Predictor Of Treatment Benefit Research Articles

Predicting neoadjuvant chemotherapy benefit using deep learning from stromal histology in breast cancer

Neoadjuvant chemotherapy (NAC) is a standard treatment option for locally advanced breast cancer. However, not all patients benefit from NAC; some even obtain worse outcomes after therapy. Hence, predictors of treatment benefit are crucial for guiding clinical decision-making. Here, we investigated the predictive potential of breast cancer stromal histology via a deep learning (DL)-based approach and proposed the tumor-associated stroma score (TS-score) for predicting pathological complete response (pCR) to NAC with a multicenter dataset. The TS-score was demonstrated to be an independent predictor of pCR, and it not only outperformed the baseline variables and stromal tumor-infiltrating lymphocytes (sTILs) but also significantly improved the prediction performance of the baseline variable-based model. Furthermore, we discovered that unlike lymphocytes, collagen and fibroblasts in the stroma were likely associated with a poor response to NAC. The TS-score has the potential to better stratify breast cancer patients in NAC settings.

Abstract OT-09-11: AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer

Abstract Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-11.

Phase II preoperative window study of SAR439859 versus letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

TPS1108 Background: Endocrine therapy targeting ER signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER2- breast cancer. This study is a 14-day preoperative non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods: This international, open-label, Phase II randomized study (NCT04191382; ACT16106) evaluates SAR439859 at two dose levels versus the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing Phase I/II study (NCT03284957; TED14856) in metastatic breast cancer (Campone. SABCS 2019. P5-11-02). Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0–1 and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological Complete Response will also be assessed. The study is currently recruiting; target enrollment: n = 126. Clinical trial information: NCT04191382 .

Preoperative chemosensitivity testing as predictor of treatment benefit in adjuvant stage III colon cancer: Preliminary analysis of the PePiTA study.

3610 Background: Although being the standard-of-care for stage III colon cancer, no biomarkers can identify patients (pts) who benefit from adjuvant chemotherapy. In metastatic pts, the lack of metabolic response (mR) in FDG-PET/CT after 1 chemotherapy cycle predicts the absence of treatment benefit. The PePiTA study aims to evaluate if the absence of mR after 1 cycle of pre-operative chemotherapy is predictive of recurrence in non-metastatic colon cancer pts. Herein, we report a preliminary analysis on surgical outcomes, adverse events and mR assessment after 1 cycle of pre-operative chemotherapy after completing the study accrual objective. Methods: Colon cancer pts eligible for curative resection and ECOG ≤1 received 1 cycle of mFOLFOX followed by surgery in this prospective, multicentre, non-randomized trial. FDG-PET/CT was performed at baseline and after 1 cycle of mFOLFOX. Adjuvant mFOLFOX was administered for up to 12 cycles for stage III pts, whereas for stage II pts the decision to pursue adjuvant chemotherapy was at investigator’s discretion. A decrease ≥15% in SUVmax after 1 cycle of chemotherapy was defined as mR (EORTC criteria) at central review. Results: mR was assessable on the primary tumor in 204/240 pts (85%). In 11 pts (4.6%), staging was modified by the baseline FDG-PET/CT, which detected metastatic disease or other tumors. Pre-operative mFOLFOX was administered to 218 pts, of which 14 (6%) had a grade ≥3 adverse event. Surgery was performed in 218 pts, with a median delay of 20 days (6 to 59) after chemotherapy. Surgical complications occurred in 28 (13%) pts, however no deaths occurred. The median SUVmax decrease between baseline and 2nd FDG-PET/CT was 24%. A mR was observed in 65.2% of the pts, whereas 34.8% showed no mR, including 3% who had progressive disease. Conclusions: One cycle of pre-operative mFOLFOX followed by a mR assessment has shown to be a feasible and safe strategy, raising interest on the potential of neoadjuvant chemotherapy in colon cancer. The early mR assessment identified pts that may not benefit from chemotherapy and might have a worse prognosis. The substantiation of this hypothesis is expected with the study’s long-term results. Clinical trial information: NCT00994864.

