Positive Early Stage Breast Cancer Research Articles

Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer.

The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively.

Oncotype Dx analysis in early stage breast cancer (BC) in BRCA mutation carriers versus non-carriers.

e12065Background: While Oncotype-Dx testing has become the standard of care in early stage ER positive BC, its role in the management of BRCA associated breast cancer is not well defined. Inherited mutations in the BRCA gene are responsible for 5-10% of breast cancers. BRCA2 mutation predisposes to ER positive BC 50% of the time, while BRCA1 mutation is more commonly associated with ER negative tumors. In this report, we sought to evaluate the role of Oncotype Dx in a population of patients (pts) with known BRCA status. Methods: We performed an IRB approved single institution retrospective analysis of women with known BRCA status diagnosed with stage I-II BC (T0-T3, N0-N1). We included women diagnosed with ER and/or PR positive, Her2 neu normal BC between years 1974-2015. Tumor grade and Oncotype –Dx scores were retrieved. We evaluated the relationship between BRCA and Oncotype-Dx scores. Results: 691 pts were included in this study. 133 (19%) were BRCA1 or 2 positive and 558 (81%) were negative. 65 of th...

The impact of the 21-gene assay in the Czech Republic on adjuvant chemotherapy (CT) recommendations and costs in estrogen receptor positive (ER+) early stage breast cancer (ESBC) patients with grade 2 tumors and risk factors.

e12061Background: Conventional clinical risk factors are imprecise for determining recurrence risk. Multigene classifiers may provide useful information to resolve treatment decisions in the presen...

Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients: A nationwide study.

Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with estrogen-receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene-expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed. Data on all surgically treated early breast cancer patients diagnosed between 2004-2006 and 2012-2014 were obtained from the Netherlands Cancer Registry. ER+/Her2- patients with tumor-characteristics making them eligible for gene-expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified. We identified 3,864 patients eligible for gene-expression profile use during both periods. Gene-expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk-profile (67% and 69%, respectively) and high adherence rates to the test result were observed (86% and 91%, respectively). Without deploying a gene-expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene-expression profile was used (p 0.191). In conclusion, in ER+/Her2- early stage breast cancer patients gene-expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline-based recommendation to administer chemotherapy.

Abstract ES5-1: Predictive gene expression profiles in breast cancer, where are we?

Abstract Successful sequencing of the entire human genome offered an enormous potential for improving human health, especially in oncology. Nearly 20 years after successful completion of the human genome project, the Cancer Genome Atlas (TCGA) has catalogued the most common mutations in most cancers, including breast. Further, the technical advances that facilitate the ability to fully analyze both germline and somatic DNA and RNA has resulted in rapid (&amp;lt;4 weeks) and relatively inexpensive (&amp;lt;$3000) assays to emerge. Indeed, the NCI-sponsored Lung MAP and Cancer MATCH, and the ASCO-sponsored TAPUR, trials are now opening in the U.S., testing whether knowledge of somatic genetic changes improves patient outcomes. However, arguably, the most clinically useful product of the Human Genome Project to date has been the emergence of multiparameter gene expression assays that can be used to direct cancer care, particularly in breast cancer. The 21-gene assay was the first of these to be shown to have sufficiently high analytical validity and clinical utility to be used to identify patients with node negative, ER positive early stage breast cancer who, assuming adequate adjuvant endocrine therapy, could be spared the toxicity of adjuvant chemotherapy based on prognosis alone. Subsequently, several other assays have now been reported to be equally satisfactory for this same use context. The Oxford Overview has suggested that adjuvant chemotherapy reduces the odds of distant recurrence and death by approximately 1/3, regardless of initial prognosis. However, many retrospective correlative studies over the last 4 decades have suggested that chemotherapy may have differing relative activities within distinct biological, or more recently designated “intrinsic,” subtypes, based mostly on expression of estrogen receptor and proliferation genes. Preliminary, prospective retrospective studies by the NSABP in B20 and SWOG in S8814 have, indeed, suggested that patients with ER positive breast cancer with low recurrence scores, as determined by the 21-gene assay, not only have better prognosis than those with intermediate or higher RS, but that chemotherapy may simply not work in this category. However, these studies were both confounded by a number of biases. Therefore, before potentially life-saving chemotherapy is with-held from node positive breast cancer patients based on prediction alone, a prospective clinical trial, SWOG S1007 (the RxPonder Trial), was initiated. The primary objective of the RxPonder trial is to determine if women with node positive, ER positive breast cancer with RS &amp;lt;25 may not benefit from adjuvant chemotherapy even if their prognosis is worse than those with node negative disease. This trial, which is now fully accrued, will not only tell us if we can spare yet another group of women from receiving unnecessary or inactive chemotherapy, it also offers the promise of identification of targets that could be further interrogated with newer biological treatments in the future. Citation Format: Hayes DF. Predictive gene expression profiles in breast cancer, where are we?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES5-1.

