Berry DA Research Articles

Abstract P3-19-25: ICE3 trial - Radiation following cryoablation for low-risk breast tumors: Assessment of safety and variables that effect referral

Abstract Objectives. The ICE3 Trial is a study aimed to evaluate safety and efficacy of cryoablation in low-risk early-stage breast cancer in women ≥60 years. ICE3 Trial enrolled patients from 2014 through February 2019. In total, 206 females underwent cryoablation: however, 3 received treatment that was off protocol and 9 were excluded due to inclusion criteria. Of the 194 patients remaining, 27 had adjuvant radiotherapy. We aimed to examine treatment decisions regarding radiation referral and evaluate safety of the combined modalities in this population. Methods. The ICE3 study is a multi-center, single arm, non-randomized controlled clinical trial with 19 US sites. Data regarding factors that may affect recommendation for adjuvant radiotherapy was evaluated, including the patients' age, ethnicity, tumor characteristics and the treatment center location. We evaluated patient factors that might affect adverse events (AEs) including BMI, nicotine use, diabetes mellitus, as well as adjuvant therapy received. Results. All patients had early-stage breast cancer, 188 were Luminal A (96.9%), 194 were Her-2 negative (100%), 194 were ER positive (100%), 181 were PR positive (93.3%), 98 were Nottingham score 1 (50.5%) and the reminder (96) were Nottingham score 2 (49.5%). Overall mean age was 75.32 years (SD= 7.01), 70.81 years for the radiated group (n=27, SD=6.48) and 76.05 years (n=167, SD=6.83) for the non-radiated group respectively. We evaluated the number and percentage of patient’s receiving radiation at each center as a substitute for referral pattern at the centers. In the entire cohort, 27 of 194 patients (13.32%) underwent radiotherapy. We observed a wide range of variability between the centers (0%-60%) of patients underwent radiotherapy). The age of patient (P-value=0.0006) and the center (P-value=0.0009) were the only factors that appeared to influence if the patient received adjuvant radiation. In all but one center, the mean age of patients who received radiotherapy was lower than those who did not. Other factors including ethnicity, Nottingham score, tumor borders, tumor size, depth and shape did not impact the decision to offer radiation. Regarding safety evaluation, we compared factors leading to device-related AEs between radiated and non-radiated groups. In the total cohort, 21 of 194 patients had mild AEs (10.8%). In the radiated group, 5 AEs occurred in 3 of 27 patients (11.1%). AEs were classified as mild and included injection site pain, bruising, localized edema and breast infection. In the non-radiated group, 36 AEs occurred in 18 of 167 patients (10.8%). AEs were classified as non-serious; 31 were mild and 5 were moderate and included pain, bruising, hemorrhage, rash, induration and thermal injury. We also considered other factors such as age, adjuvant therapy, BMI, nicotine use and whether the patient had diabetes mellitus. No statistically significant factor was observed to effect AE. Conclusions. Cryoablation in the ICE3 trial was used as a replacement for surgical resection in patients with low-risk breast tumors. Many of these patients were elderly and could avoid radiation based on data from CALGB 93431. Still, 13.32% of patients received radiation and contributing factors seem to be patient’s age and referral practice of the treatment center. AEs in the cohort were infrequent and typically minor, and there was no difference between the radiated and nonradiated groups. Radiation in the setting of cryoablation is safe with minimal short-term side effects. 1Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343.Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, Muss HB, Smith BL, Hudis CA, Winer EP, Wood WCJ Clin Oncol. 2013 Jul 1; 31(19):2382-7. Citation Format: Jill R Dietz, Richard E Fine, Susan K Boolbol, Roni Haziza. ICE3 trial - Radiation following cryoablation for low-risk breast tumors: Assessment of safety and variables that effect referral [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-25.

One year on: The impact of COVID-19 on clinical research

One year on: The impact of COVID-19 on clinical research

Abstract P3-08-04: Transient state change, but not permanent subtype change, after HER2-targeted therapy for HER2-positive breast cancer

