bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-06-44: Role of uPA and PAI-1 mRNA expression as prognostic factors in molecular subtypes of breast cancer
Authors: Witzel I , Milde-Langosch K , Schmidt M , Karn T , Rody A , Wirtz R , Jänicke F , Müller V
Published: August 2014

Background: Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) determined by ELISA from fresh-frozen tumor tissue have been evaluated as prognostic factors in prospectively randomized trials in node-negative breast cancer. However, uPA and PAI-1 mRNA expression might reveal new clinically relevant information using paraffin-embedded tumor tissue.

Methods: We evaluated uPA and PAI-1 mRNA expression with the Affymetrix HG-U 133A array also within molecular subgroups of breast cancer in a finding cohort of breast cancer patients (cohort A; n = 548). We validated mRNA expression in a cohort of HER2 positive breast cancer patients (cohort B, n = 347). For uPA and PAI-1, mRNA values below and above the median were compared in two different probesets. “Luminal”, “triple-negative” and “HER2 positive” subcohorts were defined by ESR1 and ERBB2 mRNA expression using pre-defined cut-offs.

Results: In cohort A, elevated PAI-1 mRNA expression was associated with shorter disease-free survival (DFS) and overall survival (OS), elevated uPA mRNA expression was associated with shorter OS. Regarding different molecular subgroups, 71% (n = 388) of tumors had a luminal, 13% (n = 69) a HER2 positive and 17% (n = 91) a triple-negative subtype. Only in the HER2 positive subgroup, elevated PAI-1 mRNA expression was associated with shorter disease-free survival and overall survival (p = 0.003 for DFS and p = 0.012 for OS). Same results were found for uPA in HER2 positive patients (DFS, p = 0.027 and OS, p = 0.011). In contrast, no association between both markers and DFS and OS could be seen in the luminal or triple-negative subgroups. In the HER2 positive validation cohort B elevated uPA and PAI-1 mRNA expression showed a strong association with shorter DFS (p = 0.013 for PAI-1, p = 0.001 for uPA).

Conclusion: Results of this study demonstrate that the prognostic impact of uPA and PAI-1 mRNA expression was observed mainly in patients with HER2 positive tumors.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-44.
Abstract P6-06-46: Treatment decisions and five year outcomes of the oncotype Dx test: An independent assessment
Authors: Bhargava R , Brufsky AM , Lembersky BC , Jankovic R , Puhalla SL , Oesterreich S , Lee A , Dabbs DJ
Published: August 2014

INTRODUCTION: Oncotype DX (ODx) was validated to provide prognostic information in ER+ lymph node negative tumors. The work of Paik et al. (JCO 2006 23:3737) has provided evidence of predictive power of ODx for chemotherapy, but there is contrary literature in this regard (Ionnadis JP Oncologist 2007, 12: 301-11; NICE Guideline March 2013 http://guidance.nice.org.uk/DT4). The specific aims of our institutional study are to determine (1) how ODx influenced treatment decisions and (2) the outcomes of patients who had ODx.

METHODS: Tumor registry follow-up information was supplied for 580 patients who had ODx and follow-up (mean/median 60/63 months).

RESULTS: (Table 1) Distribution of RS was 40% intermediate (232/580), 15% high RS (87/580) and 45% (261/580) low RS. Hormonal therapy was recommended to 96% (558 of 580), but refused by 3% (16 of 580) and for 1% data was unavailable. In the high RS group, chemo was recommended to 90% (79 of 87), of which 6 (8%) refused. In the intermediate RS group, chemo was recommended to 49% of the patients of which 20 (18% of recommended) refused. In the low RS group, chemo was recommended to 12% of the patients of which 8 (26% of recommended) refused. Most chemotherapy treatment decisions made at our institution were based on oncotype DX. High RS group recurrence was 9% (7 of 87) of which 2 patients died. Of these 7 patients, 3 did not receive chemotherapy (2 were recommended but refused). The recurrence rate in the intermediate RS group was 6.5% (14 of 232) of which 3 patients died. Of these 14 patients, 8 did not receive chemotherapy based on clinician's judgment. The recurrence rate in the low RS group was 1% (3 of 261) and there were no deaths due to breast cancer. Of these 3 cases, one received chemotherapy.

Oncotype DX Type of Recurrence vs Recurrence ScoresType RecurrenceHigh RSIntermediate RSLow RSTotalLocoregional49114(Scores)(35,38,47,63)(19,20,20,23,24,26,26,27,29)(16) Distant2529(Scores)(31,61)(19,19,22,29,30)(2,11) Local or Distant1  1Total714324

Conclusion: (1) The oncotype DX recurrence score is prognostic when low risk and high risk categories are considered. (2)The large number (40%) of intermediate RS appears to be a prognostic limitation of the test. (3) Of patients that recurred, (50%) received chemotherapy and were somewhat equally distributed between the high RS and the intermediate RS categories. Further follow-up of this cohort should address concerns of clinical utility of the Oncotype Dx test, especially for the intermediate RS category.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-46.
Abstract P6-06-57: Progesterone receptor status and Ki-67 index may predict early relapse in luminal B/HER2 negative breast cancer patients
Authors: Zong Y , Zhu L , Wu J , Chen X , Huang O , Fei X , He J , Chen W , Li Y , Shen K
Published: August 2014

Purpose

Few studies has documented early relapse in luminalB/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making.