Abstract P5-08-06: Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer

Abstract Background: Gene expression profiling assays estimate prognosis &amp; predict benefit from adjuvant chemotherapy in patients (pts) with estrogen receptor positive (ER+) early stage breast cancer (ESBC). The 21-gene recurrence score (RS) and 70-gene signature (MP) are widely used assays. Pts may have both tests performed to adjudicate discordant results. We compared RS and MP in pts with both tests and evaluated their impact on adjuvant treatment decisions. Methods: This was a retrospective clinical cohort study from 5 centers from 2007-2014. Eligibility included ER+ ESBC with RS and MP results from the same tissue sample; exclusions included carcinoma in situ, primary metastatic disease, &amp; bilateral breast cancer. Two definitions of RS risk were evaluated (Genomic Health [GH] or TAILORx [TRx]): low risk (GH:0-17) or (TRx:0-10); intermediate risk (GH:18-30) or (TRx:11-25); and high risk (GH:&amp;gt;31) or (TRx:&amp;gt;26). Demographic, clinicopathologic (CP) data, and treatment decisions were extracted from medical records. Agreement was assessed between RS and MP using weighted kappa scores. CP factors were assessed with the t-test and chi-square test. Results: 123 pts were identified from UCSF or 4 US Oncology Network practices. 60 pts had low risk RS (GH); 27 were low risk by MP (45% agreement). 15 cases had a low risk RS (TRx); 9 were low risk by MP (60%). 10 pts had high risk RS (GH); 8 were high risk by MP (80.0%). Similarly, 18 cases had high risk (TRx) RS;16 were high risk by MP (88%). Using the RS GH risk definition, there was poor agreement for low risk RS/MP and high risk RS/MP (kappa=0.169). However, using the TRx RS risk definition, there was good agreement for low risk RS/ MP and high risk RS/MP (kappa=0.509). 53 pts had intermediate risk RS by (GH); by MP 16 were low risk (30%), and 37 were high risk (70%). 90 pts had an intermediate risk RS by TRx; by MP 34 were low risk (37.8%), and 56 were high risk by MP (62.2%). Using TRx RS increased the number of pts classified as intermediate risk compared to GH RS (73.2 vs 43.1%). Complete adjuvant treatment data were available for 90 patients. Of 40 pts with low risk RS (GH), 25% received chemotherapy associated with node status but not tumor size, grade, or MP. Of 10 pts with high risk RS (GH), 70% received chemotherapy without association with CP features or MP. For the 45 pts with intermediate risk RS (GH), 53% received chemotherapy, without correlation with CP features. Receipt of chemotherapy was positively associated with MP high risk, but this was not significant (odds ratio 2.08, 95% CI 0.54-8.01); p-0.29. Conclusion: Concordance in risk prediction between RS and MP was greater using RS defined by TRx compared to GH, and RS using TRx increases those categorized as intermediate risk. There appeared to be no correlation between CP features and decisions to use chemotherapy across risk groups. Interestingly, in those with intermediate risk RS (GH or TRx), there was a non-significant trend toward use of chemotherapy in those with high risk by MP. Although gene expression tests are used frequently to aid in treatment decisions in ESBC, considerable variation exists in their application in clinical practice. Citation Format: Jiang H, Denduluri N, Majure M, Favret A, Rugo HS. Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-06.

Abstract P4-14-11: Efficacy and cardiac safety in neoadjuvant treatment of Her2 positive breast cancer with concomitant nonpegylated liposomal doxorubicin, docetaxel and dual blockade with trastuzumab and pertuzumab: A retrospective analysis