Mechanical Dyssynchrony: A Risk Factor but not a Target

This editorial refers to ‘Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial’[†][1], by J. Gorcsan et al. , on page 49. Among patients with a left ventricular ejection fraction (LVEF) 140 ms) and, more specifically, left bundle branch block have emerged as predictors of treatment benefit.5–8 Imaging-based assessments of the timing of LV regional contraction—termed intraventricular mechanical synchrony—including numerous M-mode, Doppler, tissue Doppler and strain-based measures, were developed out of a desire to better understand the physiologic underpinnings of LV dyssynchrony and to better identify patients most likely to benefit from CRT. The relationship between electrical … [1]: #fn-2

Diagnosing lung cancer in the 21st century: are we ready to meet the challenge of individualized care?

Histologic and molecular subtyping have become increasingly important as predictors of treatment benefit in lung cancer. The objective of the present study was to determine whether current diagnostic approaches provide adequate tissue to allow for individualized treatment decisions. Our retrospective cohort study of new lung cancer patients seen at an academic centre between July 2007 and June 2008 collected baseline demographic and diagnostic information, including mode of diagnosis, type of diagnostic material, and pathology diagnosis. Of the 431 study patients, 20% had stage i or ii non-small-cell lung cancer (nsclc), 24% stage iii disease, and 39% stage iv nsclc. Three quarters of the small-cell lung cancer (sclc) cases were extensive stage. Diagnostically, 18% of patients had sclc; 30%, adenocarcinoma; 27%, squamous-cell cancer; 2%, large-cell carcinoma; 1%, bronchoalveolar carcinoma; 1%, mixed histology; 18%, nsclc not otherwise specified; 4%, other; and 2%, no pathology diagnosis. Surgical pathology material was available in 80% of cases, and cytology material alone in 20%. Surgical pathology material was more common in patients with early-stage than with advanced disease (89% for stages i and ii vs. 74% for stages iii and iv, p < 0.0001). The pathology report included ambiguous terms in 24% of cases: "consistent" (12%), "suspicious" (3%), "favour" (2%), "suggestive" (2%), "likely" (1%), "compatible" with malignancy (1%), "at least" (1%), "atypical" (0.5%), and "no pathology" (1.5%). Current diagnostic approaches in most lung cancer patients appear adequate, but complete histopathologic identification is missing in nearly 20% of cases, and some uncertainty as to the final diagnosis is expressed in 24% of pathology reports. Some improvement in diagnostic sampling and pathology reporting are required to allow for implementation of current treatment approaches.

Mortality by Treatment in Patients >80 Years of Age with Gastroesophageal Cancer Seen in a 20-Year Period at a Single Medical Center

The treatment approach to patients 80 years of age and older with gastroesophageal cancer at Baylor Scott and White in Temple, Texas, has historically favored conservative measures in the form of palliation and observation. To evaluate this trend in practice, the administered treatments and subsequent patient outcomes of this group were retrospectively reviewed. The study group included all patients 80 years of age and older with a diagnosis of gastroesophageal cancer seen at our facility between 1991 and 2010. Of the 117 cases, 49% received none of the available treatment modalities. The median overall survival (OS) of patients who received treatment, however, was significantly longer than the OS of those who did not, regardless of modality. Specifically, surgical intervention offered an almost double median OS compared with no therapy (6.8 vs. 3.9 months, respectively; P = 0.02); chemotherapy, an almost 4-fold OS benefit (14.8 vs. 3.9 months; P = 0.03); and radiation therapy, a >3-fold OS benefit (11.1 vs. 3.5 months; P = 0.04). These results further substantiate chronological age as an inaccurate predictor of treatment benefit, and age alone should not dictate the administration or withholding of available treatment options.

Preoperative (preop) chemosensitivity testing as predictor of treatment benefit in adjuvant stage III colon cancer (CC): Interim analysis of the PEPITA study.