Patients and Methods

A total 398 patients with luminalB/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival (DFS) and Cox regression to identify prognostic factors.

Results

Absence of progesterone receptor (PR) expression was associated with higher tumor grade (p< .001) and Ki-67 index (p = .010). PR-absent patients received more chemotherapy than the PR-present group (p = .009). After a median follow-up of 2 years, 17 patients (4.3%) had early relapses and 6 patients (1.5%) had died. The 2-year disease-free survival (DFS) was 97.2% in the PR-present and 88.6% in the PR-absent groups (Log-rank p = .004). Also, patients with a high Ki-67 index (defined as >30%) had a reduced DFS when compared with low Ki-67 index group (≤30%) (97.6% vs 91.3%, respectively, Log-rank p = .025). In multivariate analysis, PR absence was significantly associated with a reduced DFS (HR = 4.031, 95% CI 1.293-12.574, p = .016).

Conclusion

PR absence was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-57.
Abstract P6-07-09: What should be done after PHARE and HERA? Using value of information analysis as a guide
Authors: Conter HJ
Published: August 2014

Background:

Adjuvant trastuzumab therapy totaling 12 months (AT-12) is the current standard of care in the treatment of early-stage, HER-2/neu amplified breast cancer. Two studies, PHARE and HERA, examined whether the duration of adjuvant trastuzumab should be decreased safely to 6 months (AT-6) or increased to 2 years (AT-24), respectively. Could the implementation of value of information (VOI) analysis inform future clinical trial priority setting in this sphere?

Methods:

A Markov health-state transition model was employed to compare 3 adjuvant therapy options: AT-12, AT-6, and AT-24. Patients transitioned through 3 health states, disease free, metastatic recurrence, and death, over 3-month time intervals. The simulation was run using a lifetime time horizon. Transition probabilities of the health states in the AT-12 cohort were estimated from the National Surgical Adjuvant Breast and Bowel Project B-31 and North Central Cancer Treatment Group N9831 trials. Based on the efficacy assumptions that provided the foundation for HERA, the AT-24 probabilities were imputed. AT-6 transition probabilities were assumed to equal AT-12 probabilities. Health outcomes were measured in quality adjusted life years (QALY) and costs in 2012 United States dollars. Health outcomes and costs were discounted to the present value by 5% annually, compounded quarterly.

Result:

In the reference case, AT-24 had an incremental cost-effectiveness ratio of $57,784/QALY. Probabilistic sensitivity analysis revealed that AT-24 was likely to be 0.3%, 11%, 58%, and 93% cost effective at a threshold willingness-to-pay (WTP) of $20,000, $40,000, $60,000, and $80,000/QALY, respectively. At a WTP threshold of 65,000, the expected VOI payoff from conducting the HERA trial was computed as $204,692 per patient treated per year. Conversely, AT-6 would be expected to cost $100,592 less than AT-12 over a patient's life, corresponding to an expected $249,564 per patient per year payoff for the PHARE trial.

Since neither PHARE nor HERA were able to achieve their primary objectives, a new trial testing the duration of trastuzumab could be considered. Employing the same model, AT for 9 months would be expected to save $50,596 per patient compared to AT-12. The VOI of such a trial is estimated to be $224,504 per patient treated per year.

Conclusion:

Despite the results of PHARE and HERA, VOI analysis suggests that a non-inferiority trial examining 9 months of AT compared to AT-12 should be considered. The actual value of such a trial may be even greater if new HER-2 targeted therapies may be added to AT in the future. However, determining the total net benefit to society of performing such research requires information on its associated budgetary outlays. Cooperative groups should make the their individual trial expenses public to facilitate improved collective decision-making on future trials.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-09.
Abstract P6-08-01: Analysis of patient-reported outcomes following nipple-sparing mastectomy and implant reconstruction
Authors: Pharmer LA , Koslow SB , Martins D , Theodore R , Christos PJ , Talmor M , Simmons RM , Tousimis E , Swistel AJ
Published: August 2014

Background: Nipple-sparing mastectomy (NSM) is gaining popularity among women undergoing prophylactic and therapeutic mastectomy. Using the BREAST-Q, a validated condition-specific patient-reported outcome instrument which measures postsurgical patient satisfaction and health-related quality of life (HR-QoL), we sought to determine whether satisfaction and HR-QoL differ between patients undergoing NSM and skin-sparing mastectomy (SSM) with immediate implant reconstruction.

Methods: From 2005 to 2012, a total of 572 patients underwent mastectomy; of these 261 patients (46%) had NSM. All mastectomy patients were mailed the BREAST-Q reconstruction questionnaire consisting of 3 scales (scored 0-100): Satisfaction with Breasts, Satisfaction with Outcome, and Psychosocial Well-Being. Excluded from this analysis were males, autologous tissue reconstruction, and conversion from NSM to SSM. Comparisons were made between NSM and SSM groups using univariable analysis and multivariable linear regression models (MVA).