Abstract Background: Approval to pertuzumab as part of a complete treatment regimen for patients with early stage breast cancer (EBC) before surgery (neoadjuvant setting) was granted by the FDA in September 2013. Since then, the relevance of neoadjuvant treatment in Her2 overexpressing breast cancer has increased considerably. This for instance has been emphasized by the results of the Neosphere Study, in which dual blockade of Her2 was combined with docetaxel as chemotherapy backbone and resulted in favorable pCR rates. But it is likely, that anthracyclines could play an important role in enhancing the effectiveness of the above mentioned treatment. However, there is only little data about the cardiac safety of this combination. The use of liposomal doxorubicin might be a valuable alternative with low cardiotoxicity, as it has been shown in comparable publications without the use of pertuzumab. Therefore we report pCR-rate and cardiac safety of a single arm, retrospective, multicenter analysis of neoadjuvant treatment for Her2 positive EBC with liposomal doxorubicin, docetaxel, trastuzumab and pertuzumab. Methods: In this study 42 women with Her2 positive EBC were investigated in 4 oncological departments in Austria. 41 patients were treated with liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) concurrent with trastuzumab and pertuzumab in standard dosage for 6 cycles as neoadjuvant therapy. One patient refused to receive a chemotherapy but agreed to be treated with combined antibody therapy alone. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥ 50%. Cardiac function was measured by LVEF and was examined at regular intervals (cycles 0-3, cycle 6, FU). Clinical response was evaluated by diagnostic breast imaging after cycles 3 and 6. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 1.3 years. Results: Median age of the patients was 49 years. After 6 cycles of treatment the pCR rate was 76.2%. In this cohort a negative estrogen-and/or progesteron receptor was predictive for pCR (p&amp;lt;0.001). These patients achieved pCR in 95.2%. The antibody only treatment in one case also resulted in a pCR. No patient progressed during treatment. Only one of the patients (2,4%) suffered symptomatic heart failure after surgery. The patient initially presented with an LVEF of 16%. Conclusions: In this multicenter analysis we observed a considerably high rate of pCR in HER2-positive EBC treated with liposomal doxorubicin, docetaxel, trastuzumab and pertuzumab. Especially the group of hormone receptor negative patients showed a remarkable response rate. The addition of liposomal doxorubicin entails a very favorable cardiotoxicity profile. This regimen is a safe treatment option in patients with HER-2 positive breast cancer. Citation Format: Egle D, Hubalek M, Hager C, Poyßl C, Lang A, Jäger T, Volgger B, Abdel-Azim S, Tiechl J, Angerer J, Marth C. Efficacy and cardiac safety in neoadjuvant treatment of Her2 positive breast cancer with concomitant nonpegylated liposomal doxorubicin, docetaxel and dual blockade with trastuzumab and pertuzumab: A retrospective analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-11.

Abstract P2-08-21: Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer

Abstract Background Elevated levels of intratumoral uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to identify patients who might particularly benefit from adjuvant chemotherapy. The clinical utility of ELISA-based protein analysis is, however, greatly limited by the requirement of fresh tumor tisssue. We have therefore evaluated in a large clinical trial patient cohort with long-follow-up whether immunohistochemical detection of uPA and PAI-1 in FFPE archived tumor samples is also able to identify women with poor prognosis. Patients and Methods 547 postmenopausal women with hormone receptor–positive, early breast cancer who had received at least 5 years of endocrine therapy in the prospectively designed ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. uPA and PAI-1 protein expression was evaluated by immunohistochemistry, and correlated with distant-disease free (DDFS) and overall survival (OS). Results Stromal co-expression of uPA and PAI-1 was detected in 166 of 276 (60%) evaluable tumor samples and was weakly associated with tumor size (p=0.012, Chi Square test) but not with age, nodal status, grading, or receptor status. Women with intratumoral uPA/PAI-1 expression were more likely to have a shorter DDFS in multivariate analysis (HR for relapse p=1.870; 95% CI 1.184-2.955; p=0.007 Cox regression analysis) and and OS (adjusted HR for death p=1.291; 95% CI 0.928-1.795; p=0.129) than women without. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DDFS (p&amp;lt;0.0001 log rank test) and OS (p=0.020). Conclusions Stromal co-expression of uPA and PAI-1 in breast cancer samples predicts poor DDFS and OS in postmenopausal women with hormone-receptor positive early-stage breast cancer who receive endocrine therapy. Citation Format: Singer CF, Filipits M, Jahn S, Abete L, Jakesz R, Greil R, Bauernhofer T, Kwasny W, Seifert M, Fitzal F, Schmitt M, Moinfar F, Gnant M. Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-21.

