Citations

205 Background: Central review is an important trial management and validation tool. Multisite trials require data systems to accommodate diverse image acquisition and review. Breast cancer is challenging as its imaging objects are not always easily shared across departments. Quality Assurance Review Center (QARC) has a diverse portfolio of facile data acquisition and powerful informatics support that meets these needs. We report on the role of QARC in three of the current breast cancer trials from the American College of Surgeons Oncology Group. Methods: QARC data management system includes secure network infrastructure and a validated relational operating database (MAX). QARC has data acquisition/imaging re-distribution expertise for real time response reviews, response measuring tools and corresponding data archive for secondary reviews. MAX includes query ability; records link to digital information. QARC underwent systematic information systems validation process for 21 CFR Part 11. DICOM/non-DICOM files are stored in the QARC PACS. On-site/remote reviewers use MAX to retrieve, view, annotate and save images. Data extracted is securely sent to partner statistical centers. Results: In Z1031, a neoadjuvant endocrine therapy trial, all of the mammographic exams are archived at QARC. For Z1071, a sentinel lymph node trial, pre- and post-treatment ultrasound (US) images of 321 patients were remotely reviewed. For Z1072, the cryoablation US, pre and post-cryoablation MRI for 40 of 47 cases were remotely archived, retrieved and transferred to investigator workstation for post-processing and review. The other 7 patients did not have evaluable imaging studies. In all three trials, the costs of shipping hardcopies of exams and travel to QARC for central review functions were eliminated. Conclusions: QARC data management systems provide diverse informatics supports for multi-institutional trials, ranging from archives of images, provide remote access and download of data, and central review. The vibrant informatics supports meet the growing needs of clinical trials. Future directions include radiation field review for breast cancer trials and the incorporation of pathology microarray analysis as DICOM objects.

144 Background: Many patients require hospitalization after mastectomy, predominantly for pain management and treatment of postoperative nausea and vomiting (PONV). In order to improve a woman's perioperative experience after mastectomy and facilitate mastectomy on an outpatient basis, we initiated a clinical pathway for perioperative management of unilateral mastectomy patients at Mayo Clinic Rochester. Methods: The clinical pathway consists of preoperative oral medications (celecoxib and gabapentin), preoperative ultrasound guided paravertebral block using bupivacaine, intraoperative anesthesia management with total intravenous anesthetic, and minimal use of long-acting opioids and postoperative acetaminophen and oxycodone. All patients are evaluated by the surgical team on the afternoon after surgery and if patients are recovering well are discharged on the day of surgery. The following morning, the surgical team telephones the patient to follow up on management of pain, nausea or vomiting, and drain output. Results: Eighteen patients have been treated on this clinical pathway. Mean age of patients was 66 (range 51-81). Majority of patients (n=16, 89%) underwent unilateral mastectomy with sentinel lymph node biopsy, with 1 patient undergoing bilateral mastectomy and 1 patient undergoing mastectomy and axillary dissection. All patients are evaluated by the surgical team on the afternoon of surgery. Fourteen patients (78%) were without evidence of hematoma or PONV, pain was well-controlled on oral medications and they were discharged on the day of surgery. On morning after telephone calls, pain scale ratings ranged from 1 to 3 and no patients verbalized complaints of nausea. Four patients (22%) treated on this clinical pathway required overnight observation in the hospital, one for urinary retention, two for pain control, and one for high sanguineous drain output. Conclusions: The clinical pathway presented provides preemptive analgesia and regional anesthesia for patients undergoing mastectomy, enabling the majority of patients to be discharged on the day of surgery. The clinical pathway is a safe and effective way to improve the perioperative experience of breast surgery patients and decrease hospital admission.