Results: The BREAST-Q completion rate was 27% with a median time from surgery to survey of 36 months (range 4 to 86). Women undergoing NSM, compared to SSM, were younger (mean 46 v 50 years; p = 0.01), more likely to be married (80% v 52%; p = 0.001), have bilateral mastectomies (79% v 59%; p = 0.01), and had less time between surgery and BREAST-Q completion (median 25 v 49 months; p<0.001). 19 NSM patients (25%) and 7 SSM patients (13%) underwent prophylactic mastectomy (p = 0.07). There were no differences regarding tumor characteristics or treatment. Patients undergoing NSM, compared to SSM, had a higher unadjusted mean score for Satisfaction with Breasts (71 v 60; p<0.001), Satisfaction with Outcome (80 v 69; p = 0.003), and Psychosocial Well-Being (84 v 74; p = 0.006). On MVA analysis, NSM (compared to SSM) was associated with greater Satisfaction with Breasts (adjusted mean difference: +13, 95% Confidence Interval[CI]: 6-21, p = 0.001), Satisfaction with Outcome (adjusted mean difference: +17, 95% CI: 7-27, p = 0.001), and Psychosocial Well-Being (adjusted mean difference: +12, 95% CI: 3-22, p = 0.013), after controlling for age at mastectomy, marital status, laterality, cancer vs. non-cancer diagnosis, post-mastectomy radiation treatment, and time from mastectomy to BREAST-Q completion. Not being married (adjusted mean difference: +8, 95% CI: 2-15, p = 0.014) and having a bilateral mastectomy (adjusted mean difference: +8, 95% CI: 1-14, p = 0.029) were also significant predictors of increased Satisfaction with Breasts.

Conclusion: These findings suggest that, in the setting of implant reconstruction, NSM is associated with higher patient satisfaction with their breasts, overall outcome, and improved emotional/social well being.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-01.
Abstract P6-08-04: Prognostic significance of quality-of-life scores in early stage and relapsed breast cancer: Results from seven randomized trials of the International breast cancer study group
Authors: Lee CK , Coates AS , Hudson M , Ribi K , Bernhard J
Published: August 2014

We performed an individual patient meta-analysis to investigate the prognostic value of patient self-reported quality-of-life (QL) scores at baseline, and at several times prior to and following disease relapse on subsequent overall survival (OS) in seven randomized trials of the International Breast Cancer Study Group.

Patients with early stage breast cancer who participated in randomized trials that compared adjuvant therapies, and who had subsequent disease relapse, completed QL assessments for physical well-being, mood, appetite, nausea and vomiting, arm swelling, flushing, coping effort, and utility at study entry, prior to and after disease relapse. We tested the relationships between baseline QL scores and OS using Cox regression analyses. We performed landmark analyses to assess the relationships between pre-relapse QL scores with OS using QL assessments at 1, 2 and 3 months prior to disease relapse, at the time of relapse and at two subsequent QL assessments where these were available. All Cox models were stratified by trial and included other factors related to QL and/or outcome.

Among 8,024 patients, 3,834 (48%) had disease relapse after a median follow-up time of 12 years. Amongst these patients, QL score at baseline, and at 1, 2, and 3 months prior disease relapse were not significantly prognostic for OS. At disease relapse, scores for physical well-being (hazards ratio [HR] per 10 unit increase of QL score for death, 1.05; P = 0.003), mood (HR 1.05; P = 0.007), appetite (HR 1.08; P<0.001), and utility (HR 1.13; P = 0.008) were prognostic for subsequent OS. Nausea and vomiting (HR 1.05; P = 0.11), arm swelling (HR 1.00; P = 0.20), flushing (HR 1.01; P = 0.73), and coping effort (HR 1.02; P = 0.29) were not prognostic for subsequent OS. At post-relapse assessments at median times of 1 (HR 1.07; P<0.001), 6 (HR 1.08; P<0.001) and 10 months (HR 1.13; P<0.001) after disease relapse, scores for physical well-being showed increasing prognostic significance. Scores for mood, nausea and vomiting, appetite, coping effort and utility showed patterns similar to those for physical wellbeing, but scores for arm swelling and flushing were not prognostic for subsequent OS.

These findings confirm and extend those of Coates et al. (J Clin Oncol 2000;18:3768 - 3774) based on two of the trials included in the present analysis. At baseline and prior to relapse, QL scores did not have any prognostic significance for subsequent OS. At and after disease relapse, QL scores substantially predicted for subsequent OS, with stronger association for QL scores later in the course of relapsed disease. Patient perception of the severity of underlying illness after relapse might be a potential reason that determines the reported QL scores and thus contributes to their prognostic significance.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-04.
Abstract P6-08-09: A national survey on oncology clinicians’ recommendations and knowledge of contraception for women with cancer
Authors: Giordano SB , York SL , Gosiengfiao Y , Smith K , Kiley J
Published: August 2014

PURPOSE

Women with cancer have specific reproductive health needs and often look to their oncology clinicians for recommendations and guidance. This study's purpose was to determine contraceptive knowledge and recommendations of oncology clinicians.

METHODS

An online survey was emailed to U.S.-based medical and pediatric oncologists and oncologic advanced practice clinicians caring for women age 13-45 years. The primary outcome was regular recommendation to start or continue contraception during cancer treatment. Knowledge of pertinent information on contraception was calculated based on percent correct answers to questions on contraceptive failure rates and safety.

RESULTS

18.5% of subjects responded to questionnaires (612 initiated surveys of 3334 requests). Pediatric clinicians constituted the majority of the 577 participants meeting inclusion criteria (pediatric oncologists: 48.7%; pediatric advanced practice clinicians: 38.1%). Most clinicians (81.8%) recommend contraception. The mean contraceptive knowledge score was 47.5% (SD: ±17.6%), with 27.2% answering ≥60% questions correctly.

