression of the lobular structures developed in preparation for lactation. Analyses of apoptosis, immune cell infiltration, and collagen deposition confirmed human postpartum breast involution is characterized by wound healing-like, tissue remodeling programs.

Conclusion: Human postpartum breast involution is a dominant tissue-remodeling process that returns the gland to a morphological state largely indistinguishable from the never-been-pregnant gland. Further, involution occurs within a defined window of time. Our data implicate postpartum breast involution as window of risk for breast cancer progression and suggest a rational window for intervention.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-01.
Abstract P1-05-02: COX-2 expression in normal mammary epithelium is estrogen responsive and predicts expression in DCIS and invasive ductal carcinoma
Authors: Schedin P , Fornetti J , Jindal S , Borges V
Published: August 2014

Background: Cyclooxygenase-2 (COX-2) overexpression is implicated in the poor prognosis of young women's breast cancer. Understanding the regulation of COX-2 expression in normal premenopausal breast tissue and its relationship to malignancy is anticipated to provide insight into COX-2 as a potential therapeutic target for young breast cancer patients.

Methods: To investigate COX-2 regulation and expression, quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 83 premenopausal women with known clinical reproductive histories as well as on rat mammary glands with distinct estradiol and progesterone exposures. To determine the stability of COX-2 expression over time, a small cohort of women with serial breast biopsies 2-3 weeks apart was evaluated.

Results: COX-2 expression in normal adjacent breast tissue was predominantly epithelial, varied >40-fold between individual women, and was independent of proximity to tumor and tumor biology. COX-2 upregulation occurred in alveoli during pregnancy and with estradiol and progesterone exposure in the rat. Though these data demonstrate ovarian hormone regulation, COX-2 expression was relatively stable for each individual premenopausal woman over a 2-3 week assessment window. Furthermore, COX-2 expression levels in normal epithelium independently predicted COX-2 expression levels in tumors.

Conclusions: COX-2 expression in the adjacent normal breast epithelium is highly variable across premenopausal women, and may be further modified by ovarian hormone exposure. Moreover, COX-2 expression in the normal breast independently predicts COX-2 expression in tumors, implicating women with high COX-2 expression in the normal breast epithelium as high risk patients who may benefit from COX-2 inhibitor therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-02.
Abstract P1-06-12: The therapeutic sensitivity of ER+/Her2+ breast cancer cells is attenuated in 3D matrix culture and involves switching from AKT to MAPK pathways
Authors: Gangadhara S , Smith C , Gee J , Nicholson R , Barrett-Lee P , Hiscox S
Published: August 2014

Increasing evidence points to interplay between a tumour and components of its microenvironment as a significant determinant of therapeutic sensitivity and response. Thus, a better understanding of this phenomenon is crucial for the development of more effective treatment strategies. Around half of HER2+ breast cancers express the ER. Despite the effectiveness of endocrine and HER2-targeted therapies for such tumours in pre-clinical, two-dimensional models, response can be variable clinically. Here we have investigated the impact of 3D culture within an extracellular matrix on the signaling pathway activity and therapeutic response to trastuzumab and endocrine (tamoxifen and fulvestrant) treatment of ER+/Her2+ breast cancer cell models.

ER+/Her2+ BT474 and MDAMB361 cells were grown as 2D monolayers or as 3D cultures in Matrigel and their proliferative response to trastuzumab (0-100nM) and endocrine (tamoxifen or fulvestrant, 0-100nM) mono- and combination therapy assessed using coulter counting and immunocytochemical staining of the proliferation antigen, Ki67. A comparison of signaling pathway activation in 2D versus 3D culture, and in response to treatment in these contexts, was investigated using Western blotting.