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. Pertuzumab (P) has established survival benefit in the metastatic setting, and received accelerated approval in the neoadjuvant setting when combined with trastuzumab (H) and docetaxel(D) as part of a complete treatment regimen for early breast cancer. We tested its ability, when combined with standard therapy (paclitaxel, T, and H) to improve pCR (ypT0ypN0) over TH in the adaptively randomized, phase II, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive BC ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to control (TH, qwk x 12) or THP (P, q3wk x 4) followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. To compare THP to TH we utilized all control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the experimental arms was based on current Bayesian probabilities of superiority over control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a 2-arm, N = 300 phase III randomized 1:1 trial of THP vs. TH with pCR endpoint. Results: THP met the predictive probability criterion and graduated in 3 signatures: all HER2+, HER2+/HR+, and HER2+/HR- (See Table 1). Final accrual: 44 THP and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial efficiently evaluates agents in biomarker-defined pt subsets. THP -> AC substantially improves pCR rates over standard TH -> AC in all 3 HER2+ signatures, including HR+ and HR- subsets. APHINITY, a trial of adjuvant pertuzumab with a primary outcome of invasive disease-free survival, is ongoing. Table 1Signature*Estimated pCR Rate (95% probability interval)Signature*THPControl (TH)Probability THP Is Superior to ControlPredictive Probability of Success in Phase IIIHER2+54% (38%-70%)22% (5%-39%)99.8%96%HER2+/HR+44% (24%-63%)17% (0%-34%)99%91%HER2+/HR-74% (53%-95%)33% (6%-59%)99.8%98%*HR = Hormone Receptor Citation Format: Meredith Buxton, Angela M. DeMichele, Stephen Chia, Laura van't Veer, Jo Chien, Anne Wallace, Henry Kaplan, Julie Lang, Douglas Yee, Claudine Isaacs, Stacy Moulder, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Susan Minton, Andres Forero, Rita Nanda, Anthony Elias, Larissa Korde, Rebecca Viscuzi, Hope Rugo, Richard Schwab, Fraser Symmans, Melissa Paoloni, Nola Hylton, Michael Hogarth, Julia Lyandres, Jane Perlmutter, Ashish Sanil, Christina Yau, Laura Esserman, Don Berry, I-SPY 2 TRIAL Investigators. Efficacy of pertuzumab/trastuzumab/paclitaxel over standard trastuzumab/paclitaxel therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT106.

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) -> AC substantially improves pCR rates over standard TH -> AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.

Abstract Support: Alliance U10CA180821; Alliance Statistical Center grant U10CA180882; ACOSOG grant U10CA76001 HER2 gene amplification and its corresponding overexpression are present in approximately 12% of invasive breast cancers. While HER2-targeted agents (e.g. trastuzumab, pertuzumab, and lapatinib) are effective treatments, resistance remains a major cause of death from HER2-positive breast cancer. Mechanisms of resistance are poorly understood. Without a molecular understanding of these mechanisms, therapeutic advances will be delayed. We have generated molecular profiles of primary HER2-positive breast cancers treated on a neoadjuvant clinical trial, and compared features associated with response to treatment. The American College of Surgeons Oncology Group (ACOSOG) Z1041 trial in HER2-positive breast cancer was designed to compare the pathologic complete response (pCR) rate of a regimen of paclitaxel and trastuzumab, followed by trastuzumab administered with fluorouracil, epirubicin, and cyclophosphamide (FEC-75) to a regimen of FEC-75 alone followed by paclitaxel and trastuzumab. The trial identified no difference in pCR rates between the regimens (Buzdar et al., The Lancet Oncology 2013). In supplement to the tissues obtained from 37 of the patients enrolled in the Z1041 trial, an additional 11 cases were obtained from a single institution study (201101961) of patients treated with neoadjuvant trastuzumab that had pre-treatment core biopsies suitable for genomic studies. We have extracted genomic DNA from both pretreatment tumor biopsies and blood samples of these 48 patients and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have extracted high quality RNA from 42 of the 48 biopsies, and have processed RNA-seq profiles of the tumors. Among patients in this cohort, 24 (50%) achieved a pCR. Because no difference was observed between arms of the Z1041 trial, patients with or without a pCR were directly compared without adjusting for treatment regimen. On average, each tumor and normal sample pair were sequenced to a depth of 49.4x and 32.5x by WGS respectively. In total, 15,027 candidate somatic variants were identified in known genes, including 11,606 missense, 860 nonsense, and 418 frameshift insertions or deletions. Preliminary results identified mutations in HER2 that were associated with the failure to achieve pCR in several cases. Furthermore, tumors assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR (19 compared to 8) than tumors with genomic features indicative of either the luminal or basal-like subtypes (3 compared to 12); a significant difference in the proportion of cases that achieve pCR (Fisher's exact test p-value = 0.0032). The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those patients who will not respond to the current standard of care for HER2-positive breast cancer. Citation Format: Lesurf R, Griffith O, Griffith M, Watson MA, Hoog J, Ellis MJ, Ota D, Suman VJ, Meric-Bernstam F, Leitch AM, Boughey JC, Unzeitig G, Buzdar AU, Hunt KK, Mardis ER. The genomics of response to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer – Results from the ACOSOG Z1041 (Alliance) trial. [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 PD6-02.