Abstract Background: In CALGB 40601 (Alliance, NCT00770809), a neoadjuvant phase III trial of paclitaxel and trastuzumab with or without lapatinib for 12 weeks for patients with HER2-positive breast cancer, 33% of pretreatment tumors were Luminal A subtype, however, 69% of post-treatment samples with residual disease were Luminal A subtype. In addition, 71% of Luminal B (12/17) and 67% of HER2-Enriched (6/9) tumors changed into Luminal A, while 80% of Luminal A (20/24) remained Luminal A (Carey et al. J Clin Oncol. 2016). It is not known whether this shift to Luminal A was transient or permanent. Methods: We selected matched pairs of pre- and post-treatment 40601 samples with tumor purity >10% based upon DNA analyses to ensure all samples contained tumor. PAM50 intrinsic subtyping was applied to the 40601 samples gene expression data using a two-step normalization process based on The Genome Cancer Atlas, and PAM50 training set. In addition, a HER2-enriched expression subtype patient-derived xenograft (PDX) tumor called WHIM35, was studied and was either untreated (n=10), or treated with lapatinib at 220 mg/kg for 1 week (wk) (n=5), for 2 wks (n=8), or for 3 wks (n=4). We also treated WHIM35 tumors with lapatinib for 2 wks (on) and then removed laptinib for 1 wk (off) (n=6), or for 2 wks on and 2-4 wk off (n=6), and finally for 3 wks on, and 1 wk off (n=3). PAM50 intrinsic subtyping was applied to the PDX gene expression data and subtype assessed as well as a genomic-based proliferation score. ANOVA p-values were calculated by comparing median values across all gene signature or correlation scores. Results: We found 10 pairs of 40601 samples that kept their tumor purity values, however, their subtype changed to Luminal A after treatment (i.e., in the residual disease), and in these cases no minor tumor subclone became a dominant clone in the post treatment sample. Pretreatment subtypes were 6 Luminal B, 3 Luminal A, and 1 HER2-enriched. The tumor purity values did not change after the treatments, but correlation to Luminal A was significantly higher (p=0.01), while correlation to HER2-enriched (p=0.004) and proliferation signature scores (p=0.003) were significantly lower in the post-treatment samples. Among the WHIM35 PDX tumors, one sample changed its subtype from HER2-enriched to Luminal A after the lapatinib treatment and the rest remained HER2-enriched, suggesting environmental differences between patient samples and the PDX model. However, correlation to Luminal A was significantly higher in all lapatinib treated WHIM35 samples (p=8.3e-12), and notably went back to the initial low levels just one week after removing lapatinib. Likewise, correlation to HER2-enriched (p=1.2e-10) and proliferation signature scores (p=6.2e-12) also got lower while treated with lapatinib, but went back to the initial levels after cessation of treatment. Conclusions: Our findings suggest that the apparent subtype change during HER2-targeting therapy is not permanent, but is more likely a transient state change from a HER2-enriched subtype into a more Luminal A-like state. When we plan additional treatment strategies using residual disease phenotypes, it may not be clear what is the true subtype of the sample due to this inherent plasticity. Citation Format: Tanioka M, Parker JS, Henry LN, Tolaney S, Dang C, Krop IE, Harris L, Polley M, Berry DA, Winer EP, Carey LA, Perou CM. Transient state change, but not permanent subtype change, after HER2-targeted therapy for HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-04.

Abstract GS3-02: Invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab

Abstract Purpose Dual HER2 targeting increases pathologic complete response (pCR) rate to neoadjuvant therapy and improves outcomes in both early and metastatic HER2-positive disease. CALGB 40601 is a randomized phase III trial examining the impact of dual HER2 blockade consisting of trastuzumab (H) and lapatinib (L) added to paclitaxel (T) on pCR, considering tumor and microenvironment molecular features. We previously found that pCR was numerically but not significantly increased with dual therapy, and that tumor molecular subtype and evidence of immune activation significantly and independently affected pCR (Carey et al, JCO 2016). In this secondary analysis, we sought to evaluate the effects of treatment arm and gene expression-defined subgroups on invasive disease free survival (IDFS). Patients and Methods Patients (Pts) with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment with equal probabilityto paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. A paclitaxel plus lapatinib (TL) arm was closed early based on reports of futility from other trials. A secondary endpoint was IDFS, defined as the time from surgery until local or distant recurrence, new primary, or death from any cause, whichever was first. Gene expression signatures were identified by RNA sequencing. Results Between 12/2008 and 2/2012, 305 pts were enrolled. 261 pts had IDFS and gene expression information available (THL, n = 103; TH, n =101; TL, n = 57); there were no significant differences in clinical characteristics between this subset and the entire population. The median IDFS follow-up was 4.6 years with 40 IDFS events having occurred (THL, n=7; TH, n=19; TL, n=14). IDFS was significantly longer in the THL arm compared to standard TH (HR=0.34; 95% CI: 0.14-0.82; p=0.02). IDFS was also significantly longer among pCR than non-pCR pts (HR=0.40; 95% CI: 0.19-0.81; p=0.01), and did not differ by hormone receptor (HR) status, clinical stage, tumor size, race, menopausal status or age. Among gene expression signatures, only immune activation measured by an IgG signature was associated with longer IDFS (HR=0.71; 95% CI: 0.51-0.98; p=0.04); this signature was previously also associated with pCR. Multivariate analysis showed dual therapy (HR=0.35; p=0.02), pCR (HR=0.36; p=0.01), IgG (HR=0.69; p=0.05), and molecular subtype (LumA vs HER2E, HR=0.24, p=0.005) were associated with longer IDFS. A subgroup analysis by hormone receptor status revealed that among pts with HR+ disease, pts with luminal A experienced longer IDFS (HR=0.23; p=0.02) compared to those with luminal B or HER2-enriched molecular subtypes. Conclusion Dual HER2-targeting with lapatinib added to 16 weeks of TH produced significantly longer IDFS than TH alone, despite modest effects on pCR. Similar to pts with HER2-negative disease, pts with luminal A had better IDFS than those with other molecular subtypes. Immune activation as measured by RNA-based signature independently predicted both pCR and IDFS. Support: U10CA180882, U10CA180821, U24CA196171, P50-CA58823, Susan G Komen, BCRF Citation Format: Krop IE, Hillman D, Polley M-Y, Tanioka M, Parker J, Huebner L, Henry NL, Tolaney SM, Dang C, Harris L, Berry DA, Perou CM, Partridge A, Winer EP, Carey LA. Invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-02.