385 Background: Adjuvant chemotherapy (CT) improves stage III CC outcome but is not effective for all patients (pts). PePiTA’s main hypothesis is that absence of metabolic response (MR) of the primary tumor after 1 preop CT course predicts absence of benefit from adjuvant CT (at 3-year DFS). This strategy's aim is to spare pts from useless toxicities, improve healthcare resource allocation, and guide translational research. This interim analysis was performed for safety and feasibility of MR assessment (MRA). Methods: Pts ≥ 18 years, with PS ≤ 1, diagnosed with CC considered for curative resection are eligible, after signed consent. Baseline PET is repeated after 1 CT cycle, followed by surgery. PET quality insurance and MRA are performed centrally and the result is blinded for investigators. Results: From 2010 to 2013, 114 pts—M/F (55%/45%), median age 66 (26-81), ECOG 0/1(92%/8%)—were included in 15 Belgian centers. 11 pts were excluded from analysis: 2 hyperglycemia at baseline PET; 2 withdrew consent; 6 PET-revealed stage IV CC; and 1 second cancer. Preop CT was associated with 5% grade (gr) 3-4 neutropenia, 1% gr 3 diarrhea, 1% gr 3 hypokaliemia, 1% peritonitis and 1% gr 3 thromboembolic events. Colectomies were performed in all pts after a median of 20 days (interquartile interval 18-21): 32 right (31%), 69 left (67%), and 2 procedures not detailed. Pathology showed stages 0 (1%), I (13%), II (34%), III (47%), IV (7%), without lymph node downstaging. Postoperative morbidity is 9% (95%CI 5-16%) and includes fistulas (4%), transient ischemic attack (1%), ileus (2%), and evisceration (1%), but no death. Technical or methodological reasons prevented MRA in 19/103 pts. Median SUVmax was 14.4 (4.9-47.8) at baseline, and 10.9 (0-39.3) on day 14. 2 pts presented with complete MR. For the others, median delta SUVmax was -22% (-60 to +31%). MR was observed in 60% of pts, and was absent in 40%, with equal distribution for stages II and III (p = 1.00). Conclusions: 1 course of CT is feasible before curative surgery for CC, without inducing excessive toxicity, delay or surgical morbidity. MRA indicated metabolic signs of chemoresistance in 40% of the primary tumors. Clinical trial information: NCT00994864.

Abstract P4-14-03: Preoperative carboplatin-paclitaxel-bevacizumab in triple negative breast cancer: Final results of the phase II CA.Pa.Be study

Abstract Introduction: Management of triple negative breast cancer (TNBC) is still a major challenge: a significant proportion patients relapse despite adjuvant chemotherapy, and the median survival from relapse rarely exceeds 1 year. Angiogenesis activation as well as impairment in mechanisms of DNA repair are frequently described in sporadic TNBCs, but the role of angiogenesis inhibitors and platinum salts is still controversial. This is a phase II trial of preoperative carboplatin-paclitaxel in combination with bevacizumab in TNBC patients with previously untreated, stage II-III disease. The primary aim of the study is the pathologic complete response (pCR) rate. Among the secondary aims: safety, breast conserving surgery rate, early response assessment with dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI), biomarker analyses. Methods: Patients with hormone receptor negative (ER and PgR &amp;lt;1%), HER2 negative stage II-III breast cancer are eligible. At baseline, patients undergo breast DCE-MRI, followed by a single dose of bevacizumab 5 mg/kg (day -7). DCE-MRI is repeated prior to start chemotherapy (CT). On day 1, patients start CT with paclitaxel 80 mg/sqm+carboplatin AUC2 on days 1,8, 15 q 28, combined with bevacizumab 10 mg/kg on days 1 and 15. Patients received 5 preoperative cycles and undergo surgery within 6 weeks from the last CT course. Bevacizumab is omitted on cycle 5, to minimize the risk of surgical complications. Tissue samples are centralized to evaluate treatment effect on several tissue markers, as well as to identify potential predictors of treatment benefit. The sample size is estimated with the two-stage Simon's design, on the basis of a 40% expected pCR rate. A total of 43 patients are required, with the combination deemed worthwhile in case of at least 13 pCRs. Results: the accrual of the 44 planned patients is completed. Patients characteristics were as follows: median age 46 yrs (29-74); clinical stage IIA: 38.2%, IIB: 35.3%, III: 26.5%; ductal histology: 89%; histologic grade 3: 95%. Notably, 59% of the patients had clinically involved axillary nodes. At present, 33 patients are assessable for toxicity. Bevacizumab-associated adverse events (AEs) were mild: grade 1-2 hypertension occurred in 3 patients (9%) and grade 1 bleeding in 9 patients (27%). No grade 4 non-hematologic AEs were recorded; Grade 3 AEs were: liver function tests abnormalities in 3 patients, diarrhea in 3 patients, and neuropathy in 1 patient. Thirty-one patients underwent surgery, 16 patients (51%) received breast conserving surgery. A pCR in breast and axillary lymph-nodes was achieved in 16 patients (51%); 25 patients (81%) had negative axillary nodes (yN0). Conclusions: No unexpected toxicity was observed by combining bevacizumab to neoadjuvant platinum-taxane based CT. This combination is active in TNBCs, and the rate of pCR is in the expected range. Moreover, 80% of the patients have nodal negativity at surgery, and these results are of particular interest taking into account the high proportion of patients with clinically involved nodes at the time of diagnosis. The final results along with biomarkers data and early response assessment with DCE-MRI will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-14-03.