Abstract Background: Tumor-infiltrating lymphocytes (TIL) have prognostic and potentially predictive significance in the (neo)adjuvant treatment of high-risk breast cancer. However, quantitative TIL measurement is not routinely performed. It is unclear why some tumors attract large quantities of TIL while others do not. We sought to confirm the association between TIL and pathologic complete response rate (pCR) and to further use next generation sequencing (NGS) to identify genes and gene pathways associated with the presence/absence of TIL. Methods: We studied 140 women with high risk stage I-III breast cancer, enrolled in the Breast Cancer Genome Guided Therapy Study (BEAUTY), obtaining serial biopsies for DNA/RNA sequencing and MRI imaging to assess response to neoadjuvant chemotherapy (NAC) with taxane (+/- trastuzumab+/-pertuzumab for HER2+ disease) followed by AC or (F)EC. Diagnostic pre-NAC core needle biopsies and surgical resection specimens post-NAC were available from 110 patients. Stromal TIL were semi-quantitated on a scale of 1-4 (with 1: ≤10/hpf, 2: subtle infiltrate >10/hpf, 3: moderate infiltrate readily visible at low power magnification, 4: dense infiltrate with innumerable lymphocytes). For this analysis, low TIL was defined as scores of 1-2 vs. high defined as 3-4. Using pre-NAC biopsies, RNAseq was performed using the Illumina HiSeq2000 and the Mayo Analysis Pipeline for RNAseq (MAP-Rseq) for quality control, sequence alignment, and gene counts. The quantity of TIL was associated with transcripts across the transcriptome after conditional quantile normalization. Differentially expressed genes were obtained using EdgeR analysis, using a false discovery rate of 0.05, and pathways were evaluated using GAGE methods. Results: The pCR and residual cancer burden (RCB)-0/I rates by stromal TIL status within each molecular subtype are presented in the table. A diverse spectrum of 1344 genes with differential expression between tumors with high vs. low stromal TIL was identified. The genes with >2.0-fold change (FC) and p<1e-09 included S100A7 (4.49 FC), LCN2 (2.48 FC), and ART3 (2.82 FC) (genes known to be involved in immune regulation), as well as TDRD1 (2.71 FC) (a gene related to ERG [ETS-related gene] expression). In addition, the "regulation of actin cytoskeleton" pathway was upregulated in tumors with high TIL, while the "Hedgehog signaling" and "Wnt signaling" pathways were downregulated. Molecular SubtypeStromal TILspCR rate n (%)RCB-0/I rateLuminal AHigh------Luminal ALow0/9 (0%)0/9 (0%)Luminal BHigh1/9 (11.1%)1/8 (12.5%)Luminal BLow3/24 (12.5%)6/23 (26.1%)ER+/HER2+High3/9 (33.3%)4/9 (44.4%)ER+/HER2+Low1/6 (16.7%)1/6 (16.7%)ER-/HER2+High8/9 (88.9%)7/7 (100%)ER-/HER2+Low4/8 (50.0%)6/8 (75.0%)Triple NegativeHigh10/19 (52.6%)13/19 (68.4%)Triple NegativeLow7/14 (50.0%)9/13 (69.2%) Conclusions: We identified genes and gene pathways associated with high TIL expression in breast tumors prior to NAC that provide insight into the interactions between TIL and tumors. TIL can be easily semi-quantitated on H&E and along with these novel biomarkers, may contribute to the personalization of breast cancer therapy. Citation Format: Moyer AM, Boughey JC, Kalari KR, Suman VJ, McLaughlin SA, Moreno-Aspitia A, Northfelt DW, Gray RJ, Sinnwell JP, Carlson EE, Dockter TJ, Jones KN, Felten SJ, Conners AL, Wieben ED, Ingle JN, Wang L, Weinshilboum RM, Visscher DW, Goetz MP. Differential mRNA expression patterns in breast tumors with high vs. low quantity of stromal tumor–Infiltrating lymphocytes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-05.