Abstract P5-11-18: Trajectory of patient (Pt) reported physical function (PF) during and after neoadjuvant chemotherapy in the I-SPY 2 trial

Abstract Background Patients (pts) receiving chemotherapy for breast cancer experience toxicities impacting short and long-term quality of life (QOL). Within I-SPY 2, a trial adaptively randomizing stage II/III breast cancer pts to neoadjuvant chemotherapy +/- an investigational agent, we are collecting pt reported outcome (PRO) data to understand the impact of investigational agents on QOL. This PRO sub-study provides a unique opportunity to study QOL longitudinally and explore how pt and tumor characteristics, exposure to investigational therapies, and surgical outcome impact QOL. Methods Pts enrolled in this trial receive paclitaxel (T) +/- an investigational agent for 12 weeks followed by 4 cycles of doxorubicin and cyclophosphamide (AC). Surveys include the EORTC QLQ-C30 and BR-23, and PROMIS measures for QOL metrics including but not limited to physical function (PF), anxiety, and depression. Surveys are administered pre-chemotherapy to 2 years post-surgery. PF data from the EORTC and PROMIS instruments was analyzed for 238 pts at 5 sites (UCSF, UCSD, U of Pennsylvania, U of Minnesota, and Swedish Cancer Center). 48 pts completed baseline, inter-regimen (between T and AC), pre-operative and post-surgery surveys. Of the 48 pts 32 completed a 6-month follow up (FUP) and 31 completed a 1-year FUP survey. A linear mixed effect model, adjusting for HER2 status and treatment type was used to evaluate changes in PF over time. Sample size is small and statistics are descriptive rather than inferential. Results Median age of pts in this analysis was 50 (range 27-72). Table 1 shows PROMIS & EORTC PF scores in this cohort.Time Point PROMISEORTC nMeanSEMeanSEPre-TreatmentAll4852.51.092.02.0 HER2+1553.51.594.12.2 HER2-3352.11.391.12.8Inter-RegimenAll4845.51.282.22.7 HER2+1548.62.384.44.2 HER2-3344.11.381.23.4Pre-SurgeryAll4843.91.179.42.3 HER2+1545.12.275.34.1 HER2-3343.41.381.32.86-Month FUPAll3248.11.487.41.9 HER2+1247.52.285.03.3 HER2-2048.41.888.92.41 Year FUPAll3148.91.488.43.1 HER2+949.12.988.95.4 HER2-2248.81.788.33.8 At baseline, mean PROMIS PF scores were higher than the US average (mean = 50) but declined as expected throughout treatment. HER2+ patients experienced a similar degree of recovery as HER2- pts post-surgery despite adjuvant treatment with Herceptin. Analysis of post-operative PROMIS PF indicated an average score within the U.S. general population (mean =50) but did not return to higher functioning seen at baseline levels (mean 52.5, p-value < 0.05). Analysis of the EORTC PF sub-scale demonstrated a similar trend; however, the baseline and post-operative difference was not significant (p-value=0.15 for both FUP). Finding supports PROMIS PF ability to measure high functioning cancer patients. Conclusions: Among a subset of pts who completed all surveys in the I-SPY 2 QOL substudy, PF did not return to baseline at 6-12 months post-operatively. Through transition to an electronic platform of data collection we hope to improve compliance with survey completion. We continue to analyze other QOL measures and plan to correlate QOL data with treatment arm, adverse events, comorbidities, and response to neoadjuvant treatment. Citation Format: Shah M, Jensen R, Yau C, Straehley I, Berry DA, DeMichele A, Buxton MB, Hylton NM, Perlmutter J, Symmans WF, Tripathy D, Yee D, Wallace A, Kaplan HG, Clark A, Chien AJ, I-SPY 2 Investigators, Esserman LJ, Melisko ME. Trajectory of patient (Pt) reported physical function (PF) during and after neoadjuvant chemotherapy in the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-18.