Whilst culture of both cell lines in 3D matrices did not significantly affect their endogenous growth rate, 3D culture resulted in a significant loss of PI3K/AKT pathway activity in both cell lines and augmented (BT474) MAPK signaling. The growth inhibitory effects of both trastuzumab and endocrine treatment, either as single agents or in combination, were significantly attenuated in 3D cultures when compared with 2D cultures (% growth inhibition ± sem: 65%±3.8 (3D) vs. 82%±1.3 (2D), p<0.01 [BT474+trastuzumab], 34%±6.4 (3D) vs. 56%±2.2 (2D), p<0.02 [BT474+tamoxifen], and 51%±0.88 (3D) vs. 70%±0.48 (2D), p<0.0001 [MDAMB361+tamoxifen], 53%±7.2 (3D) vs. 77%±0.60 (2D), p<0.02 [MDAMB361+fulvestrant]). Similar effects were observed in Ki67 levels, with a greater suppression of Ki67 in 2D versus 3D culture in response to treatments. Trastuzumab and endocrine treatments, either as monotherapies or in combination, suppressed MAPK signaling in 2D monolayers in contrast to 3D culture, where MAPK activity was maintained (BT474) or augmented (MDAMB361). Consequently, inhibition of MAPK signaling using U0126 in 3D cultures significantly improved trastuzumab and endocrine response in these cells.

These data demonstrate that ER+/Her2+ breast cancer cells significantly alter their signaling pathway activity when cultured in a 3D, matrix-enriched environment, which may in turn act to limit response to a range of endocrine and targeted therapies. Targeting of such adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-12.
Abstract P1-06-13: Periostin controls cytokine production to maintain breast cancer stem cells
Authors: Lambert AW , Ozturk S , Papageorgis P , Abdolmaleky H , Thiagalingam S
Published: August 2014

Recent evidence suggests that the molecular heterogeneity inherent to breast cancer, which underlies metastasis, resistance to treatment and disease recurrence, can be driven by a distinct subpopulation of tumor cells referred to as cancer stem cells (CSCs). Basal-like breast cancer represents a particularly aggressive disease subtype and the tumor cells share phenotypic similarities to breast cancer stem cells. However, the extracellular cues and intracellular pathways that CSCs rely on remain unclear. Working with a breast cancer progression model system we found the invasive breast cancer cell line to exhibit numerous stem-like characteristics. Gene expression profiling, along with a careful review of the literature, identified a secreted extracellular matrix molecule, periostin (POSTN), which we hypothesized to be required for the maintenance of a cancer stem cell state. POSTN expression was increased in numerous basal-like breast cancer cell lines, as well as in cells grown as mammospheres and in the CD44+/CD24- fraction of tumor cells. Furthermore, CSC-like lines displayed increased surface levels of the integrin alpha-v beta-3 heterodimer, a known receptor for POSTN, suggesting that hyperactivation of a POSTN signaling axis could potentially regulate the CSC state. Using stable cell lines expressing an shRNA directed at POSTN or ITGB3 we have found that POSTN signaling is required for efficient mammosphere formation and for the maintenance of an ALDH-positive CSC population. Disruption of this signaling axis resulted in decreased production of cytokines, including IL-6 and IL-8 - known regulators of CSCs - as well as downstream STAT3 signaling. Furthermore, high POSTN expression is associated with a worse clinical prognosis in ER-negative breast cancer. Therefore, we suggest that POSTN signaling through integrin receptors may enrich for highly tumorigenic breast CSCs in a subset of basal-like tumors, leading to aggressive and recurrent malignancies. This reveals a previously unknown link between POSTN signaling and cytokine production, and suggests that basal-like cancers can establish a microenvironmental niche supportive of cancer stem cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-13.
Abstract P1-08-09: EGFR expression is associated with decreased response from HER2 targeted therapeutics in the neo-adjuvant setting in the NeoALTTO trial
Authors: Rimm DL , Holmes E , Schalper K , Bradbury I , Zarrella E , Ellis C , Baselga J , Eidtmann H , Piccart M , Harbeck N , Pusztai L , Perez E
Published: August 2014

Background: Epidermal Growth Factor Receptor (EGFR, HER1) is known to heterodimerize with HER2 and may modulate the effectiveness of trastuzumab or lapatinib. Historically, it has been difficult to measure, but recently we reported a new, standardized, quantitative immunofluorescence assay and a novel EGFR antibody which showed that high levels of EGFR were associated with decreased benefit in the concurrent arm of the North Central Cancer Treatment Group (NCCTG/Alliance) N9831 trial (Rimm et al, SABCS 2012). Here we assess its value in the neo-adjuvant setting in the NeoALTTO trial.

Methods: NeoALTTO randomized 455 breast cancer patients to neoadjuvant trastuzumab, lapatinib or both and showed benefit in both single anti-HER2 therapy arms, and the combination therapy showing about twice as much benefit as either single drug arm. We used the previously described AQUA method of quantitative immunofluorescence to measure EGFR levels using the D38B1 antibody on between 4 and 140 fields of view per slide on 353 specimens. The averaged EGFR score was standardized to the absolute concentration using cell lines and western blots and the 13 ng/ug total protein established in the N9831 trial was tested to determine predictive value for pathological complete response (pCR) defined as ypT0/is.