Preoperative chemosensitivity testing as Predictor of Treatment benefit in Adjuvant stage III colon cancer (PePiTA): Protocol of a prospective BGDO (Belgian Group for Digestive Oncology) multicentric study

BackgroundSurgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available.Identifying which patients are unlikely to respond to adjuvant chemotherapy from among those who are eligible for such treatment would be a major step towards treatment personalization. It would spare such patients from unnecessary toxicities and would improve the allocation of societal healthcare resources.Methods/designPePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer.The study’s primary objective is to examine the ability of PET/CT-assessed tumor FDG uptake after one course of preoperative chemotherapy to predict the outcome of adjuvant therapy, as measured by 3-year disease-free survival.Secondary objectives are to examine the predictive value of changes in PET/CT-assessed tumor FDG uptake on overall survival, to define the best cut-off value of FDG uptake for predicting treatment outcome, and to analyse the cost-effectiveness of such preoperative chemo-sensitivity testing.At study planning, exploratory translational research objectives were 1) to assess the predictive value of circulating tumor cells for disease-free survival, 2) to examine the predictive value of single nucleotide polymorphisms for disease-free survival with respect to genes related either to toxicity or to drug targets, 3) to assess genomic rearrangements associated with response or resistance to FOLFOX treatment, 4) to identify an immunologic signature associated with metabolic tumor response to FOLFOX therapy and, finally, 5) to create a bank of frozen tumor samples for future studies.DiscussionPePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer.EudraCT number2009-011445-13Trial registrationClinicalTrials.gov number, NCT00994864

Proteinuria as a predictive factor in metastatic colorectal cancer patients treated with bevacizumab.

e14070 Background: Efficacy of bevacizumab -which is widely used at metastatic colorectal cancer (mCRC)- on clinical survival has been proved. But parameters predicting this clinical efficacy are unknown at present. With this study, we aimed to investigate the predictors of treatment benefit with bevacizumab based chemotherapy in patients with mCRC. Methods: Thirty-six successive patients with mCRC receiving bevacizumab based chemotherapy were enrolled into the study. Hypertension, 24-hour proteinuria and other routine parameters were recorded before and during the treatment with certain intervals. After a 1-year follow up, relationship of progression free survival (PFS) and response with various parameters and especially proteinuria, was evaluated. Results: Of 36 patients included, 20 (55.6%) were male and 16 (44.4%) were female, where mean age was 57. Overall median PFS was calculated as 275 days (9.8 months). Patients with basal proteinuria higher than 114 gr/day had a lower median PFS as 184 days (6.5 months) (p=0.046), where median PFS of patients with basal proteinuria equal to or lower than 114 gr/day was not reached. Therefore, higher level of renal proteinuria is a negative prognostic factor in these patients. Similarly, PFS was observed to be lower at patients with high LDH levels (p=0.0024, Exp(B)=23). Bevacizumab response was observed to be better at patients with favorable performance status (p=0.05), who have a single liver metastasis (p=0.034) and who tend to be hypertensive during the treatment (p=0.034). Conclusions: In conclusion, we demonstrated that basal proteinuria and LDH levels may be prognostic at patients with mCRC receiving bevacizumab-based treatment. In the literature, there has been no study up to now that questions basal proteinuria as a prognostic factor for patients receiving bevacizumab-based treatment. This observation is an important step for more focused use of bevacizumab. We believe that it is important to investigate whether basal proteinuria really has a predictive role in this group of patient with further studies, and this has practical and clinical implications.