Cost-effectiveness assessment of lumpectomy cavity boost in elderly women with early stage estrogen receptor positive breast cancer receiving adjuvant radiotherapy

Background and purposeBreast radiotherapy (RT) for elderly women with estrogen receptor positive early stage breast cancer (ER+ESBC) improves local recurrence (LR) rates without benefitting overall survival. Breast boost is a common practice, although the absolute benefit decreases with age. Consequently, an analysis of its cost-effectiveness in the elderly ESBC populations is warranted. Material and methodsA Markov model was used to compare cost-effectiveness of RT with or without a boost in elderly ER+ESBC patients. The ten-year probability of LR with boost was derived from the CALGB 9343 trial and adjusted by the hazard ratio for LR from boost radiotherapy trial data, yielding the LR rate without boost. Remaining parameters were estimated using published data. ResultsBoost RT was associated with an increase in mean cost ($7139 vs $6193) and effectiveness (5.66 vs 5.64 quality adjusted life years; QALYs) relative to no boost. The incremental cost-effectiveness ratio (ICER) for boost was $55,903 per QALY. On one-way sensitivity analysis, boost remained cost-effective if the hazard ratio of LR with boost was <0.67. ConclusionsBoost RT for ER+ESBC patients was cost-effective over a wide range of assumptions and inputs over commonly accepted willingness-to pay-thresholds, but particularly in women at higher risk for LR.

Risk factors for brain metastasis as a first site of disease recurrence in patients with HER2 positive early stage breast cancer treated with adjuvant trastuzumab

PurposeThe aim of this study was to determine risk factors for brain metastasis as the first site of disease recurrence in patients with HER2-positive early-stage breast cancer (EBC) who received adjuvant trastuzumab. MethodsMedical records of 588 female patients who received 52-week adjuvant trastuzumab from 14 centers were evaluated. Cumulative incidence functions for brain metastasis as the first site of disease recurrence and the effect of covariates on brain metastasis were evaluated in a competing risk analysis and competing risks regression, respectively. ResultsMedian follow-up time was 36 months. Cumulative incidence of brain metastasis at 12 months and 24 months was 0.6% and 2%, respectively. HER2-enriched subtype (ER− and PR−) tumor (p = 0.001, RR: 3.4, 95% CI: 1.33–8.71) and stage 3 disease (p = 0.0032, RR: 9.39, 95% CI: 1.33–8.71) were significant risk factors for development of brain metastasis as the first site of recurrence. ConclusionsIn patients with HER2 positive EBC who received adjuvant trastuzumab, HER2-enriched subtype (ER− and PR−) tumor and stage 3 disease were associated with increased risk of brain metastasis as the first site of disease recurrence.

Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.

Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I–III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45–87), 79 % postmenopausal, 60 % stage I). BCI predicted a low risk of late recurrence in 59 % of patients versus intermediate/high in 24 and 17 %, respectively. Physician recommendations for extended endocrine therapy changed for 26 % of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54 %. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3631-9) contains supplementary material, which is available to authorized users.

Practice Patterns of Radiation Field Design for Sentinel Lymph Node Positive Early-Stage Breast Cancer

Abstract Background Recent randomized trials have led to decreased use of completion axillary lymph node dissection (ALND) in early-stage breast cancer patients with a positive sentinel lymph node (SLN), causing controversy surrounding radiotherapy coverage of the axilla. We investigated the practice variation among radiation oncologists for regional nodal coverage for clinicopathologic scenarios and evaluated axillary field design decision-making processes. Materials and Methods A customized, web-based questionnaire was e-mailed to 983 community (n = 617) and academic (n = 366) radiation oncologists with a breast cancer subspecialty practicing in the United States. The survey consisted of 18 multiple-choice questions evaluating general clinical preferences surrounding radiation therapy (RT) field design for patients with early-stage breast cancer and a positive SLN. Seven case scenarios were developed to investigate the field design in the setting of specific clinical and pathologic risk factors. Nodal coverage was classified as standard tangents (STs), high tangents (HTs), STs and a supraclavicular field (SCF), or STs and full axillary coverage (AX). Results A total of 145 evaluable responses were collected, with a response rate of 15.0%. Of the respondents, 12 (8.3%) reported using completion ALND for patients with 1 to 3 positive SLNs without extracapsular extension (ECE) and 66 (45.5%) performed ALND with 1 to 3 positive SLNs with ECE. For micrometastatic SLNs, with no lymphovascular system invasion, 115 (87.1%) used STs or HTs. The use of neoadjuvant chemotherapy (NAC) influenced RT field design for patients with a positive SLN without ECE, with 64 (48.5%) using STs and SCF or STs and AX treatment without NAC and 94 (70.7%) using SCF and AX after NAC. With macrometastatic SLN involvement, most respondents preferred SCF (45.27%) and AX (45.66%). In contrast, for micrometastatic involvement, HTs (43.61%) were frequently chosen. Forty (27.8%) reported using online predictive nomograms to predict further axillary involvement, with no difference between the academic and community radiation oncologists ( P = .11). Conclusion In SLN biopsy-positive early-stage breast cancer with omission of completion ALND, axillary RT is increasing used to cover the undissected axilla. Most respondents use SCF or AX for patients with low to intermediate pathologic features. Online prediction nomograms are used by a few practitioners to assist in clinical decision-making in this setting.