Recommending contraception was associated with rating contraception as important (aOR 3.49, 95% CI: 1.46, 8.38); comfort with contraceptive counseling (aOR 1.77, 95% CI: 1.04, 3.00); regular referral to a gynecologist/women's health care provider (aOR 2.92, 95% CI: 1.44, 5.94); and frequency of patients discussing contraception (aOR 4.21, 95% CI: 1.55, 11.43). Advanced practice nurses/physician assistants were less likely to correctly answer ≥60% of contraceptive knowledge questions (aOR 0.44, 95% CI: 0.27, 0.71).

CONCLUSION

Oncology clinicians recommend young women with cancer use contraception but lack essential knowledge to provide adequate counseling.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-09.
Abstract P6-08-11: Count us, know us, join us global survey: Comparing the feelings and needs of advanced breast cancer patients in the United States with patients in Latin America, Europe, and Asia
Authors: Miller H , Percassi D
Published: August 2014

Background: Advanced breast cancer (stage III and stage IV/metastatic) (ABC) is the most serious form of breast cancer, with nearly 250,000 people across the globe living with the disease. Because ABC often metastasizes to the brain, bone, or liver, it has important health implications, requires life-long treatment, and is usually fatal. Support needs for this patient group are unique, yet rarely met. Hoping to identify new approaches to meeting the needs of this community, a global survey was commissioned by Novartis Oncology in partnership with the global advocacy community. Method: Harris Interactive conducted an online survey between October 2012 and March 2013. It was completed by 1,273 female metastatic breast cancer patients ages 21+ from 12 countries (United States [US], Canada, Mexico, Brazil, Argentina, United Kingdom, Germany, Russia, India, Lebanon, Taiwan, and Hong Kong). Total sample data are not weighted and are representative only of the individuals surveyed. A global post-weight was applied to ensure that all countries received an equal weight in the global and regional data. Results: Patients in the US (70%) are more likely than patients in most other countries surveyed to feel isolated from the non-metastatic community (40% globally). In addition, US patients (73%) are significantly more likely than their counterparts in most other countries to often feel that no one understands what they are going through (63% globally). Patients in the US (53%) are also more likely than those in most other countries to say that support from friends and family has diminished since their initial advanced diagnosis (41% globally), and employed US patients (34%) are more likely than those in many other countries to believe their colleagues look at them differently as a result of their metastatic breast cancer (17% globally). Women in the US were most likely to be actively seeking information (97%) compared with patients in other countries (77% globally). Although more US women patients are active information seekers, they are most likely to be unsatisfied with the information that is currently available compared to patients in the other countries (31%; 51% globally). Conclusions: Despite the significant amount of attention paid to breast cancer in the US and the resources available, many US women with metastatic breast cancer feel more alone and isolated than do their counterparts in most other countries surveyed. These US women are also significantly more likely than their counterparts in other countries to often feel as though no one understands what they are going through. More needs to be done to help women in the US feel supported emotionally throughout their entire ABC journey.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-11.
Abstract P6-09-08: Withania somnifera extract inhibits invasion and metastasis of MDA-MB-231 cells by inhibiting CCL2 and CD44 high/CD24low stem cells
Authors: Khazal KF , Simon L , Odemuyiwa S , Hill D , Grubbs C
Published: August 2014

Standard approaches to the treatment of cancer, including surgery, chemotherapy, and radiation, when used alone or in combination, have had limited efficacy in curing the disease. These treatments frequently produce debilitating side effects, such as nausea, vomiting, loss of hair, and suppression of immunity. Due to these side effects, interest in other cancer treatments, including herbal extracts, has increased. Traditional herbal extracts are considered to be safe and economically feasible as alternative medicines to treat cancer. An alcoholic extract of the roots of Withania somnifera (WS), a traditional herbal remedy, has immunostimulatory, radiosensitizing, and anticancer effects. Knowledge of the medicinal properties of this plant motivated us to investigate its efficacy as an antitumor agent against breast cancer

MDA-MB-231 human breast cancer cells were used as a model. Tests included an MTT assay for cell viability, an assay for testing of migration of cancer cells, PCR analysis for cytokines, evaluation of gene expression, an immunohistopathological assay for expression of cytokines in isolated tissues, and xenografts in nude mice to evaluate inhibition of tumor growth.

In cell cultures, WS showed antiproliferative and anti-invasive effects against MDA-MB-231 breast cancer cells; it also inhibited the metastasis of xenografted MDA-MB-231 cells to the lungs of treated mice. These findings were substantiated in vitro by use of a microarray technique. WS caused down-regulation of cytokines CCL2, CXCL1, CXCL2, CXCL3, IL-1b, and TGF-β3. CCL2 is the cytokine considered to be most responsible for the metastasis of breast cancer cells. The inhibition of CCL2 by WS was confirmed in sections of xenografted treated tumors and in cell culture by use of immunohistochemical and flow cytometry techniques, respectively. WS caused 50% inhibition of CD44-bearing breast cancer stem cells, the predominant stem cells of the MDA-MB-231 breast cancer cell line. This finding will be further pursued by sorting CD44high/CD24low stem cells by use of flow cytometry.