Quantitative copy number analysis by Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness

IntroductionOur group has previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of BRCA1-mutated breast cancers. We have shown that the so-called BRCA1-likeaCGH profile is also present in about half of all triple-negative sporadic breast cancers and is predictive for benefit from intensified alkylating chemotherapy. As aCGH is a rather complex method, we translated the BRCA1aCGH profile to a Multiplex Ligation-dependent Probe Amplification (MLPA) assay, to identify both BRCA1-mutated breast cancers and sporadic cases with a BRCA1-likeaCGH profile.MethodsThe most important genomic regions of the original aCGH based classifier (3q22-27, 5q12-14, 6p23-22, 12p13, 12q21-23, 13q31-34) were mapped to a set of 34 MLPA probes. The training set consisted of 39 BRCA1-likeaCGH breast cancers and 45 non-BRCA1-likeaCGH breast cancers, which had previously been analyzed by aCGH. The BRCA1-likeaCGH group consisted of germline BRCA1-mutated cases and sporadic tumours with low BRCA1 gene expression and/or BRCA1 promoter methylation. We trained a shrunken centroids classifier on the training set and validation was performed on an independent test set of 40 BRCA1-likeaCGH breast cancers and 32 non-BRCA1-likeaCGH breast cancer tumours. In addition, we validated the set prospectively on 69 new triple-negative tumours.ResultsBRCAness in the training set of 84 tumours could accurately be predicted by prediction analysis of microarrays (PAM) (accuracy 94%). Application of this classifier on the independent validation set correctly predicted BRCA-like status of 62 out of 72 breast tumours (86%). Sensitivity and specificity were 85% and 87%, respectively. When the MLPA-test was subsequently applied to 46 breast tumour samples from a randomized clinical trial, the same survival benefit for BRCA1-like tumours associated with intensified alkylating chemotherapy was shown as was previously reported using the aCGH assay.ConclusionsSince the MLPA assay can identify BRCA1-deficient breast cancer patients, this method could be applied both for clinical genetic testing and as a predictor of treatment benefit. BRCA1-like tumours are highly sensitive to chemotherapy with DNA damaging agents, and most likely to poly ADP ribose polymerase (PARP)-inhibitors. The MLPA assay is rapid and robust, can easily be multiplexed, and works well with DNA derived from paraffin-embedded tissues.

Quantitative copy number analysis by multiplex ligation-dependent probe amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness, and as such treatment response.

10513 Background: Our group has previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of BRCA1-mutated breast cancers. We have shown that the so-called BRCA1-likeaCGH profile is also present in about half of all triple negative sporadic breast cancers and is predictive for benefit from bifunctional alkylating agents. As aCGH is a rather complex method, we translated the BRCA1aCGH profile to a Multiplex Ligation-dependent Probe Amplification (MLPA) assay, to identify both BRCA1-mutated breast cancers and sporadic cases with a BRCA1-likeaCGH profile. Methods: The most important genomic regions of the original aCGH based classifier (3q22-27, 5q12-14, 6p23-22, 12p13, 12q21-23, 13q31-34) were mapped to a set of 34 MLPA probes. The training set consisted of 39 BRCA1-likeaCGH breast cancers and 45 non-BRCA1-likeaCGH breast cancer patients, which had previously been analyzed by aCGH. Part of the sporadic tumors showing a BRCA1-likeaCGH profile had a low BRCA1 gene expression or BRCA1 promoter methylation. We trained a shrunken centroids classifier on the training set and validated in on an independent test set of 22 BRCA1-likeaCGH breast cancers and 19 non-BRCA1-likeaCGH breast cancer patients. Results: The training set of 84 patients could accurately be predicted by PAM (10-fold cross-validated accuracy, 94%). The classifier trained on the training set correctly predicted BRCA-like status of nearly all 41 breast tumors. Two out of 41 were misclassified, resulting in a specificity and sensitivity of both 95%. The assay performed equally well in identifying BRCA1 mutated as BRCA1-like patients. Conclusions: Since the MLPA assay can identify BRCA1-mutated and BRCA1-like sporadic breast cancer patients, this method could be both applied in clinical genetic testing, but also as a predictor of treatment benefit. BRCA1-like tumors are highly sensitive to chemotherapy with DNA damaging agents, and also to PARP-inhibitors. The MLPA assay is rapid and robust, can easily be multiplexed, and works well with DNA derived from paraffin-embedded tissues.