Clinical utility of genetic signatures in selecting adjuvant treatment: Risk stratification for early vs. late recurrences

Adjuvant endocrine therapy (ET) reduces the odds of distant recurrence and mortality by nearly one-half in women with hormone receptor (HR) positive early stage breast cancer. While the risk of recurrence is lower for HR positive than negative patients during the first 5–7 years, HR positive patients suffer ongoing recurrences between 0.5 and 2% year over subsequent years. Extended adjuvant ET further reduces recurrence during this late phase of follow-up. ET is associated with post-menopausal side effects (hot flashes, sexual dysfunction, mood changes, and weight gain), and occasional major toxicities (thrombosis and endometrial cancer with tamoxifen; bone mineral loss and possibly heart disease with AIs) persist throughout therapy. Accurate and reliable estimates of the risk of recurrence after five years of ET for women with prior HR positive breast cancer would permit appropriate extended ET decisions. The risk of long-term relapse is related to lymph node status and size of tumor, but these are relatively crude. Several groups have investigated whether multi-parameter tumor biomarker tests might identify those patients whose risk of recurrence is so low that extended ET is not justified. These assays include IHC4, the 21-gene “OncotypeDX”, the 12-gene “Endopredict,” the PAM50, and the 2-gene “Breast Cancer Index (BCI)” assays. The clinical validity of all these tests for this use context have been established, with at least one paper for each that shows a statistically significant difference in risk of distant recurrence during the 5–10 years after the initial five years of adjuvant endocrine therapy. However, the stakes are high, and although each of these represents a “prospective retrospective” study, they require further validation in subsequent datasets before they should be considered to have “clinical utility” and are used to withhold potentially life-saving treatment. Perhaps more importantly, the clinical breast cancer community, and especially the patient, need to determine how low the risk of late recurrence needs to be to forego the toxicities and side effects of extended adjuvant ET.

Cost-Effectiveness of the 21 Gene Assay in Patients with Node-Positive Breast Cancer

Aim: Breast cancer is the most common type of cancer for women. Most guidelines recommend patients with lymph-node positive (LN+) early stage breast cancer to undergo adjuvant chemotherapy to prevent or delay distant recurrence. This may lead to frequent, general usage of chemotherapy accompanied with high costs and side effects. The Oncotype DX, also called 21 Gene Assay, by Genomic Health is a genomic test which predicts the individual risk of breast cancer recurrence as well as the benefits of chemotherapy. Economic analyses have indicated the cost-effectiveness of the 21 Gene Assay for patients with LN- breast cancer. This paper discusses recent research on the cost-effectiveness of using this assay for patients with LN+ breast cancer. Methods: A systematic literature research was undertaken using the following databases: Pubmed, Embase, Business Source Complete and EconLit. Studies found were analysed for study design, parameters, and analysis of uncertainty. The transferability of the results to Germany was examined using a list of criteria. Results: 7 relevant economic analyses were identified. Incremental cost-utility ratios ranged from cost-savings of € 3 548 per patient to additional costs of € 9 113 per QALY gained. The transferability of the results to Germany is limited particularly by differences in the medical cost approach, in absolute and relative prices in health-care, and by practice variation. Conclusion: There is evidence that the cost-utility of the assay when used for LN+ breast cancer is basically comparable to that for the use with the LN- type. More precise results for Germany would require valid data on the risk of recurrence as well as on the description and evaluation of health-related quality of life of patients.

Management of older women with early-stage breast cancer.