Results: In NeoALTTO, 19% of the patients had EGFR levels above 13 ng/ug, compared to 16% in NCCTG N9831. The pCR rate was 35.3% in the patients with low EGFR, compared with 29.8% for high EGFR but this difference was not statistically significant. However, when adjusted for treatment and hormone receptor (HR) status, high EGFR is statistically significantly associated with lower response rate(p = 0.038). Continuous analysis measures were not significant. The effect on overall response at 6 weeks was also weakly significant when adjusting for treatment and HR status (p = 0.06). Surprisingly, for HR negative patients in the lapatinib only arm, the pCR rate in the low EGFR group was 47.2% compared with 16.0% in the high group. While this difference is statistically significant (p = 0.014), it should be interpreted cautiously because of the small numbers of patients and the multiple tests performed.

Conclusions: High expression of EGFR by the AQUA platform appears to be associated with decreased pCR rate from HER2 targeted therapy in the neoadjuvant setting. This observation is consistent with NCCTG N9831. Although underpowered, high EGFR levels predicted decreased pCR rate from lapatinib, the opposite of that anticipated for this small molecule dual EGFR/HER2 inhibitor. Further studies are required to determine the clinical utility of this assay and the biological mechanisms underlying these observations.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-09.
Abstract P1-08-17: Impact of claudin-3 and basal-markers expressions on pathological complete response to neoadjuvant chemotherapy and prognosis in triple negative breast cancer
Authors: Nogi H , Kamio M , Kato K , Toriumi Y , Suzuki M , Uchida K , Takeyama H
Published: August 2014

Background

Triple negative breast cancer (TNBC) has responded well in the neoadjuvant setting, with rates of pathologic complete response (pCR) commonly higher than for other breast tumor types. However, more than half of TNBC patients do not achieve a pCR and have a very poor prognosis. Cluster analysis identified 6 TNBC subtypes displaying unique gene expression, including basal-like and a mesenchymal stem-like (claudin-low) subtype. The object of this study was to evaluate the clinical utility of claudin-3 and basal-markers expressions in the prediction of pCR and prognosis in a cohort of breast cancer patients receiving the combination of taxane and anthracycline as neoadjuvant chemotherapy.

Materials and Methods

A prospective data base of 412 Japanese women with stage I/II/III breast cancer who received neoadjuvant chemotherapy was analyzed. The regimens were 6 cycles of concurrent administration of doxorubicin (50 mg/m2) and docetaxel (60 mg/m2) or 4 cycles of epirubicin (100 mg/m2), 5-fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). We performed immunohistochemical staining for ER, PgR, HER2, epidermal growth factor receptor (EGFR), cytokeratin 5/6 and claudin-3 using specimens obtained at diagnosis by core needle biopsy. Based on immunoreactivity, TNBC tumors were classified into basal/claudin-high (BCH), basal/claudin-low (BCL), non-basal/claudin-high (NBCH) and non-basal/claudin-low (NBCL).

Results

The overall pCR of this patient cohort was 19%. pCR was observed 30 cases of 84 TNBC (36%) and 50 cases of 328 non-TNBC (15%)(p<0.0001). Among the TNBC tumors, pCR rate was significantly different between subgroups. BCH 50%, BCL 23%, NBCH 83% and NBCL 43% (p = 0.039). The 5-year overall survival rate was significantly different between TNBC and non-TNBC. TNBC 81% and non-TNBC 94% (p = 0.0017). The 5-year overall survival rate was different between triple-negative subgroups. BCH 92%, BCL 78%, NBCH 83% and NBCL 46%.