Abstract P6-11-02: Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial

Abstract Background:Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods:Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results:Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganetespib Is Superior to ControlPredictive Probability of Ganetespib Success in a Phase 3 Trial Ganetespib N = 93Control N = 140 All HER2-26% (16%-37%)18% (8%-28%)91%47%HR+/HER2-15% (4%-27%)14% (4%-24%)60%19%HR-/HER2-38% (23%-53%)22% (9%-35%)96%72% Conclusion:The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen's likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van't Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-02.

Abstract PD1-03: Multivariate analysis of subtype and gene expression signatures predictive of pathologic complete response (pCR) in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

Abstract Support: U10CA180821, U10CA180882 Background: The addition of either carboplatin (Cb) or bevacizumab (Bev) to standard neoadjuvant chemotherapy (NACT) increases pCR rates in TNBC overall and in the dominant subset of basal-like cancers (Sikov et al, JCO 2015; Sikov et al, SABCS 2014). Multigene expression signatures more accurately reflect tumor biology for response prediction and prognosis than individual gene expression. We evaluated the ability of multivariate analysis of gene expression signatures to create predictive models for achievement of pCR in TNBC. Methods: RNA sequencing was successful on 389 pretreatment samples from patients with available pCR data, and used to assign PAM50 subtype and calculate gene signatures scores for 489 published expression signatures. Elastic net, a penalized regression model for high dimensional variable selection, was used to select features associated with pCR in all TNBC and in the basal-like subset. Models were derived in a training set (2/3 of samples) and validated in a separate test set (1/3). A separate model was derived using 196 TNBC samples from patients treated only on the standard NACT +/- Cb arms for application to external TNBC neoadjuvant data sets not treated with Bev. Results: Consistent with our prior partial data set, 343 (88%) of the cancers were classified basal-like, in whom the in breast pCR rate was 54%; the remainder were classified normal-like (n=32) or HER2-enriched (n=14) with a non-basal pCR rate of 56%. Elastic Net analysis in all TNBC generated a model of 23 signatures and treatment assignment with 68% sensitivity and 64% specificity. The area under the curve was 0.64 (p-value=0.0019). Nineteen modules, including immune cell signatures (Th1, NK, IgG), immunoglobulin variable region expression, addition of Cb and Bev and expression of genes at regions 15q25, 17p11.2-13.3, and 8p22 were positively associated with response. The latter two regions are associated with aggressive breast cancer, and while not part of the 17p13 signature, this region contains TP53, a gene important in TNBC. Six modules were associated with resistance, including luminal progenitor, TGFB, NOTCH, FOS/JUN, 8p amplicon, and eosinophil signatures. When limited to basal-like samples, a model including 32 modules and addition of Cb and Bev was generated, with 62.3% sensitivity and 59.1% specificity. Seventeen features were selected in both models. Omitting Bev-treated patients, a model using just the gene expression signatures was developed. The predictive value of this model will be assessed using an external cohort of TNBC patients treated with neoadjuvant docetaxel and Cb (NCT01560663) and results presented. Conclusions: Multivariate analysis of gene expression signatures derived from pretreatment samples enabled the construction of models to predict achievement of pCR in TNBC. These models performed well on our test set, and will be assessed for their predictive ability in other TNBC data sets. If validated by future analyses, this could help us identify patients likely to achieve pCR with standard NACT and may benefit from the addition of agents such as Cb or Bev. ClinicalTrials.gov Identifier: NCT00861705. Citation Format: Hoadley KA, Hyslop T, Fan C, Berry DA, Hahn O, Tolaney SM, Sikov WM, Perou CM, Carey LA. Multivariate analysis of subtype and gene expression signatures predictive of pathologic complete response (pCR) in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD1-03.