Breast cancer is a disease of aging. The average age at diagnosis is 61, and the majority of deaths occur after age 65. Caring for older women with breast cancer is a major challenge, as many have coexisting illness that can preclude optimal breast cancer treatment and which frequently have greater effect than the breast cancer itself. Older patients with cancer should be screened or have a brief geriatric assessment to detect potentially remediable problems not usually assessed by oncologists (e.g., self-care, falls, social support, nutrition). Older women with early-stage breast cancer should be treated initially with surgery unless they have an exceedingly short life expectancy. Primary endocrine therapy should be considered for patients who have hormone receptor-positive tumors and a very short life expectancy, an acute illness that delays surgery, or tumors that need to be downstaged to be resectable. Sentinel node biopsy should be considered for patients in whom it might affect treatment decisions. Breast irradiation after breast-conserving surgery may be omitted for selected older women, especially for those with hormone receptor-positive early-stage breast cancer that are compliant with adjuvant endocrine therapy. The majority of older women with stage I and II breast cancer have hormone receptor-positive, HER2-negative tumors, and endocrine therapy provides them with optimal systemic treatment. If these patients have life expectancies exceeding at least 5 years, they should be considered for genetic assays to determine the potential value of chemotherapy. Partnering care with geriatricians or primary care physicians trained in geriatrics should be considered for all vulnerable and frail older patients.

Abstract P4-11-15: Risk stratification within luminal B breast cancer using a second generation prognostic RNA signature

Abstract Background: Indication to adjuvant chemotherapy in early stage ER-positive breast cancer is usually based on clinico-pathological parameters, and has been recently improved by the introduction of prognostic expression profiles. Clinical or molecular features are efficient in identifying low-risk (pT1, histological grade 1, pN0, low RS, Luminal A subtype) and high-risk patients (&amp;gt;pT1, grade 3, N2, high RS). However, a large group of patients with intermediate clinical or molecular characteristic (grade 2, intermediate RS, luminal B) fall into the category between distinctly low and distinctly high risk and receive no treatment guidance from current decision tools. Methods: From a population of 1929 chemo-naïve, hormone treated, luminal B (Her-2 negative), pT1-pT3, pN0-N1a breast cancer patients diagnosed and treated at the European Institute of Oncology from 1997 to 2005, we selected a random subcohort of 555 cases, in a case-cohort design. All the patients with local or distant metastasis which were not already included were added to the subcohort, leading to a total of 704 patients (208 with local or distant recurrences and 496 random controls). Luminal B status was determined by the immunohistochemical analysis of ER, PgR, HER2 and Ki-67, according to the 2011 St. Gallen criteria. FFPE sections of the primary tumor were analyzed for the mRNA expression of 43 genes by multiplex quantitative PCR. A molecular score (MS) was calculated from the average expression of 23 cell cycle progression genes, the average expression of seven lymphocyte specific genes and the expression of PR and ABCC5, based on a model derived from an independent training cohort. A combined score of MS and the clinical variables of tumor size, grade and node status was modeled in the training cohort and applied to the Luminal B set. The association between MS and the risk of distant metastasis was evaluated in a weighted multivariable Cox regression model, adjusted for traditional clinical factors and Ki-67 labeling index (LI). Results: 640 samples, including 102 distant metastasis, had full clinical and expression data. In the 500 samples from the subcohort, median Ki67 LI was 21% (IQR=11%, Q1=16%, Q3=27%). Either one unit increase of Ki-67 LI (HR 1.06, 95%CI (1.04-1.08), p&amp;lt;0.0001) and of MS (HR 3.4, 95%CI (2.5-4.6), p&amp;lt;0.0001) were highly significant predictors of distant recurrence in univariable analysis. In multivariable analysis, the MS provided independent significant prognostic information after adjustment for Ki-67 LI, tumor size, grade and node status (HR 4.3, 95%CI (2.5-7.3), p=&amp;lt;0.0001). Using the combined score of MS and clinical variables, 383 patients or 77% of the subcohort had an estimated 10 year risk of distant recurrence of ≤10%. Similar results were obtained when samples were re-defined according to 2013 St. Gallen guidelines. Conclusions: The MS provides important prognostic discrimination beyond traditional clinico-pathological characteristics, including Ki-67 LI, in Luminal B breast cancer, and contributes in identifying a subset of patients which may be successfully treated with endocrine therapy only. Citation Format: Giancarlo Pruneri, Vincenzo Bagnardi, Davide Disalvatore, Giuseppe Curigliano, Nicole Rotmensz, Carmen Criscitiello, Darl D Flake II, Susanne Wagner, Alexander Gutin, Jerry Lanchbury, Massimo Barberis, Francesca Lombardi, Giuseppe Viale. Risk stratification within luminal B breast cancer using a second generation prognostic RNA signature [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-15.