Conclusions

This study indicated that claudin-3 and basal-markers might be predictive biomarkers of pCR and prognosis in triple negative breast cancer patients treated with neoadjuvant chemotherapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-17.
Abstract P1-08-21: Detection and monitoring of circulating endothelial cells, circulating tumor cells and disseminated tumor cells during neoadjuvant breast cancer treatment including bevacizumab
Authors: Mathiesen RR , Borgen E , Sætersdal AB , Fangberget A , Schirmer C , Stav I , Fagerland MW , Wist E , Engebråten O , Naume B
Published: August 2014

Background: Results from studies with bevacizumab in addition to traditional neoadjuvant therapy (NAT) indicate a need for predictive biomarkers. As a sub-study of the NeoAva study (a neoadjuvant study), the aim was to investigate the potential association between the presence of circulating endothelial cells (CECs) in peripheral blood (PB), circulating tumor cells (CTCs) in PB and disseminated tumor cells (DTCs) in bone marrow (BM) at different time points during NAT +/- bevacizumab and at one year follow-up, and therapy response.

Patients and methods: A total of 150 HER2-negative patients with cT2-4 (≥ 2.5cm) N0-3 M0 status were randomized to receive NAT with or without bevacizumab. In this sub-study, 90 patients have so far been analyzed. Of these, 82 received chemotherapy (FEC100→taxane) and 8 received endocrine therapy (letrozole) + / - bevacizumab. Therapy response was evaluated according to the RECIST criteria and achievement of pathological complete response (pCR). Number of CECs, CTCs and DTCs were assessed at baseline after 12 weeks, at surgery (after 24 weeks) and at one year follow-up. Blood samples were analyzed by CellSearch® to assess CEC and CTC counts. The detection of DTCs was performed by immunocytochemical analysis of 2 × 106 BM mononuclear cells.

Results: The pathological complete response rate was 10 out of 90 (11.1%), eight of these patients received bevacizumab. For bevacizumab-treated patients with a change in CEC counts from baseline to time of surgery below median change (27 CECs), 35% (6/17) achieved pCR compared to 6% (1/18) in the group with a CEC count-increase above median change (p = 0.035). The corresponding pCR rates for patients not receiving bevacizumab (median CEC change 131 CECs) were 0% (0/15) and 13% (2/14), respectively. Stepwise testing of thresholds for CEC changes in the bevacizumab-arm revealed significant associations to pCR for change-values between 20 and 40. CTC- and DTC-status or -changes were not associated with tumor response or CEC changes.

Conclusion:

The presented results indicate that the level of change in the number of circulating endothelial cells during neoadjuvant therapy including bevacizumab is associated with the pathological complete response rate in breast cancer patients. This supports additional testing of CECs as a surrogate marker for response to this treatment. The analyses will be up-dated with results from the rest of the included patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-21.
Abstract P1-09-08: Breast cancer (BC) outcomes after implementation of “Seguro popular” at the National Institute of Medical Sciences and Nutrition, Salvador Zubiran (INCMNSZ) in Mexico
Authors: Castro Sánchez A , Meneses Medina MI , Chávarri Guerra Y , Pérez Álvarez SI , León Rodríguez E , Armengol Alonso A
Published: August 2014

Background: In Mexico 60% of newly diagnosed BC patients present with locally advanced disease. In the United States, 88-95% of patients present with early stage disease, however in Mexico, only 10% of patients are diagnosed at this stage. The Seguro Popular (SP), a national insurance scheme for Mexico's poor and uninsured population, was implemented for BC in 2007. The SP covers diagnostics, local and systemic treatment for BC patients. The INCMNSZ is a third level hospital where patients receive diagnosis and treatment for non-malignant diseases, and also routinely conducts BC annual mammography screening for women ≥ 50 years old. We aimed to evaluate BC outcomes in our patients following the implementation of SP at our institution.

Methods: From January 2011 to May 2013, we prospectively evaluated a cohort of 93 patients with BC included in the SP program at the INCMNSZ. A retrospective cohort of 99 patients without SP access who received neoadjuvant chemotherapy from January 2007 to December 2009 was used for comparative analysis. Complete pathologic response (pCR) was defined as complete absence of invasive tumor in breast and axillary nodes. We used Fisher's exact test to compare pCR between groups.

Results: A total of 93 patients were diagnosed with BC and included in the SP program. 10 patients were excluded from the analysis- (5 were lost to follow-up and 5 had missing data. Median age was 52 (46-59) years and 37 patients (45%) were premenopausal at diagnosis), median follow up 11.8 months. 20 patients (24%) had stage I, 36 (43%) stage II, 7 (8%) stage III, and 20 (24%) stage IV. 55 (66%) patients had hormone receptor (HR) positive (ER + and/or PR+), 15 (18%) HER2+ and 13 (16%) had triple negative (TN) tumors. Thirty-two (39%) patients received neoadjuvant chemotherapy. 27% of patients achieved pCR (17% in HR positive, 20% in TN and 50% in HER2+ tumors) compared to 15% in the non SP cohort (11% in HR positive, 22% in TN and 14% in HER2+ tumors). HER2+ tumors from the SP cohort reached significantly higher pCR rates than in the non SP cohort (p = 0.029).