Abstract S3-05: Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer

Abstract Background: RNA profiling and mutational analyses in CALGB 40601 (NCT00770809) found significant impact on pathologic complete response (pCR) rates from tumor (intrinsic subtype, p53 mutation) and microenvironmental (immune cell) features. Integrated analysis across platforms is needed to better understand the roles of these different factors with respect to response to HER2-targeted therapies. Methods: We performed a comprehensive genomic analyses on pCR, defined as no invasive tumor in the breast, by integrating clinicopathological information with somatic mutation status, 422 segment-level DNA Copy Number Alterations (CNAs), and 510 gene expression signatures using mRNAseq and DNA exome sequencing from 213 pre-treatment tumors. Excluding 48 samples in the TL arm that was closed early due to futility, and 4 Normal-like tumors, the dataset consisted of 161 patients from TH and THL arms including 47 HER2-enriched (HER2E), 8 Basal-like, 54 Luminal A, and 52 Luminal B, all of whom received H. The main analysis was performed using the Elastic Net on multivariate logistic regression models for predicting pCR. The samples were divided into a training and a test set, then models were built to predict pCR by 10-fold cross-validation in the training set, then applying the best model onto the test set to construct ROC curves and evaluate prediction accuracy by calculating area under ROC (AUC). We also used the DawnRank, a network-based bioinformatics tool that integrates DNA and RNA data to identify driver genes, to find predictors of resistance to H-containing therapies. Results: Among clinicopathological factors, clinical estrogen/progesterone receptor (ER/PgR) status and intrinsic subtype by PAM50 were statistically associated with pCR, but treatment arm (TH vs THL) and stage were not. In the Elastic Net analysis, the models incorporating either gene signatures (AUC: 0.724) or CNAs (AUC: 0.777) were more predictive of response than mutation status model (AUC: 0.635). Gene signatures and CNAs were further combined with either mutation status (AUC: 0.773), clinical ER/PgR status (AUC: 0.787) or ER/PgR status plus intrinsic subtype (AUC: 0.784). The combination with the highest AUC comprised gene signatures, CNAs, and ER/PgR status, and demonstrated that CNAs at Chromosome (Chr.) 6p, 10q22, or 11q23, the signature of Correlation to HER2E, and a T-cell signature, positively predicted pCR and that Luminal and PgR gene signatures were negative predictors. The CN gain of Chr.6p, which contains the HLA genes, predicted for pCR and was associated with higher expression of HLA genes and B cell / IgG signatures. The CN loss of Chr.11q23 including CD3D, CD3E, and CD3G was also identified by DawnRank as a region associated with resistance. Conclusions: Tumor genetics (CNAs), tumor RNA subtype (HER2E, Luminal), and the microenvironment (immune cells) were independently predictive of response to H-containing therapies and biologically and clinically important for HER2-positive breast cancer, supporting integrated RNA- and DNA-based tumor assessments to clarify response to HER2-targeting. Support: U10CA031946/033601/180821/180882/180888. Citation Format: Tanioka M, Fan C, Carey LA, Hyslop T, Pitcher BN, Parker JA, Hoadley KA, Henry NL, Tolaney S, Dang C, Krop IE, Harris L, Berry DA, Mardis E, Perou CM, Winer EP, Hudis CA. Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-05.

Abstract P2-11-02: A longitudinal look at toxicity management within a platform trial: Lessons from the I-SPY 2 TRIAL

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate a series of investigational agents or regimens when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent (I) +paclitaxel (T) qwk, doxorubicin & cyclophosphamide (AC) q2-3 wk x 4 vs. T+/-HP/AC (control arm(s)). Although the primary endpoint is pathologic complete response (pCR) at surgery, a key secondary aim is to evaluate the toxicity profiles of these investigational agents. Distinct aspects of safety monitoring in a platform trial, as well as the specificities of safety management in a potentially curative population make the experiences from I-SPY 2 valuable to the community. Methods: Inclusion and exclusion criteria are uniformly applied to all women in I-SPY 2. When a new investigational agent/regimen is planned for the trial, agent specific laboratory/hematologic limits or additional required tests are added, as needed. Eligibility criteria remain in the trial for its duration and apply to all investigational and control arms. Laboratory and adverse event data are collected and monitored in real time. The lead investigator of the investigational agent/regimen who chaperones a specific agent/regimen through the trial (“Agent Chaperone”), Medical Monitor, I-SPY 2 Agents Committee, CRO safety group, and an active DSMB that meets monthly oversee the management of toxicities within each investigational agent/regimen of the trial. Toxicity profiles for an investigational agent/regimen are compared to their relevant control. Safety analyses are intention to treat. Results: From March 2010-May 2016, eleven (11) investigational agents/regimens have opened (and 6 have completed evaluation) and 973 women have been randomized. These agents/regimens span a variety of mechanisms of action including targeted therapies such as small molecule inhibitors and antibodies, as well as immunotherapies. Additions to the trial's eligibility criteria have been made with new investigational arms. Adverse events of special interest have been monitored for each investigational arm and specific toxicities treated uniformly when applicable. A risk-based monitoring plan has been implemented that focuses on the collection and review of the trial's most critical data elements including serious adverse events and drug specific safety issues, allowing for a more efficient and focused effort. Safety issues have been quickly addressed and requirements updated, when needed, given the importance of limiting (or avoiding) long-term safety complications within this neoadjuvant patient population. Accrual to the trial has (been) maintained over time and the safety of trial participants has been well managed. Conclusion: A platform trial requires an evolving, and focused safety-monitoring process that adapts as new investigational agents are included. I-SPY 2's infrastructure and team science approach has created a system to manage patients across multiple arms with different risk profiles. These practices will support the safe evaluation of additional new combinations and regimens and serves as a guide for safety management within standing platform trials. Citation Format: Paoloni M, Lyandres J, Buxton MB, Berry DA, Esserman LJ, DeMichele A, Yee D. A longitudinal look at toxicity management within a platform trial: Lessons from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-02.