Abstract P1-09-29: A new model of care for breast cancer survivorship

Abstract Background Breast cancer (BC) is the most common cancer diagnosed in women. With advances in diagnostics and therapy, early stage disease has an estimated 85% 10-year overall survival. Cancer survivors have unique needs including screening for recurrence, psychosocial concerns, as well as routine health maintenance. There is growing evidence to support the safe transition from oncologist to primary care. This is challenging in the era of complex adjuvant and extended adjuvant programs, which are standard of care for women with hormone receptor positive BC. In February 2013 the Wellness Beyond Cancer Program (WBCP), developed at the Ottawa Regional Cancer Program, started accepting BC patients. A risk stratification system enables the treating oncologist to determine the most appropriate care provider stream based on patient complexity and/or risk of relapse. There are three possible streams: primary care provider (PCP), nurse practitioner (NP), or oncologist. The program offers education on general and breast specific cancer survivorship issues. Unique to our program is a hormone re-assessment review (HRR), scheduled in advance, to discuss switching hormonal therapies and/or extended adjuvant strategies. A rapid re-entry system is in place for those with evidence of disease recurrence or a new primary. Specific aims The aims of our study are: 1. To describe unique aspects of WBCP developed for early stage BC patients 2. To assess efficacy of the WBCP 3. To evaluate safety of the HRR 4. To examine patient and primary care giver satisfaction with the program Methods All BC patients eligible for discharge through the WBCP will be included in the evaluation. We will evaluate patients by examining needs assessments completed at time of referral and one year later, as well as completed patient and PCP satisfaction surveys. The proportion of patients with changing scores, increasing or decreasing, will reflect improvements or worsening of needs. The proportion of both patients and PCP that are/are not satisfied with the program will be recorded and examined further. For the HRR we will code the proportion of patients where the consult was requested and was "scheduled vs. not scheduled". Finally, the number/proportion of patients and reasons for re-entry will be captured. Results February 2013–June 2014, 1339 BC patients were referred to the program, 584 patients to PCP, 740 to NP, and 15 remaining with their oncologist. Early results are reported here with results of the surveys expected by December 2014. 7 patients have required re-entry for disease recurrence and 30 HRR have been booked. No cancer specific negative outcomes have been reported. Survey results addressing patient needs, empowerment and concerns are being collated, with PCP satisfaction results to be reported. Conclusion Our institution has endorsed evidence-based recommendations for an organized survivorship program and has taken it a step further by developing a strategy to address the unique long term needs of hormone positive early stage breast cancer. Early feedback supports that this program has increased patient and caregiver knowledge of survivorship issues and anticipates improved patient empowerment, without compromising cancer specific outcomes. Citation Format: Moira Rushton, Robin Morash, Gail Larocque, Carrie Liska, Roanne Segal. A new model of care for breast cancer survivorship [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-29.

Abstract P5-10-18: The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial

Abstract Background Early stage HER2 amplified breast cancer has a generally favorable prognosis with over 95% of patients showing 2-year disease free survival (DFS) when treated with adjuvant trastuzumab. However, a subset of these tumors are refractory to treatment and present a challenge for the oncologist, particularly when clinical and histologic parameters, including the patient’s nodal and hormonal status, are indicative of lower-risk HER2 positive disease. In this study we describe the genomic landscape of three clinically lower-risk patients with HER2 amplified tumors who relapsed on adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). All patients’ tumors showed high-level HER2 amplification ratios by FISH (8.51-14.46) and were analyzed in parallel with a fourth clinically matched 2-year DFS patient’s tumor from the same trial with high HER2 gene amplification (FISH ratio 11.38). Methods Primary tumor genomic DNA analysis was performed from archival tissue by next generation sequencing (NGS) on the Illumina HiSeq 2500 platform in a CLIA certified laboratory. Tumors were screened for point mutations and copy number alterations (CNAs) by NGS using a targeted-whole exome 613 gene panel. CNAs detected by NGS were confirmed on a DNA microarray featuring high-density probe coverage of the same 613 genes on the targeted panel. CGH chromosome ratio plots were overlaid with algorithmically derived NGS copy number data to generate a map of the chromosomal genomic landscape for each patient’s tumor. Results High-level HER2 gene amplification status was confirmed, and co-amplified chromosome 17 genomic regions were detected in all three relapsed patients’ tumors. High-level HER2 amplification was also confirmed in the non-relapsed patient’s tumor but co-amplified regions were not detected on chromosome 17 or elsewhere in this patient’s tumor genome. Two of the relapsed ER negative tumors shared focal high-level CCNE1 gene amplifications on chromosome 19. High-level MAP3K3 gene amplification on chromosome 17 was detected in the one ER positive tumor from a relapsed patient. Focal PIK3CA gene amplifications were not identified in any of these tumors, but two tumors (one from the relapse group and one non-relapse) were positive for activating H1047R mutations. Conclusions Combined NGS and CGH analysis of HER2 positive early stage breast cancer can be performed in the clinical laboratory to reveal the tumor’s chromosomal genomic landscape. Combined with other test results, this tumor map can help identify patients at high-risk for relapse and reveal alternative predictive biomarkers of therapeutic response. Citation Format: Shelly Gunn, Chris McCaskill, Linda Daley, Agnes Puskas, Lina Asmar, Yunfei Wang, Stephen Jones. The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-18.