Discussion: Our results confirmed that about half of our patients were diagnosed with early stage BC, which highlights the importance of a screening program at our institution. Increased pCRs in the HER2+ subgroup may reflect wider access to trastuzumab after implementation of SP. Although we acknowledge a short period of follow-up in our cohort, our results in pCR are comparable to those previously reported in the literature. We believe the SP had a positive impact on access to care and outcomes in our patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-08.
Abstract P1-09-11: Can patient navigation help overcome barriers to breast cancer treatment in patients with health care disparities?
Authors: Elrafei T , Castaldi M , Shaker A , Stanise T , Gralla R , Matquez M , Bodner W , Reed L , Strakhan M , Alexis K
Published: August 2014

Background: Patient navigation has been demonstrated to aid in adherence to breast cancer screening initiatives. Fewer studies have documented benefit for patients undergoing treatment, and especially among those with barriers to care. Cancer health disparities affecting low-income and minority patients are well documented. Causes of poor outcomes include treatment delays coupled with social and financial barriers. This report examines the impact of patient navigation on adherence to prescribed cancer treatment, including in patients receiving treatment in adjuvant and metastatic breast cancer settings.

Methods: This Patient Navigation project (supported by an Avon Foundation grant) was initiated at our public safety net hospital to test whether there was sufficient benefit to warrant a larger randomized trial. Health care coverage included 58% Medicaid, 7% uninsured or undocumented. This study was conducted over a 4 month period with new medical oncology practice patients. Those deemed to be at high risk for non-adherence received navigated care. Navigator duties included care coordination, appointment reminders, patient education materials, translation services, and transportation arrangement. Data collected prospectively included patient characteristics, cancer type, time from referral to first RT, and compliance with visits; this was compared with usual care controls during the 4 month period.

Results: Patient Navigation Program patient characteristics: N = 52 patients (42% breast cancer, 12% prostate cancer, 10% lung cancer and 36% with other cancers). Mean age = 55; 48% Black, 38% Hispanic, 8% Asian, 6% White. The table below gives the results of percentage of adherence to visits (and time to first RT) for all patients in the study receiving navigated care, for just the patients with breast cancer receiving navigated care, and for the usual care control (no navigated care).

Table 1. NAVIGATED CARE: ALL PATIENTS (N = 52)NAVIGATED CARE: BREAST CANCER (n = 22)USUAL CARE GROUPPhysician Visits (Medical Oncology)(141 Visits) 90% (95% CI: 84%-95%)(56 Visits) 91% (95% CI: 80%-97%)(2021 Visits) 79% (95% CI: 77%-81%)Chemotherapy Treatment(107 Treatments) 95% (95% CI: 89%-99%)(30 Treatments) 97% (95% CI: 83%-99%)(1656 Treatments) 86% (95% CI: 84%-88%)Time to first RT32 Days (n = 25)35 Days (n = 8)30 Days

Conclusions: This Patient Navigation Program is associated with observed improvements in adherence to chemotherapy and in follow up physician visits. No impact on time to first RT was shown. These results document that a Patient Navigation Program can help overcome barriers to good cancer care.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-11.
Abstract P1-09-12: The interplay of biologic factors, race, and delivery of care in improving breast cancer outcomes
Authors: Weber JJ , Kachare SD , Vohra NA , Fitzgerald TF , Wong JH
Published: August 2014

Importance: A marked disparity exists in the breast cancer mortality of women diagnosed in Eastern North Carolina (ENC) when compared to women diagnosed in the rest of North Carolina (RNC).

Objective: To identify modifiable factors associated with the increased mortality of women diagnosed with breast cancer in ENC.

Design: Retrospective cohort study of women diagnosed with breast cancer in North Carolina between January 1, 2004 and December 31, 2007.

Setting: North Carolina Central Cancer Registry.

Participants: Females diagnosed with either invasive or non-invasive breast cancer in North Carolina during the designated time period.