In summary, WS caused inhibition of proliferation and invasion of breast cancer cells in culture and growth of xenografted cancer cells in mice. These effects may be associated with inhibition of cytokines such as CCL2 and CD 44high/CD 24low s.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-08.
Abstract P6-10-01: Evaluation of post-progression survival (PPS) in advanced breast cancer (ABC) according to treatment line: Correlation with PFS and OS in an unselected population
Authors: Ciccarese M , Forcignanò R , Petrucelli L , Fabi A , Chiuri VE , Cairo G , Lupo L , Gambino A , Saracino V , Ronzino G , Licchetta A , Giannarelli D
Published: August 2014

Background: MBC remains an incurable disease with a median survival of 2-3 years despite the use of new drugs. The validation of PPS as surrogate endpoint and its correlation to PFS and OS is matter of debate.

Methods: From 2006-2012 we analyzed retrospectively consecutive 192 pts treated for MBC outside of clinical trials, 103 with at least 3 lines CT, in order to evaluate post-progression survival (PPS) according to treatment line and its relation to PFS and OS. Moreover we evaluated the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy.

Results: Median age at M+ diagnosis was 59 years (30-89), median site of disease was 2 (1-6), 67% visceral, HER-2 + pts 32%, median number of anti-Her-2 treatment was 2 (0-6); median number of treatment was 3 (1-8). Median OS for all pts was 45.6 (95% CI: 36.5-54.7). Median OS for CT > = 3 vs CT < 3 was respectively 52.5 (95% CI: 43.3-61.7) and 32.3 (95% CI: 23.6-41.2) P = 0.007. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive versus negative p<0.0001) number of lines (>3 vs ≤3) p = 0.001 and number of metastatic sites (>2 vs ≤2) p<0.0001. We evaluated the relation between PFS and OS and between PPS and OS until the 6th line of therapy with a linear regression model.

 Median PFS (95% c.i.)Median PPS (95% c.i.)Median OS from M+ diagnosisCorrelation OS-PPSCorrelation OS-PFS1st line11.0 (9.5-12.5)29.9 (18.2-41.6)Not reachedP<0.0001 OS-PPS1P<0.0001 OS-PFS12nd line7.0 (5.8-8.2)20.9 (11.7-30.0)29.1 (17.5-40.7)P<0.0001 OS-PPS2P<0.0001 OS-PFS23rd line5.6 (4.5-6.7)19.5 (14.9-24.1)41.9 (15.5-68.2)P<0.0001 OS-PPS3P<0.0001 OS-PFS34th line5.7 (4.0-7.4)15.3 (13.4-17.2)50.4 (27.4-73.4)P<0.0001 OS-PPS4P<0.0001 OS-PFS45th line3.9 (3.1-4.7)11.2 (7.8-14.5)65.9 (20.8-112.2)P = 0.004 OS-PPS5P<0.0001 OS-PFS56th line3.3 (2.6-4.0)8.2 (2.2-14.2)56.8 (48.7-64.9)P = 0.36 OS- PPS6P = 0.002 OS-PFS6

Conclusion: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until the 6th line of treatment. The utility of PPS as surrogate endpoint of OS is a valid hypothesis that could be evaluated in prospective trials of MBC.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-01.
Abstract P6-10-05: First-line chemotherapy versus first-line endocrine therapy in hormone receptor positive HER2 negative patients with metastatic breast cancer in China: Results of the study of breast cancer group of the Chinese Society of Clinical Oncology (CSCO)
Authors: Wang T , Yang TT , Yang LJ , Song HY , Ouyang CQ , Wang JX , Hu CX , Zhang JG , Xu HB , Feng FJ , Tong SZ , Jiang FZ
Published: August 2014

Background: The primary objective for metastatic breast cancer is to prolong the patients survival. So the appropriate choice of the first-line therapy strategy is very important. For the HR-positive metastatic breast cancer, we haven't strong data to head-to-head compare the chemotherapy with endocrine therapy as the first-line treatment.

Methods: Two hundreds patients with HR-positive metastatic breast cancer were enrolled at 47 cancer centers in China from 2009 to 2012. Investigators decided to give chemotherapy or endocrine therapy according to their clinical judgements. Chemotherapy and endocrine therapy regimens followed the NCCN guildline. All the patiens haven't take any treatment after relapse or metastasis. All the patients were estrogen- receptor positive and/or progesterone-receptor positive,HER2 negative. Chemotherapy or endocrine therapy was continued in the progressive disease(PD) or unacceptable toxicity. Primary endpoint was progression-free survival(PFS), second endpoints were time to failure(TTF), response rate.

Results: According to the investigator judgements, one hundred patient took chemotherapy(CT arm), another one hundreds patients took endocrine therapy(ET arm). Pt characteristics were balanced between the two arms: median age 49y/50y, median disease-free survival(DFS) 40m/30m, visceral/non-visceral metastatic 52%/40%. There was more patients with ≥2 metastatic sites in CT arm than ET arm (50% vs 32%). Following up to Dec 2012, reasons for early treatment discontinuation were : PD 25 pts, toxicity 38 pts in CT arm, PD 82 pts, toxicity 2 pts in ET ram. The median PFS was 52 weeks(95% CI 23.2-80.8 weeks) and 48 weeks(95% CI 38.9-57.0 weeks) for CT arm and ET arm(P = 0.589),respectively. The median TTF was 20 weeks and 48 weeks for CT arm and ET arm,respectively(P = 0.025). Response rate was 63% and 22% for CT arm and ET arm,respectively(P<0.001). But clinical benefit rate(CR+PR+SD≥6months) was 67% and 69% for CT arm and ET arm,respectively(P = 0.333). Subgroup analysis showed TTF were 48 weeks in ET arm and 15 weeks in CT arm(p = 0.038) for patients who had more than 2 years DFS. TTF results also indicated significant difference in single metastatic site pts and non-visceral metastatic pts between two arms. ET arm was superior to CT arm.