Abstract 3731: Elevated mRNA expression of CXCL13 predicts improved outcome in patients with high-risk early breast cancer: A possible molecular predictor of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Abstract Chemokines are important in cell migration and are therefore thought to play a key role in metastasis. Chemokine (C-X-C motif) ligand 13 (CXCL13) was recently found to be overexpressed in breast cancer and its overexpression is thought to be associated with poor outcome. The aim of the present study was to explore the prognostic significance of CXCL13 on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer enrolled in a randomized phase III trial. The association of CXCL13 with hormonal receptor and HER family expression at the m-RNA level, as well as with other clinicopathological characteristics of patients was also investigated. 595 high-risk breast cancer patients were treated in a two-arm trial (HE10/97) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was extracted from 312 formalin-fixed paraffin-embedded primary tumor tissue samples followed by kinetic one-step RT-PCR for assessment of mRNA expression of CXCL13, ER, PgR, and HER2. Values of CXCL13 and HER2 mRNA above the 75th percentile were considered high expression. CXCL13 expression was correlated with known clinicopathological parameters, such as HER2, ER and PgR by IHC, tumor grade, and nodal involvement. With a median follow up of 8 years the total number of events (disease relapses) was 109/312 (35%), and the total number of deaths 78/312 (25%). High CXCL13 mRNA expression was associated with improved DFS (log-rank, p=0.043). This remained unchanged when adjusted for treatment group (Wald, p=0.045). Furthermore, CXCL13 was found to be negatively correlated (p&amp;lt;0.001) with ER and PgR mRNA expression. Results of the Cox multivariate regression analysis revealed that, in the presence of treatment group, high CXCL13 mRNA expression was associated with a significantly decreased risk for relapse (HR=0.50, 95% CI: 0.31-0.82, p=0.006) and a significantly decreased risk for death (HR=0.56, 95% CI: 0.31-0.99, p=0.047). The number of ER/PgR IHC positive patients was significantly lower in the high expression group of CXCL13 compared to the low expression group (67.5% vs 81.5%, p=0.017). Finally, higher tumor grade was more likely to be present in the high expression group of CXCL13 than in the low expression group (69.2% vs 42.7%, p&amp;lt;0.001), as was HER2 mRNA overexpression (41.4% vs 26.5%, p=0.024). Furthermore, high expression of CXCL13 was associated with lower risk for relapse in HER2 mRNA overexpressing patients. High CXCL13 mRNA expression is associated with a significantly decreased risk for relapse and death in high-risk breast cancer patients treated with dose-dense sequential chemotherapy. This association appears to be more pronounced in HER2 overexpressing patients. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3731.

Elevated mRNA expression of herstatin predicts poor outcome in patients with high-risk early breast cancer. A possible molecular predictor of treatment benefit in the context of a Hellenic cooperative oncology group trial.

Abstract Abstract #6066 Background: Herstatin is a naturally occurring product of the HER2 gene generated by alternative mRNA splicing. It functions as a secreted inhibitor that binds to the extracellular domains of EGFR and HER2, disrupting multiple receptor combinations in response to a variety of ligands. This mode of action supports the potential utility of herstatin in the development of novel therapeutics against breast cancer. The aim of the present study was to evaluate the association of herstatin with HER family expression at the m-RNA level, as well as with other clinicopathological characteristics of patients with high-risk operable breast cancer enrolled in a randomized phase III trial. The effect of herstatin on disease-free survival (DFS) and overall survival (OS) was also investigated.&amp;#x2028; Patients and Methods: 595 high-risk breast cancer patients were treated with anthracycline-based chemotherapy in the adjuvant setting (HE10/97 trial). This was a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was extracted from 279 formalin-fixed paraffin-embedded tumor tissue samples followed by kinetic one-step RT-PCR for assessment of mRNA expression of herstatin, EGFR, HER2, HER3, and HER4. Values of RNA above the median were considered as positive expression, except for EGFR, where the 75th percentile was used as a cut-off. DFS and OS were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox analysis for DFS and OS was also performed.&amp;#x2028; Results: Positive herstatin expression was found to be significantly associated with ductal histology (χ2 test, p=0.004), and marginally associated with infiltrated lymph nodes (p=0.062). Furthermore, herstatin was found to be strongly correlated with HER2 expression (r=0.783, p&amp;lt;0.001) and weakly correlated with HER3 expression (r=0.144, p=0.02). Positive herstatin expression was associated with poor DFS and OS (log-rank, p=0.004 and 0.008, respectively). This remained unchanged when adjusted for treatment group, whereas no interaction between herstatin and treatment was identified. Interaction of HER2 overexpression (&amp;gt;75th percentile) with herstatin was found to be significant for OS (Wald, p=0.03), thus implying a possible prophylactic effect of herstatin in the subgroup of patients with HER2 overexpression.&amp;#x2028; Conclusions: Herstatin was shown to be associated with a poor prognosis. Given the high correlation between herstatin and HER2, this finding may reflect the effect of HER2 on patient's prognosis. Our results suggest that the effect of herstatin may be altered in case of HER2 overexpression. This hypothesis should be investigated in future studies, focusing in patients with HER2 overexpression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6066.