Abstract Background: Tumorigenesis involves both genetic and epigenetic changes. Epigenetic alterations are reversible and are promising cancer therapeutic targets. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferase inhibitor, is FDA approved for hematological malignancies. However, the effect of decitabine in breast cancer is not completely understood. Previous reports indicated that one decitabine mechanism involves regulation of protein levels for DNMT1, the major DNA methyltransferase that methylates hemimethylated CpG di-nucleotides in DNA. However, the E3 ligase involved in this process has not been identified. Whether decitabine also regulates DNMT3A and 3B in a similar fashion remains unclear. Therefore, our goals were to 1) understand mechanisms underlying decitabine action, 2) test the antitumor activity of decitabine in breast cancer models and 3) identify biomarkers associated with response to decitabine. Methods and Results: Western blots of breast cancer cell lines showed that DNMT1, DNMT3A, and DNMT3B protein levels decreased following decitabine treatment without a reduction in mRNA levels. Bioinformatic analysis of DNA methyltransferase sequences revealed a potential TRAF6 binding motif, and the interaction with TRAF6 (TNF receptor-associated factor 6) was confirmed by IP. TRAF6 functions as an E3 ligase. To determine whether TRAF6 might be the E3 ligase responsible for the degradation of DNMTs after decitabine treatment, we knocked down TRAF6 by RNA interference or knocked out the TRAF6 gene by CRISPR/Cas9. Down regulation of TRAF6 attenuated DNMT ubiquitination and increased DNMT protein levels, suggesting that TRAF6 might mediate proteasome-dependent degradation of all three DNMTs. This was further confirmed by reconstituting the knockout cells with WT and a TRAF6-C70A mutant, followed by assessing DNMT protein levels. Global DNA methylation was also increased after TRAF6 depletion and was confirmed in TRAF6 knock out cells in which DNMT levels were unaffected by decitabine. Cell cytotoxicity and colony forming assays showed that TRAF6 knockout cells were resistant to decitabine, suggesting that a major decitabine mechanism of action is through the regulation of TRAF6 which, in turn, degrades DNMTs, leading to decreased global methylation. Finally, decitabine significantly induced TRAF6 at both mRNA and protein levels, a process that might create positive feedback leading to increased degradation of DNMT proteins upon decitabine treatment. Based on these results, we further hypothesized that levels of the three DNMTs might influence decitabine response. Using 18 breast cancer patient derived xenograft (PDX) models, we found a wide range of DNMT protein levels regardless of ER/HER2 status. DNMT levels in the PDX models were directly associated with sensitivity to decitabine treatment, confirming our hypothesis. Conclusion: Our data showed that decitabine might be an effective agent for treating breast cancer and revealed a novel mechanism underlying decitabine treatment. Baseline DNMT protein levels may serve as a biomarker for predicting decitabine drug response. Citation Format: Yu J, Qin B, Boughey JC, Moyer AM, Visscher DW, Sinnwell JP, Yin P, Thompson KJ, Docter TJ, Kalari KR, Suman VJ, Wieben ED, Felten SJ, Conners AL, Jones KN, McLaughlin SA, Copland JA III, Moreno Aspitia A, Northfelt DW, Gray RJ, Ingle JN, Lou Z, Weinshilboum R, Goetz MP, Wang L. Regulation of DNA methyltransferases via TRAF6 determines breast cancer response to decitabine. [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 P3-07-51.