Abstract P6-11-04: The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent(I) +paclitaxel(T) qwk, doxorubicin & cyclophosphamide(AC) q2-3 wk x 4 vs. T/AC (control arm). The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Regimens may also leave the trial for futility (< 10% probability of success) or following accrual of maximum sample size (10%< probability of success <85%). We report the results for experimental arm Ganitumab, a type I insulin-like growth factor receptor (IGF1R) inhibitor. IGF1R inhibitors are known to induce insulin resistance and all patients assigned to Ganitumab received metformin. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ and HER2+ tumors were ineligible for randomization. Hemoglobin A1C≥ 8.0% were ineligible. MRI scans (baseline, 3 cycles after start of therapy, at completion of weekly T and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganitumab was given at 12mg/kg q2 weeks and metformin at 850mg PO BID, while receiving ganitumab. Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. Ganitumab/metformin was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Results: Ganitumab/metformin did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual to this arm stopped. Ganitumab/metformin was assigned to 106 patients; there were 128 controls. We report probabilities of superiority for Ganitumab/metformin over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganitumab/metformin and control, for each of the 3 biomarker signatures, using the final pathological response data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganitumab/ Metformin Is Superior to ControlPredictive Probability of Success in Phase 3 Ganitumab/ Metformin N = 106Control N = 128 All HER2-22% (13%-31%)16% (10%-23%)89%33%HR+/HER2-14% (4%-24%)12% (4%-19%)66%21%HR-/HER2-32% (17%-46%)21% (11%-32%)91%51% Conclusion: The I-SPY 2 adaptive randomization study estimates the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. The value of I-SPY 2 is to give insight about the performance of an investigational agent's likelihood of achieving pCR. For Ganitumab/metformin, no subtype came close to the efficacy threshold of 85% likelihood of success in phase 3, and this regimen does not appear to impact upfront reduction of tumor burden. Our data do not support its continued development for the neoadjuvant treatment of breast cancer. Citation Format: Yee D, Paoloni M, van't Veer L, Sanil A, Yau C, Forero A, Chien AJ, Wallace AM, Moulder S, Albain KS, Kaplan HG, Elias AD, Haley BB, Boughey JC, Kemmer KA, Korde LA, Isaacs C, Minton S, Nanda R, DeMichele A, Lang JE, Buxton MB, Hylton NM, Symmans WF, Lyandres J, Hogarth M, Perlmutter J, Esserman LJ, Berry DA. The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-04.

SC28.04 Adaptive Clinical Trial Designs

SC28.04 Adaptive Clinical Trial Designs

Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Abstract Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons <0.0001: Table 1 pCR BreastpCR Br/AxpCR Br/Ax or RCB IYes/No N (%)231 (52%)/212 (48%)207 (47%)/236 (53%)266 (60%)/177 (40%)EFS-HR0.33 (0.22-0.50)0.30 (0.19-0.46)0.29 (0.20-0.43)OS-HR0.28 (0.17-0.46)0.20 (0.11-0.36)0.21 (0.13-0.34) Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Table 2 CbBevN (Yes/No)225/218222/221EFS - HR0.84 (0.58-1.22) p=0.360.80 (0.55-1.17) p=0.25OS - HR1.15 (0.74-1.79) p=0.530.76 (0.49-1.19) p=0.23 Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [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 S2-05.

Mammography for Older Women?

Mammography for Older Women?