Main Outcome Measures: Race/ethnicity, hormone receptor status, pathologic T, N and stage grouping at the time of diagnosis, delivery of adjuvant chemotherapy, and survival.

Results: A total of 27,631 women were diagnosed with breast cancer during the study period. Women in ENC were slightly older than in RNC (59.2 y v. 58.5 y, p<0.001). There was no difference in the pathologic T (p = 0.62), N (p = 0.26) or Stage Grouping (p = 0.25) at diagnosis between ENC and RNC patients. Women in ENC were less likely to be White (68.9% v. 80.0%, <0.001)), ER positive (53.4% v. 59.4%, p<0.001), PR positive (44.8% v. 49.4%, p<0.001), or to receive adjuvant chemotherapy (78.7% v. 81.3%, p = 0.02). The median survival of ENC patients was significantly worse than RNC patients (39 months v. 43 months, p = 0.003). By univariate analysis, improved median survival was associated with ER status (p<0.001), PR status (p<0.001), Race/ethnicity (p<0.001) and delivery of timely chemotherapy (p<0.0001). By Cox Regression analysis, ER negative status (RR 1.03; 95% CI 0.85 to 0.98, p = 0.01), African American (RR 0.94; 95% CI 0.89 to 0.99, p = 0.03), and adjuvant chemotherapy within 90 days of surgery (RR 1.40; 95% CI 1.30 to 1.50, p<0.001) remained significant predictors of survival.

Conclusions: The poor outcomes observed in ENC can be attributed to recognized prognostic primary patient and tumor characteristics. However a failure in process of care remains significantly associated with poorer outcomes. Improved timing of delivery of chemotherapy could affect breast cancer mortality.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-12.
Abstract P1-13-01: Risk of recurrence following 5 years of adjuvant hormone therapy for hormone receptor positive early breast cancer.
Authors: Lohrisch C , Speers C , Chia S , Kennecke H , Ellard S , Tyldesley S
Published: August 2014

Background

Introduction

The MA.17 study and combined analysis of the ATLAS and aTTom studies provide evidence of DFS and modest OS benefit from 10 years of hormone therapy (HT) for hormone receptor positive early breast cancer. The benefit may be less for women diagnosed today, due to advances in chemotherapy, initial HT, and radiation therapy since the era when these trials were conducted. Side effects accrue to all users of longer HT while benefit is experienced only by those who avoid recurrence, which is related to the baseline prognostic factors such as stage, grade, and disease biology.

Methods

To enhance informed patient-physician discussions, starting with a cohort of 10815 stage I-III hormone receptor breast cancer diagnoses between 1989 and 2004, we examined event-free survival (EFS) in years 5 to 10 among 1,061 premenopausal (<45 years at diagnosis) and 6,615 menopausal (≥50 years at diagnosis) women without documented relapse, CLBC, or death within the first 5 years. All patients were referred to the BC Cancer Agency (BCCA) with newly diagnosed disease, and all patients had adjuvant HT. EFS was defined as freedom from recurrence, from CLBC, or from breast cancer death without prior documented recurrence.

Results

Median follow up for the 7676 patients is 11 years. Event rates (including CLBC) in the second 5 years from diagnosis for stage I, II and III cancers were 6%, 12%, 23% for the pre-menopausal cohort, and 5%, 14%, 26% for the post-menopausal cohort. EFS in years 5-10 varied significantly by grade as shown below:

EFS years 5-10 after ER+ early Breast CancerStage, gradeAge 45 and younger at diagnosisAge 50 and older at diagnosis NEvents% EFS years 5-10 (95% CI)NEvents% EFS years 5-10 (95% CI)I, grade 1110698.2 (92.9,99.5)10375795.4 (93.7,96.6)I, grade 21741692.1 (86.7,95.3)133811194.6 (93.1,95.7)I, grade 368593.4 (83.2,97.5)3642994.8 (91.8,96.8)II, grade 174889.6 (78.0,95.3)6056193.0 (90.5,94.9)II, grade 22905186.3 (81.6,89.9)177330786.6 (84.8,88.2)II, grade 32103090.4 (85.4,93.8)82318781.9 (78.9,84.5)III, grade 160100531175.6 (59.6,86.0)III, grade 2591574.3 (60.6,84.1)2526774.3 (67.8,79.8)III, grade 3521178.0 (62.1, 87.9)1504072.0 (62.8,79.3)CI, confidence Intervals

Recurrences (excluding CLBC) after 10 years was 2% for the 10815 cases (representing 12% of all recurrences).