Abstract Background: Both HR deficiency and BRCA mutation status predict response to platinum-based therapy and BRCA mutation status predicts docetaxel resistance. However, the association of either biomarker with response to the individual elements of either AC or taxanes (T) is unknown since T is commonly given concomitantly with or after anthracyclines (A). We evaluated the association of HRD and BRCA mutation status with response to neoadjuvant weekly T followed by AC or (F)EC in high-risk breast cancer. Methods: We studied 140 high risk Stage I-III breast cancer patients (pts), enrolled in the breast cancer genome guided therapy study (BEAUTY), obtaining biopsies for DNA/RNA sequencing and MRI imaging to assess response to neoadjuvant weekly T (+trastuzumab+/-pertuzumab for HER2+ disease) followed by AC or (F)EC. Germline BRCA status and HR status of tumor samples (Myriad laboratories) were obtained. HR deficient tumor was defined as HRD score ≥42 or BRCA mutation. MRI response by changes in tumor size after 12 weeks of T was classified by WHO criteria. pCR was defined as ypT0/Tis ypN0. Both MRI response after T and pCR (after T and AC) were examined in terms of germline BRCA mutation (gBRCAmut vs. gBRCAwt) and tumor HR deficiency. Results: Of 140 pts enrolled, 8 withdrew consent and 2 carboplatin treated pts were excluded. Germline data were available for 124/130 pts. 12 patients had BRCA deleterious germline mutations (4 BRCA1, 8 BRCA2). MRI partial (PR)/complete response (CR) rate to T was 47.3% (95% CI: 37.8-57.0%) in the BRCAwt group and 66.7% (95% CI: 34.9-90.1%) in the BRCAmut group. No MRI CR's were observed in BRCA1 mut pts. In contrast, pCR rate was 50% in the 12 gBRCAmut pts (95% CI: 21.1-78.9%) and 31.3% in the 112 gBRCAwt pts (95% CI: 22.8-40.7%). HR deficiency status has thus far been determined for 74 pts: 26 pts have HD deficient tumors: 18 TNBC, 5 Luminal B, 2 ER-/HER2+; and 1 ER+/HER2+. Determination of HR deficiency is ongoing and will be reported for the full cohort in terms of 12 week MRI response to T and pCR to T+AC. HR deficientMolecular Subtypeyes (%)no (%)TBD (%)Luminal A0/112/11 (18.2)9/11 (81.8)Luminal B5/37 (13.5)13/37 (35.1)19/37 (51.3)Luminal NOS0/21/2 (50)1/2 (50)ER+/Her2+1/17 (5.8)14/17 (82.4)2/17 (11.8)ER-/Her2+2/20 (10)11/20 (55)7/20 (35)Triple Negative18/43 (41.9)6/43 (18.6)17/43 (39.5)germline BRCA statusMRI partial response after T (%)MRI complete response after T (%)pCR after T&AC (%)BRCA11/4 (25)0/42/4 (50)BRCA25/8 (62.5)2/8 (25)4/8 (50)BRCAwt35/112 (31.3)18/112 (16.1)35/112 (31.3) Conclusion: In the setting of neoadjuvant weekly T followed by AC, pCR rates were non-significantly higher in pts with BRCA1 mutations. While we observed no overall association between BRCA mutation status and response rates to taxanes; nearly all MRI responses to taxanes (partial and complete) were observed in the BRCA2 group. Prospective studies are needed to validate these findings and to determine whether BRCA status can be used to select therapy. HR deficiency is uncommon in luminal A and HER2+, frequent in TNBC, and the association of HRD with both MRI response to taxanes and pCR will be reported at the meeting. Citation Format: Boughey JC, Kalari KR, Suman VJ, McLaughlin SA, Moreno Aspitia A, Moyer AM, Northfelt DW, Gray RJ, Vedell PT, Tang X, Dockter TJ, Jones KN, Felten SJ, Conners AL, Hart SN, Visscher DW, Wieben ED, Ingle JN, Hartman A-R, Timms K, Elkin E, Jones J, Wang L, Weinshilboum RW, Goetz MP. Role of germline BRCA status and tumor homologous recombination (HR) deficiency in response to neoadjuvant weekly paclitaxel followed by anthracycline-based chemotherapy. [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 P3-07-29.