PANEL PROBIT WITH FLEXIBLE CORRELATED EFFECTS: QUANTIFYING TECHNOLOGY SPILLOVERS IN THE PRESENCE OF LATENT HETEROGENEITY

SUMMARYIn this paper, we introduce a Bayesian panel probit model with two flexible latent effects: first, unobserved individual heterogeneity that is allowed to vary in the population according to a nonparametric distribution; and second, a latent serially correlated common error component. In doing so, we extend the approach developed in Albert and Chib (Journal of the American Statistical Association 1993; 88: 669–679; in Bayesian Biostatistics, Berry DA, Stangl DK (eds), Marcel Dekker: New York, 1996), and in Chib and Carlin (Statistics and Computing 1999; 9: 17–26) by releasing restrictive parametric assumptions on the latent individual effect and eliminating potential spurious state dependence with latent time effects. The model is found to outperform more traditional approaches in an extensive series of Monte Carlo simulations. We then apply the model to the estimation of a patent equation using firm‐level data on research and development (R&D). We find a strong effect of technology spillovers on R&D but little evidence of product market spillovers, consistent with economic theory. The distribution of latent firm effects is found to have a multimodal structure featuring within‐industry firm clustering. Copyright © 2012 John Wiley & Sons, Ltd.

Myelodysplastic Syndromes: It Is All in the Genes

REFERENCES 1. Hershman DL, Wilde ET, Wright JD, et al: Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer. J Clin Oncol 30:806-812, 2012 2. Mukherjee S: The Emperor of All Maladies. New York, NY, Scribner, 2010, pp 423-429 3. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 4. Giordano SH, Duan Z, Kuo Y-F, et al: Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst 98:382-388, 2006 5. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 6. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B Experience. J Clin Oncol 25:3699-3704, 2007 7. Piccart-Gebhart MJ: Mathematics and oncology: A match for life? J Clin Oncol 21:1425-1428, 2003 8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005 9. Venturini M, Del Mastro L, Aitini E, et al: Dose-dense adjuvant chemotherapy in early breast cancer patients: Results from a randomized trial. J Natl Cancer Inst 97:1724-1733, 2005 10. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006 11. Bonilla L, Ben-Aharon I, Vidal L, et al: Dose-dense chemotherapy in nonmetastatic breast cancer: A systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845-1854, 2010 12. Citron ML: Dose-dense chemotherapy: Principles, clinical results and future perspectives. Breast Care (Basel) 3:251-255, 2008 13. Hershman D, Neugut AI, Jacobson JS, et al: Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196-205, 2007 14. Smith TJ, Hillner BE: Bending the cost curve in cancer care. N Engl J Med 364:2060-2065, 2011 15. Goldhirsch A, Wood WC, Coates AS, et al: Strategies for subtypes: Dealing with the diversity of breast cancer—Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22:1736-1747, 2011

ES6-3: Breast Cancer in the Older Adult.

Abstract Breast cancer is a disease associated with aging. In the US, the median age of breast cancer diagnosis and death is 61 years and 68 years, respectively. The number of older adults in the US is rising, and the number of individuals age 65 and older is expected to double by the year 2030. This demographic shift will lead to an increase in the number of individuals diagnosed with breast cancer. It is estimated that from 2010 to 2030 there will be a 57% growth in the number of new cases of breast cancer in patients age 65 and older.1 A challenge in caring for older adults with breast cancer is that they have been historically underrepresented in clinical trials that set the standard for breast cancer care.2 However, a growing body of evidence-based literature can be utilized to inform and optimize the care of the older adults with breast cancer. This presentation will focus on the treatment of early stage breast cancer in older adults, including the risks and benefits of local and systemic therapies, as well as survivorship issues. Recently reported phase III studies have led to advances in the treatment of older adults with breast cancer. A phase III randomized study evaluated the role of radiation therapy following lumpectomy in patients age 70 and older with stage I hormone receptor (HR) positive breast cancer who received treatment with tamoxifen. Receipt of radiation therapy was associated with a decrease in the risk of locoregional recurrence; however, there was no difference in overall survival. The study results underscore the importance of competing comorbidity as a cause of death in older adults with early stage breast cancer.3 The role of axillary lymph node dissection was evaluated in a randomized study of women over age 60 with node-negative, HR positive breast cancer who received treatment with tamoxifen. Patients were randomized to breast surgery and axillary dissection, or breast surgery alone. There was no difference between disease-free and overall survival in the 2 study arms.4 A phase III randomized study evaluated the efficacy of standard adjuvant IV chemotherapy (doxorubicin and cyclophosphamide [AC] or cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) versus oral chemotherapy (capecitabine) in patients age 65 and older with stage I-III breast cancer. Those patients who received standard chemotherapy showed improvement in progression-free and overall survival compared with patients who received capecitabine. This study demonstrates that IV polychemotherapy regimens remain the standard of care for older adults who are prescribed adjuvant chemotherapy.5 These phase III studies advance our understanding in the care of older adults with breast cancer. Furthermore, they demonstrate the feasibility and importance of accruing older adults to phase III trials, which will improve our evidence-based care of this growing population.