Conclusions: Our results indicate first-line chemotherapy has higher response rate than first-line endocrine therapy for HR-positive meatstatic breast cancer, but chemotherapy has shorter maintaining therapy time. First-line endocrine therapy was more suitable than first-line chemotherapy for pts with DFS≥2y, single metastatic site and non-visceral metastatic.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-05.
Abstract P6-12-01: Survival of women with inflammatory breast cancer: A large population based study
Authors: Dawood S , Lei X , Dent R , Gupta S , Sirohi B , Cortes J , Cristofanilli M , Bucholz T , Gonzalez-Angulo AM
Published: August 2014

Background

The introduction of efficacious polychemotherapy regimens and targeted biologicals has contributed to significant improvements in survival of women with breast cancer. However, our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared to those with non-inflammatory breast cancer. We undertook this population based study to see if there have been improvements in survival among women with stage III IBC, over time.

Methods

We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Follow up cut off was December 31st 2010. Patients were defined as having IBC according to the AJCC 6th edition criteria. Patients were divided into 4 groups according to year of diagnosis: 1990-1995, 1996-2000, 2001-2005 and 2006-2010. Breast cancer specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across groups using the log rank statistic. Cox models were then fitted to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics.

Results

7,679 patients with IBC were identified of whom 1,084 patients (14.1%) were diagnosed between 1990-1995, 1,614 patients (21.0%) between 1996 -2000, 2,683 patients (34.9%) between 2001-2005 and 2,298 patients (29.9%) between 2006-2010. Median follow-up was 30 months. The 2-year BCSS for the whole cohort was 71%. 2-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005 and 2006-2010 respectively (p<0.0001). The absolute increase in 2-year BCSS over the immediately preceding time period were 5%, 5%, and 4%, respectively. Significant improvements in survival over time were also observed among patients younger and older than age 35 years. In a multivariable cox regression analysis increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risk of death from breast cancer (HR = 0.98, 95% CI: 0.97 – 0.99, P < 0.0001).

Conclusion

There has been a significant improvement in survival of patients diagnosed with IBC over a two decade time span in this large population based study. This suggests that therapeutic strategies researched and evolved in the context of non inflammatory breast cancer have also had a positive impact in women with IBC.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-01.
Abstract P6-12-11: Celecoxib inhibits the growth of IBC tumors by suppressing the regulation of cancer stem-like cells by nodal
Authors: Reyes ME , Zhang D , Eckhardt B , Masuda H , Pirman DA , Reuben JM , Woodward W , Yang P , Hortobagyi GN , Wang X , Ueno NT
Published: August 2014

Background: Inflammatory breast cancer (IBC) is an aggressive type of breast cancer with no known molecular targets for treatment. Although erythema is commonly associated with IBC, the molecular mechanism of inflammation in the pathogenesis of IBC remains unknown. We have previously shown that EGFR is an emerging target in IBC (Zhang D. et al Clin Can Res 2009). As crosstalk between EGFR and COX-2 plays an important role in the inflammatory response in several cancers, including breast cancer, we hypothesized that COX-2 promotes the tumorigenesis and metastasis of IBC cells.

Methods: Using clinically derived IBC and non-IBC tumor samples, a Spearman's Rank correlation coefficient analysis was performed to analyze the expression levels of COX-2 and EGFR in IBC and non-IBC. The levels of COX-2 metabolites, prostaglandins (PGs) PGE2 and PGF2α, were measured in IBC and non-IBC cell lines by HPLC/MS method. Cell migration and invasion assays were performed using SUM149 and KPL-4 IBC cell lines treated with PGs or the COX-2 inhibitor, celecoxib. We evaluated the epithelial to mesenchymal transition (EMT)-like phenotype in 3D culture of SUM149 cells treated with celecoxib, and the stem-like population by mammosphere formation, and CD44+/CD24− and aldefluor+ population by FACS. We treated preclinical IBC xenograft mice with celecoxib and measured tumor growth, PGs levels, and the expression of EMT protein markers. Nodal, a stem cell regulator and potential biomarker for breast cancer progression, was evaluated in IBC cells following treatment with celecoxib and recombinant Nodal or transfection with Nodal cDNA.

Results: EGFR and COX-2 expression levels positively correlated within IBC, but not non-IBC tumors. Elevated levels of PGE2 and PGF2α were identified in multiple IBC cell lines suggesting that COX activity is elevated within IBC compared to non-IBC cells. PGs altered EMT protein markers and promoted cell migration and invasion, while Celecoxib inhibited EMT and migration and invasion in SUM149 and KPL-4 cells. Celecoxib treatment inhibited tumor growth in mice, and downregulated the expression of EMT protein markers, including Nodal. Celecoxib decreased the stem-like CD44+/CD24−, and aldefluor+ population and the formation of mammospheres. Exogenous Nodal mitigated the effects of celecoxib on cell migration and invasion and the stem-like population in SUM149 cells.