Validation of treatment induced specific adverse effect as a predictor of treatment benefit: A case study of NCIC CTG BR21

The target of novel signal transduction inhibitors may be present on normal as well as tumor cells, resulting in mechanistic adverse effects (AE) in addition to antitumor activity. As those AEs lie in the causal pathway that patients respond to the drug, may thus serve as an indicator of benefit from the drug. In this paper, we discuss issues in validating drug related AEs as predictive markers of overall survival benefit. Based on our proposed approach, we showed that erlotinib induced skin rash appears to predict a survival benefit.

The role of cathepsin D and PAI-1 in primary invasive breast cancer as prognosticators and predictors of treatment benefit with adjuvant tamoxifen

In the last few years there has been an increased interest in treatment predictive factors in breast cancer patients. The aim of the study was to analyse the role of cathepsin D and plasminogen activator inhibitor-1 (PAI-1) expression as independent prognosticators and to assess their predictive value with respect to tamoxifen treatment. This study comprises 1851 patients with primary breast cancer diagnosed during 1988–1992. Their median age was 62 years (range: 24–91). The end-point was distant disease recurrence-free interval. Adjuvant treatment with tamoxifen was given to 1136 patients (61%). The median follow-up time was 59 months (range: 39–88). Cathepsin D content was shown to be a significant independent prognosticator in multivariate Cox analysis ( P=0.02). The optimal cut-off level was 10 fmol/mg protein, other cut-off levels did not improve the results. The level of cathepsin D also appeared to predict the benefit of tamoxifen among oestrogen receptor (ER)-positive patients although this result did not reach statistical significance ( P=0.09). In a multivariate Cox analysis including 497 patients PAI-1 content was shown to be a significant independent prognosticator ( P=0.003) but did not appear to predict the benefit of tamoxifen treatment. The optimal cut-off level appeared to be 3 ng/mg protein, which was close to the median value 2.5 ng/mg (range: 0–51). We conclude that cathepsin D is a significant independent prognosticator and may possibly also predict the benefit of tamoxifen amongst ER-positive patients. PAI-1 was also found to be a strong independent prognosticator but no treatment interaction with adjuvant tamoxifen was found.

Baseline risk as predictor of treatment benefit: three clinical meta-re-analyses

A relationship between baseline risk and treatment effect is increasingly investigated as a possible explanation of between-study heterogeneity in clinical trial meta-analysis. An approach that is still often applied in the medical literature is to plot the estimated treatment effects against the estimated measures of risk in the control groups (as a measure of baseline risk), and to compute the ordinary weighted least squares regression line. However, it has been pointed out by several authors that this approach can be seriously flawed. The main problem is that the observed treatment effect and baseline risk measures should be viewed as estimates rather than the true values. In recent years several methods have been proposed in the statistical literature to potentially deal with the measurement errors in the estimates. In this article we propose a vague priors Bayesian solution to the problem which can be carried out using the 'Bayesian inference using Gibbs sampling' (BUGS) implementation of Markov chain Monte Carlo numerical integration techniques. Different from other proposed methods, it uses the exact rather than an approximate likelihood, while it can handle many different treatment effect measures and baseline risk measures. The method differs from a recently proposed Bayesian method in that it explicitly models the distribution of the underlying baseline risks. We apply the method to three meta-analyses published in the medical literature and compare the results with the outcomes of the other recently proposed methods. In particular we compare our approach to McIntosh's method, for which we show how it can be carried out using standard statistical software. We conclude that our proposed method offers a very general and flexible solution to the problem, which can be carried out relatively easily with existing Bayesian analysis software. A confidence band for the underlying relationship between true effect measure and baseline risk and a confidence interval for the value of the baseline risk measure for which there is no treatment effect are easily obtained by-products of our approach.