Is It Time for (Survivorship Care) Plan B?

between docetaxel and gemcitabine in human gastric cancer cell lines. Clin Cancer Res 9:900-905, 2003 15. Hirth J, Watkins PB, Strawderman M, et al: The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 6:12551258, 2000 16. Hertz DL, Dees EC, Motsinger-Reif AA, et al: Breast cancer patients carrying the CYP2C8*3 variant are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment. Presented at the 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010 (abstr PD07-10) 17. Berry DA: Adaptive clinical trials: The promise and the caution. J Clin Oncol 29:606-609, 2011 18. Woodcock J, Griffin JP, Behrman RE: Development of novel combination therapies. N Engl J Med 364:985-987, 2011

The first national public breast cancer screening program in Saudi Arabia

BACKGROUND AND OBJECTIVES:Despite its relatively low incidence in Saudi Arabia, breast cancer has been the most common cancer among Saudi females for the past 12 consecutive years. The objective of this study was to report the results of the first national public breast cancer screening program in Saudi Arabia.METHODS:Women 40 years of age or older underwent breast cancer screening. Mammograms were scored using the Breast Imaging-Reporting and Data System (BI-RADS). Correlations between imaging findings, risk factors and pathological findings were analyzed.RESULTS:Between September 2007 and April 2008, 1215 women were enrolled. The median age was 45 years, and median body mass index was 31.6 kg/m2. Sixteen cases of cancer were diagnosed. No cancer was diagnosed in 942 women with R1/R2 scores, and only 1 case of cancer was diagnosed in 228 women with R0/R3 scores. However, among 26 women with R4/R5 scores, 50% had malignant disease and 35% had benign lesions. No correlation was found between known risk factors and imaging score or cancer diagnosis.CONCLUSIONS:Public acceptance of the breast cancer screening program was encouraging. Longitudinal follow-up will help in better determining the risk factors relevant to our patient population.

Schizophrenia in a worldwide perspective: explaining similarities and differences

Schizophrenia in a worldwide perspective: explaining similarities and differences

CN1 MODELING THE IMPACT OF TECHNOLOGY DIFFUSION IN BREAST CANCER TREATMENT ON THE COST-EFFECTIVENESS OF MAMMOGRAPHY SCREENING

CN1 MODELING THE IMPACT OF TECHNOLOGY DIFFUSION IN BREAST CANCER TREATMENT ON THE COST-EFFECTIVENESS OF MAMMOGRAPHY SCREENING Shih YCT, Venier J, Munsell M, Cantor SB, Elting LS, Ravdin P, Berry DA University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Adjuvant! Online, San Antonio, TX, USA OBJECTIVES: The association between treatment advances and dissemination and the cost-effectiveness of cancer screening is largely unknown. This study addressed the above association among breast cancer patients. METHODS: Using a Bayesian microsimulation model, we followed a hypothetical cohort of 1 million women born in 1960 throughout their lifetimes. We compared no screening strategy to eight mammography screening strategies that consisted of a combination of different initiation age (40 vs. 50), cessation age (74 vs. 79), and frequency (annual vs. biennial) of screening. Upon identifying the most cost-effective strategy, we then applied probabilistic sensitivity analyses (PSA) to explore the impact of different patterns of treatment dissemination on the cost-effectiveness of screening. RESULTS: At the societal willingness-to-pay (WTP) of $50,000 per life year (LY) gained and with the dissemination pattern prior to the availability of trastuzumab, the most cost-effective screening strategy was biennial screening for women aged 50–74. The probability that this strategy was more cost-effective than the no screening strategy was 0.43, followed by biennial screening 50–79 (prob = 0.41), biennial screening 40–79 (prob = 0.08), and biennial screening 40–74 (prob = 0.04). At a WTP of $100,000/LY, the probabilities increased to 0.89, 0.87, 0.76, and 0.72, respectively. Results from the PSA indicated that when adding trastuzumab to the base case dissemination pattern, the probability that the biennial screening 50–74 strategy was more cost-effective than the no screening strategy at a WTP of $100,000/LY decreased from 0.89 to 0.83, and the probability further reduced to 0.60 if the optimal dissemination pattern (e.g., all patients with HER2 overexpression received trastuzumab) was achieved. CONCLUSIONS: The finding that improvements in treatment dissemination may paradoxically lead to a reduction in the cost-effectiveness of screening suggests that identifying and designing cost-effective strategies to allocate health care resources across the continuum of cancer care is likely to yield higher gains.