Conclusion: We conclude that activation of the COX-2 inflammatory signaling pathway is critical in the development and progression of IBC. This study provides a novel insight into how inflammation may regulate cancer stem cells via Nodal, and will guide future research into the development of stem cell targeted therapies for IBC.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-11.
Abstract P6-12-14: Histone deacetylase inhibitor suberoylanilide hydroxamic acid targets breast cancer stem cells and inhibits metastasis
Authors: Chu K , Green TL , Boley KM , Cristofanilli M , Robertson FM
Published: August 2014

Introduction: Inflammatory breast cancer (IBC) is a distinct and aggressive subtype of locally advance breast cancer associated with increased aldehyde dehydrogenase 1 (ALDH1) positive cancer stem cells (CSCs). IBC is associated with a poor survival rate (40% 5-year survival), with few therapeutic strategies identified that effectively blocked the growth and metastasis of IBC. Our previous in vitro studies revealed that the pan-histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) effectively targets self-renewal of IBC tumor cells.

Materials and Methods: The IBC cell line, SUM149 was tagged with the Luciferase gene (SUM149-LUC) and their in vivo growth in immune compromised mice tested in both orthotopic and metastatic settings.

Results: SUM149-LUC rapidly develop primary tumors and metastatic lesions at a variety of locations including lung, brain, bone, liver, reproductive organs and adrenal glands. SAHA effectively blocked growth of SUM149 primary tumors and inhibited metastasis, which was synergistic with the microtubule stabilizer, Paclitaxel. The therapeutic efficacy of SAHA was associated with a significant decrease in ALDH1+ CSCs populations.

Conclusions: Collectively, these results suggest that strategies of combining agents such as SAHA that target CSCs with Paclitaxel that targets the bulk of proliferating tumor cells warrant further investigation for their potential effectiveness in IBC patients, who have the lowest survival of breast cancer patients and have few therapeutic options.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-14.
Abstract P6-12-15: Preclinical testing of a novel platelet derived growth factor receptor alpha (PDGFRa) inhibitor in inflammatory breast cancer
Authors: Joglekar M , Van Laere S , Vermeulen P , Dirix L , Carter M , Rhamchandran A , van Golen KL
Published: August 2014

Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer and carries a guarded prognosis. IBC presents with a “lumpless” primary tumor, which rapidly infiltrates and forms tumor emboli within the dermal lymphatic vessels of the skin overlying the breast. It is clear from the recent research advancements that IBC is a unique entity, not only in its clinical presentation, disease progression and response to therapy but also in its molecular expression profile. Therefore, it is essential to carry out molecular expression studies in IBC compared to non-IBC as well as to pursue these differences to study their effects on IBC phenotype. Our laboratory has demonstrated that the platelet derived growth factor receptor alpha (PDGFRa) is significantly over expressed in IBC patient samples (between 15-36%) compared to non-IBC patient samples. Using multiple approaches we demonstrate the PDGFRα activation signature in IBC patient samples and cell lines. Our data demonstrates that PDGFRα is constitutively active and localized in the cytoplasm of IBC cells. Although the receptor is intracellular, PDGFRα signaling remains intact. Thus, PDGFRα is an attractive target for therapy. Here we show that a novel PDGFR inhibitor, crenolanib, which specifically targets active PDGFR, is able to significantly inhibit IBC tumor growth and progression. In nude mice, 200 mm3 orthotopic IBC tumors did not increase in size when the mice were treated with crenolanib. In contrast, mice treated with vehicle control demonstrated a 4-fold increase in tumor growth over the 2-week course of the experiment. In addition, by using a novel in vitro IBC emboli growth model, we demonstrate that crenolanib prevents IBC tumor emboli formation and acts to sensitize IBC cells to chemotherapeutic agents. We were able to achieve a similar level of IBC cell killing with a 10-fold lower dose of chemotherapeutic agents compared to the agents by themselves. Together, these data demonstrate that PDGFRα is a viable target in IBC patients and that crenolanib is a potent and effective therapeutic agent against IBC cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-15.
Abstract P6-12-16: Treatment with indol-3-carbinol (I3C) in a mice xenograft model of canine breast carcinoma alter hormone metabolism and produce liver metastases
Authors: Illera JC , Martin-Ruz AL , Caceres S , Diez L , Gonzalez-Gil A , Peña L
Published: August 2014

Indol-3-carbinol (I3C) is a chemical component found mainly in the cruciferous family lants (i.e. broccoli, cabbage, cauliflower, etc.). I3C is considered a potential anticancer agent that is naturally present in the diet and could prevents the development of certain tumors, activating tumor suppressor genes, genes involved in apoptosis and detoxifying genes. It has been observed in vitro that suppresses cell proliferation and induces apoptosis in some breast cancers. I3C is also estrogen receptor (ER) and androgen receptor (AR)Antagonist. Therefore, studies using I3C in breast cancer animal models for its action as a preventive or therapeutic substance have started. There are no data on the influence of I3C in human and/or spontaneous or experimental canine inflammatory breast cancers, that has shown to have distinct pathogenic mechanisms. The aim of this study was to analyze the effect of I3C administration at a comparable dose used as preventive in humans in a xenograft model of canine inflammatory carcinoma established in SCID mice. Eighteen mice were used as controls and 13 mice were treated with I3C dose 150 mg/kg/day. Tumor cell proliferation was decreased in the I3C-treated xenografts (lower Ki-67 index, p <0.001), but neoplasms were more frequently ulcerated (p = 0.028), and mice had a higher number of emboli in dermis (p = 0.012) (characteristic of inflammatory breast carcinoma) and liver metastases (p = 0.05). In the treated group the presence of a subpopulation of neoplastic lipid-rich cells was characteristic (p = 0.001) togetehr with a higher content of intratumor androgens (p = 0.02) and serum steroid hormone (p <0 05). These results indicate that treatment with I3C, as administered, is not suitable for inflammatory breast carcinoma.