Conclusion

These data suggest that pre and postmenopausal women with stage I cancers of any grade, and postmenopausal women with stage II grade 1 cancers who have not experienced a relapse in the first five years can expect a less than 10% risk of recurrence, breast cancer death, or CLBC without further HT over the next 5 years. Prolonged HT in the identified groups may result in higher probability of harm than benefit and may best be avoided, although long term data will be needed to fully inform this risk benefit analysis.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-01.
Abstract P1-13-15: Risk of late recurrence of hormone receptor positive breast cancer in cases with no recurrent disease at five years after surgery
Authors: Ohno S , Koui Y , Oikawa M , Akiyoshi S , Koga C , Igawa A , Saruwatari A , Nishimura S , Nakamura Y , Taguchi K , Ishida M
Published: August 2014

Background: Among women who take 2-5 years of adjuvant endocrine therapy, more than half of all recurrences of hormone receptor (HR) positive breast cancer occur after the first 5 years. Data from large clinical trials including ATLAS, aTTom,MA17 and NSABP B-30 support extending tamoxifen or aromatase inhibitor beyond 5 year for women with HR positive breast cancer. For decision making according to extending endocrine therapy, the information of the risk of late recurrence is quietly important.

Patients and methods: In order to determine ten year disease free survival (DFS) rates, we reviewed medical records and database of patients who were treated at National Kyushu Cancer Center between 1990 and 2001. Among seven hundred fifty seven patients with HR positive breast cancer, 550 received tamoxifen for 2-5 years. Eighty eight patients had recurrence within five years after surgery, and 13 were not followed, with 83.5% of 5-year DFS after surgery. Remaining four hundred twenty six had no recurrence at the time of 5 years after surgery. To evaluate the risk of late recurrence, we analyzed the long-term results in association with clinicopathological factors for these 426 patients.

Results: Four hundred twenty six patients had 87.1% of 10-year DFS rate. According to lymph node metastasis (N), ten year DFS rates were 91.4% for 275 N-negative and 80.0% for 155 N-positive cases (P = 0.0037). As for the number of lymph node metastasis, 10-year DFS rates were 82.5%, 74.2%, and 79.1% for N1-3, N4-9, N>9, respectively. Tumor size was correlated with the prognosis, and 10-year DFS rates were 91.5% for 167 T1 (≤2 cm), 86.9% for T2 (2-5 cm), and 67.9% for T3 (>5cm) (P = 0.0334). There were no significant differences between grade and prognosis, and 10-year DFS rates of grade 1, 2 and 3 were 88.9%, 89.8%, and 96.8%, respectively (p = 0.3914). Considering the age at 5 years after surgery, no significant differences were observed as for late recurrence. Ten-year DFS rates of 96 cases of age under 50, 227 between 50 and 65, 113 over 65 was 89.4%, 85.1%, and 86.0%, respectively. Ten-year DFS rates of N-negative and N-positive were 94.3% and 81.2%, 88.1% and 80.1%, and 90.4% and 76.7% for these age criteria, respectively.

Conclusion: Patients with HR positive breast cancer require optimal information for decision making whether to receive extending endocrine therapy or not. Our data demonstrated the risk of late recurrence in relation to clinic-pathological factors, which may support the consideration about extending endocrine therapy. Relatively high risks of late recurrence with over 10% of 10 year DFS rates are there in cases with N-positive or T2-3 HR positive breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-15.
Abstract P2-02-01: Did established clinical practice regarding MRI bias the COMICE trial?
Authors: McMahon MA , Sharma N , Shaaban A , Dall BJG
Published: August 2014

Introduction: The negative COMICE study and reports of inappropriate mastectomies worldwide have served to discredit the use of preoperative MRI for the purpose of aiding conservative breast surgery. We postulate that established clinical practice regarding MRI at the time of the COMICE trial lead to bias in case selection, with more complicated cases being preselected out prior to randomisation. We reviewed the local practice at the time of COMICE.