The evolving role of adjuvant radiotherapy for elderly women with early-stage breast cancer.

Elderly patients with early-stage breast cancer (ESBC) derive a local control benefit from radiotherapy (RT) after lumpectomy, without any apparent effect on overall survival. Therefore, the use of RT is controversial. In the current study, the authors characterized updated trends in RT for elderly patients with estrogen receptor (ER)-positive ESBC. Patients aged ≥70 years with ER-positive ESBC measuring ≤2 cm after lumpectomy with negative resection margins and known RT details were identified in the National Cancer Data Base. Patients were classified by year of diagnosis and segregated into 3 groups relative to the initial publication and updated presentation of the Cancer and Leukemia Group B (CALGB) 9343 trial. RT use overall, prescription of hypofractionated RT, and use of boost RT were compared between groups using logistic regression analysis, and the influence of clinicopathologic covariates was determined with multivariable logistic regression analysis. A total of 122,796 elderly patients with ER-positive ESBC who were diagnosed between 1998 and 2011 were identified. Overall, 84,649 patients (68.9%) received adjuvant RT, with a decline observed between successive cohorts (71.3% in the pre-initial publication cohort, 69.5% in the pre-update cohort, and 64.7% in the post-update cohort; P <.001). Hypofractionated RT use increased among treated patients over time (P<.001). Boost RT was used in 67.5% of patients, with a decline noted between the pre-update and post-update cohorts (68.7% vs 57.7%; P<.001). Overall RT use as well as use of boost RT were found to be lower among older patients and those with lower-grade or smaller tumors (P<.001), whereas hypofractionated RT was used more commonly in these groups (P<.001). RT use appears to have declined in elderly patients with ER-positive ESBC, a finding that is reflective of evidence-based practice integrating mature trial data. Further research is needed to develop tools to aid in the decision-making process regarding the delivery or avoidance of RT in this setting.

Patients with HER2-positive early breast cancer receiving adjuvant trastuzumab: clinicopathological features, efficacy, and factors affecting survival.

The aim of the present study was to evaluate clinicopathological characteristics of our early stage breast cancer patients who are epidermal growth factor receptor 2 (HER2) overexpressed/ amplified (HER2+), the efficacy of trastuzumab treatment and survival results. Patients with HER2- positive early stage breast cancer receiving adjuvant trastuzumab were investigated retrospectively. Clinicopathological features of 210 patients and treatment outcome were analysed. To evaluate survival rates, the Kaplan-Meier method was used. Univariate and multivariate analyses were conducted with the Cox regression model. Mean age of the patients was 51.8, 71.9% being postmenopausal. Some 37.6% of patients were node negative, and 31% had T1 tumor size and 52.4% were positive for estrogen receptor. Of 210 patients, 89.5% completed planned 52 weeks adjuvant trastuzumab treatment. The median follow up was 27.5 months (6.0-86.0 ). Relapse free survival (RFS) was 68.0 months (95% CI: 62.1-74.0) and overall survival (OS) was 74.8 months (95% CI: 69.5-80.1). The 3 year OS for all patients was 92.0% and RFS was 79.6%. During follow up, relapse was detected at the rate of 14.3%. Trastuzumab associated cardiotoxicity was found at the rate of 3.3%. In univariate analyses, larger tumor size and grade III were significantly associated (p<0.05) with RFS. Multivariate analyses of covariates displaying p<0.05 identified grade III as an independent prognostic factor. In the present study, it was established that trastuzumab had a satisfactory safety profile and treatment efficacy as in other clinical studies and that among clinicopathological factors evaluated, only being grade 3 had a significant effect on RFS. The occurrence of relapse with adjuvant trastuzumab makes it necessary to identify molecular predictors, which will define this group better and help explain resistance to anti HER2 based therapies.