This study was funded by the research project of the Ministry of Science and Innovation SAF2009-10572.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-16.
Abstract PD2-5: Low carbohydrate dietary intervention improves insulin, hormonal levels and inflammatory markers in early stage, postmenopausal breast cancer survivors
Authors: Krie AK , Bohlen KN , Hu Y , Ageton C , Demuth H , Norfolk D , Kittelsrud J , Thomes R , Fahrendorf A , Muth J , Rojas-Espaillat LA , Davies GE
Published: August 2014

Background: Obesity has been associated with decreased disease free survival and overall survival in postmenopausal breast cancer survivors. Proposed mechanisms for this finding include elevated estradiol levels, hyperinsulinemia, and increased inflammatory mediators. This feasibility study evaluated whether a low carbohydrate, calorie restricted dietary intervention could achieve weight loss and measurable metabolic changes in a group of obese postmenopausal breast cancer survivors.

Methods: Twenty-three early stage estrogen receptor positive breast cancer survivors were enrolled on a low carbohydrate, calorie-restricted dietary intervention. At time of enrollment the patient had to be deemed postmenopausal and have a BMI >28. Patients were not allowed to have an underlying inflammatory condition or be receiving treatment for diabetes. The mean age was 57 years old (42-68) with a mean weight of 220 lbs (171-300) and mean BMI of 37 (28-48.5). All subjects had completed surgery and adjuvant chemotherapy. The majority of patients were on endocrine therapy with 61% on an AI and 35% on tamoxifen. The dietary intervention utilized 0.5g protein/pound (actual body weight), less than 40 grams of carbohydrates and 800-1200 calories per day. The program provided weekly coaching, meal replacement protein products and nutritional supplements. Subjects were medically monitored with brief physical exams and labs done every 2 weeks for the first 12 weeks, then monthly thereafter. Subjects were seen by a health coach every week. The average weight loss period spanned 23 weeks (7-59 weeks) due to the variance in weight loss goals aimed at a BMI ≤28.

Results: The mean weight loss was 19.9% of total body weight, the equivalent of 43.7 pounds. Total body fat lost was 6.86%. Weight loss averaged 5.4 pounds in week one and 2.14 pounds per week in weeks 2-19.

Statistically significant declines in the total estrogen level (p = 0.0345), estrone (p = 0.0296), and estradiol serum levels (p = 0.0296) were demonstrated. A rapid decline in fasting insulin level was seen with a 23% decline by Week 3 (p = 0.0959), 26% by Week 7 (p = 0.0139), and 42% by Week 19 (p = 0.0071). A statistically significant improvement in the CRP level compared to baseline was also demonstrated with a 40% decrease at Week 19 (p = 0.0272).

Conclusions: Our results support that a low carbohydrate dietary intervention can be used to successfully achieve weight loss and improve metabolic parameters. This feasibility study provides additional support for larger trials evaluating the role of carbohydrate restriction in breast cancer survivors.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-5.
Abstract PD2-7: Vigorous exercise across the lifespan and reduced risk of estrogen receptor negative breast cancer in African American women
Authors: Adams-Campbell LL , Palmer JR , Bethea T , Kipping-Ruane K , Rosenberg L
Published: August 2014

Background. Recreational exercise has been associated with a reduced risk of breast cancer, but evidence regarding breast cancer among African American women and about breast cancer subtypes is sparse.

Methods. We assessed lifetime vigorous exercise (average of high school, age 21, age 30, and baseline) in the Black Women's Health Study in relation to the incidence of invasive breast cancer overall (n = 1,377), estrogen receptor-positive (ER+) breast cancer (n = 556), estrogen receptor-negative (ER-) breast cancer (n = 327), and triple negative breast cancer (TN) (n = 103); analyses were based on 275,188 person years of follow-up of 44,704 African American women who were aged 30 or more at entry to the study. Cox proportional hazards models estimated incidence rate ratios (IRR) and 95% confidence intervals (CI), controlling for breast cancer risk factors.

Results. For ER- breast cancer, the IRRs for 1-2.2 hours/week, 2.3-2.9 hours/week, and 3+ hours/week relative to <1 hour/week were 0.76 (95% CI 0.52-1.11), 0.78 (95% CI 0.52-1.17) and 0.53 (95% CI 0.31-0.90), respectively; the p value for trend was 0.058. The inverse association was apparent only among postmenopausal women. There was also an inverse association, although nonsignificant, of exercise with the incidence of TN breast cancer. Vigorous exercise was not associated with a reduction in ER+ breast cancer risk.

Conclusion. These results indicate that physical activity may protect against the development of ER- breast cancer in African American women. The association, if confirmed, is of great public health importance given the high mortality associated with this subtype and its higher incidence in African American women.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-7.