Methods and materials: Retrospective analysis of all cases of Breast MRI performed to assess disease extent pre-operatively during recruitment to COMICE (December 2001 - January 2007) was undertaken. Size on mammogram/ultrasound, MRI and histology was documented. As pre-PAC's era, the information was obtained from imaging and pathology reports. Where reports did not include distance between lesions in multifocal/multicentric disease, the sum of the lesions was used (taken as immediately adjacent) so as not to overestimate the size. All cases were reviewed blinded to COMICE status. Cases with mammogram/ultrasound size >/ = 40mm were excluded as these were deemed unsuitable for conservative surgery.

Results: A total of 318 breast MRI examinations were performed in this interval to assess disease extent pre-operatively of which, 81 were excluded appropriately, for inadequate information (n = 47), size on conventional imaging >/ = 40mm (n = 18), receiving neo-adjuvant treatment (n = 6), non cancer diagnosis (n = 7) and non invasive disease (n = 3). 242 cancers from 237 patients were included comprising 77COMICE and 160NON-COMICE patients. Statistical difference was noted in the types of surgery between the groups, p<0.001. Re-excision rates were similar: COMICE = 11.7% and NON-COMICE = 8%. Mastectomy rates were however different, 15.6% of the COMICE group and 42% of the NON-COMICE group.

There was a significant difference in histological size between the 2 groups, mean size in NON-COMICE cases 32mm versus 26mm in the COMICE group (p = 0.009). There was a significant difference in the tumour types between the 2 groups (p<0.001). Notably 37% of cases in the NON-COMICE group were of lobular type compared to 13% of the COMICE group.

Conclusion: Data from this well established MRI unit has demonstrated clinical bias in the COMICE trial with more complicated cases, which benefited from MRI, being pre-selected out prior to randomisation which understated the value of MRI. MRI in appropriately selected patients in conjunction with modern oncoplastic surgical techniques will increase the opportunities for conservative surgery rather than increase mastectomy rates. An aggressive biopsy policy for MRI detected lesions is required to avoid inappropriate mastectomies.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-02-01.
Abstract P2-02-08: MRI in predicting pathological response of breast cancer after neoadjuvant chemotherapy: Correlation with tumor size and morphology changes
Authors: Woo O , Seo JH , Yang DS , Kim WY
Published: August 2014

PURPOSE

Contrast enhanced MR imaging is widely used to monitor the response of neoadjuvant chemotherapy (NAC) in breast cancer patients. The objectives of the study are 1) to assess the response of neoadjuvant chemotherapy (NAC) according to molecular biomarker status using MRI, 2) to evaluation of changes in morphological variation, and 3) to compare MR imaging-pathological size discrepancy depending on molecular biomarker status.

MATERIALS AND METHODS

Between May 2007 and March 2012, a total of 47 patients (age range, 34-65 years; mean age, 48 years) underwent NAC prior to surgery. Among them, 34 patients who performed MRI before and after NAC were enrolled. The extent of the lesion is measured by longest diameter. The response to NAC was calculated as reduction rate between pre NAC MRI and post NAC MRI. Histological grading system - Miller and Payne grade - was also recorded. Patients were divided into subgroups based on human epidermal growth factor receptor 2 (HER2), hormone receptors (HRs), and the proliferation marker Ki-67 status. The morphologic changes were classified into 1) concentric reduction, 2) fragmentation, 3) non-mass like, and 4) architectural distortion.

RESULTS

Total of 34 lesions from 34 patients were included. Among them, 12 lesions (35.3%) were pathologically proven to have no residual tumor (Miller and Payne grade 5). The mean MR reduction rate tended to be higher in HER2-positive (62.7%) and triple negative subgroups (61.9%) than HR-positive subgroup (47.7%). The mean MR imaging-pathologic size discrepancy tended to be smaller in triple negative subgroup (0.5cm) than HER2-positive (1.2cm) and HR-positive subgroups (1.4cm). All results showed no statistical significance (P>0.05). Ki-67 expression showed no significant correlations in tumor response (r = 0.17, P = 0.4) and MR imaging-pathologic size discrepancy (r = 0.1, P = 0.6). The majority of morphologic change is concentric reduction (57.6%). MRI is tended to overestimate residual size of the lesion (62.5%)

CONCLUSION

HER2-positive and triple negative subgroups showed relatively better response. Tumors were most likely to response in the manner of concentric reduction. The mean MR imaging-pathologic size discrepancy tended to be smaller in triple negative subgroup. MRI is reliable method in predicting histopathological response to NAC, but is more likely to overestimate the residual size of the lesion.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-02-08.