Abstract Background: Biomarkers to predict response to platinum-based therapy in early breast cancer are needed. HRD is a promising predictor of response to DNA damaging agents, such as platinums. We hypothesized that HRD (high HRD score ≥ 42 and/or tumor BRCA [tBRCA] mutation) would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST comprising a platinum, regardless of estrogen receptor (ER) status. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat in patients with ER-positive or triple-negative breast cancer (TNBC) (Connolly RM. JNM 2015). The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). We performed an exploratory biomarker study correlating baseline tumor biopsy HRD status with pCR. The analysis population included all patients with available HRD and pCR data. We compared the proportion of patients with pCR by HRD status using Fisher's exact test. A subset analysis compared pCR proportions by high (≥42) vs. low (<42) HRD score in those patients who did not have tBRCA mutation. A logistic regression model included HRD status, ER status, treatment arm, tumor grade and use of additional anthracycline-based non-study chemotherapy prior to definitive surgery. Results: HRD status and pCR data were available for 48/62 patients (30 ER-positive, 18 TNBC). Of these, 46% of tumors were HR deficient (n=22/48, 33% ER-positive [10/30], 67% TNBC [12/18]). We observed a significantly higher pCR rate in patients with HR deficiency vs not (50% vs 7.7%, p=0.002) in the overall population. A similar trend was observed in ER-positive (30% vs 5%, p=0.095) and TNBC (66.7% vs 16.7%, p=0.13) patients. There was no significant difference when analyzed by treatment arm (vorinostat vs placebo). In a subgroup analysis (n=40) of patients without tBRCA (25 ER-positive, 15 TNBC), a significantly higher pCR rate was observed in those with high vs low HRD score (64.3% vs 7.7%, p <0.001). After adjusting for ER status, randomized treatment, use of AC treatment, and tumor grade, patients whose tumors exhibited HR deficiency had a greater than 6 fold increase in pCR compared to those without HR deficiency (adjusted odds ratio = 6.76, 95% CI = 0.85-53.99, p=.072). Conclusion: This is the first study to evaluate the predictive role of HRD status in patients with ER-positive, HER2-negative breast cancer treated with platinum-based therapy. Our results also support prior observations that HRD status is a promising predictive biomarker of response to platinum agents in TNBC. Further evaluation of this question is warranted in both TNBC and ER-positive breast cancer. Citation Format: Connolly R, Elkin E, Timms K, Goetz M, Boughey J, Zhang Z, Walsh B, Carpenter J, Storniolo A, Watkins S, Gabrielson E, Hartman A-R, Stearns V. Homologous recombination deficiency (HRD) as a predictive biomarker of response to preoperative systemic therapy (PST) in TBCRC008 comprising a platinum in HER2-negative primary operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-13.

Abstract Background ACOSOG Z1041 (Alliance) found pathological complete response rates in women with operable HER2-positive breast cancer were similar with FEC → P+T (Arm 1) and P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. We now report DFS and OS results with a median follow up of 4.4 years (range: 26 days to 6.2 years). Methods All patients who began study treatment were included in the analyses. Stratified log rank tests and stratified proportional hazard models were used to assess differences in DFS and OS from randomization between treatment arms. Results From September 15, 2007 to December 15, 2011, 282 women with HER2-positive breast cancer were enrolled. Two patients randomized to arm 1 withdrew consent prior to treatment and are excluded from these analyses. Patient and disease characteristics of the remaining 280 women (arm 1, n=138; arm 2, n=142) were similar between treatment arms. Recurrences and deaths are shown in the table. DFS were not found to differ with respect to treatment arm (stratified logrank p=0.6870; HR stratified (Arm2/Arm1)=0.88; 95%CI: 0.48-1.61). Also, OS was not found to differ with respect to treatment arm (stratified logrank p=0.8790; HR stratified (Arm2/Arm1)=1.07; 95%CI: 0.43-2.69). Conclusions Concurrent administration of trastuzumab with anthracyclines offers no additional benefit in terms of achieving pathologic complete response or improving survival and is not needed. FEC → P+TP+T → FEC+T Arm 1Arm 2n138142Recurrences2022Deaths811 Grant Support: U10 CA76001 The study is registered with ClinicalTrials.gov, number NCT00513292. Citation Format: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Ewer MS, Hunt KK. Disease-free (DFS) and overall survival (OS) data from ACOSOG Z1041 (Alliance) a randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P+T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P+T → FEC+T) in HER2-positive operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-02.