Lj Esserman

Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can “graduate” in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2- are ineligible for randomization. MRI scans (baseline, 3 weeks 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. V+carbo was assigned to HER2- tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2- and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2- controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table. Conclusion: Adaptive randomization successfully identified a biomarker signature for V+carbo on the basis of a modest number of patients. V+carbo has graduated with a triple-negative (TN) breast cancer signature, and is the subset recommended for this regimen9s subsequent development. There is a suggestion that HR+/HER2- tumors benefit little from this regimen and inclusion of tumors in this subset would therefore dilute its effect in a subsequent trial. Analyses are currently underway to define additional biomarkers that may be predictive of response. The I-SPY 2 standing trial mechanism efficiently evaluates agents/combinations in biomarker-defined patient subsets, with future agents/combinations reported as available. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-02.

Breast cancer molecular profiles and tumor response of neoadjuvant doxorubicin and paclitaxel: The I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657).

LBA515 Background: I-SPY is a multi-center trial designed to identify predictive markers of pathological complete response (pCR) and survival of women with locally advanced breast cancers (3cm or greater). Women received neoadjuvant doxorubicin and cyclophosphamide then paclitaxel. METHODS 237 women enrolled, 216 completed serial imaging and core biopsies. Pre-treatment assays include: Agilent expression arrays, MIP aCGH, p53 gene chip and sequencing, IHC and reverse phase protein arrays (RPMA). Response to therapy was measured by serial MRI, pCR and residual cancer burden (RCB). Associations among molecular markers, pCR, RCB and survival were evaluated using chi-square test, Kaplan-Meier curves and log-rank test. RESULTS Median tumor size was 6cm, % pCR and RCB 0/1 was 27% and 36% for the entire study; % pCR rate for the 144 Agilent arrays was 25%. Distribution, rates of pCR and RCB 0/1 are shown in the Table for molecular and IHC markers. DFS and OS will be presented. Several molecular subtypes, including NKI 70 gene low, luminal A, 21 gene set low and IHC HR+, define 15-28% of patients with 3-10% pCR, yet excellent early survival. Wound healing, most discriminatory for prognosis, is not predictive of chemotherapy response. By RPMA, patients with pCR had increased phosphorylation of 4EBP1, eNOS, cAbl, STAT5, EGFR, AKT (p<0.05). In ER+ patients with poor MR response, pIRS, pIGFR, p706S were activated (p<0.05). RCB is a more refined way to measure pCR and was more predictive of DFS and OS (p=0.01) than pCR alone with a mean follow up of 3.9 years. MR volume is highly predictive of pCR and RCB. For specific subtypes, e.g. basal, RCB is predictive of DFS (p<0.00001). CONCLUSIONS LABC have aggressive biology. Response to therapy and outcome can be predicted by many biomarkers. The I-SPY data set provides a platform to compare, contrast and combine marker signatures to tailor therapy and demonstrates the power of the neoadjuvant setting. Support: ACRIN U01 CA079778 ; CALGB CA31964, CA33601; NCI SPORE CA58207. [Table: see text] [Table: see text].

Biology of breast cancers that present as interval cancers and at young age should inform how we approach early detection and prevention.

Abstract #6034 Population screening has increased the absolute number of breast cancer cases. In spite of widespread screening, there are still many patients who present with locally advanced breast cancer, often women who are young or who present with a mass between annual screens (“interval cancers”). Molecular profiling provides the opportunity to determine whether mammographically detected cancers are biologically distinct from locally advanced breast cancers. Methods: Tumor samples from the time of diagnosis (2002-2006), from patients with locally advanced breast cancers enrolled on the multi-site I-SPY TRIAL (CALGB 150007/150012 and ACRIN 6657) were compared to stage 1 & 2 tumor samples collected in 2004 from multiple community Netherlands hospitals (RASTER dataset). The NKI 70 gene set was performed on 100 of 221 patients (80 more samples pending) from I-SPY and 228 of 242 patients from the RASTER dataset. The proportion of good vs. poor prognosis profiles were compared. Additionally, we have collected data on response to chemotherapy from the I-SPY patients. Finally, mammograms from the I-SPY and RASTER datasets are being reviewed to enable classification of tumors by presentation (palpable, screen detected, and interval cancer and negative prior mammogram within 1 year). Results: I-SPY data includes 221 patients with tumors ≥3cm in size; median tumor size is 6cm; 55% were 50, with a good prognosis is 10%, 23%, and 22%, respectively. The RASTER dataset included 427 patients from age 30 to 61. NKI 70 gene profiles are available in 219 patients: 66% were Stage 1; 33% were Stage 2. Overall, 51% had a NKI 70 gene good prognosis profile. For women under the age of 40, 31% had a NKI 70 gene poor prognosis. For women 40-50, and >50, the fraction of NKI 70 gene poor prognosis is 55% and 56%, respectively. Data will be presented based on mode of detection: screen vs. palpation (never screened vs. interval). Conclusion: The key observation is that the fraction of good prognosis tumors substantially increases with age. In patients too young for screening, the fraction of poor prognosis tumors is 69%. Patients who present with locally advanced breast cancers who are too young to be screened almost always have a poor prognosis signature. This may extend to those with interval cancers. This suggests that the tumors identified by screening, although they are early stage cancers, are not the precursors of the poor prognosis tumors in young women and those with locally advanced disease. Therefore, we may not be able to rely on current screening approaches to improve outcomes for young women and those with interval cancers. Further analysis will include reviewing interval cancer cases within the I-SPY dataset and assessing prognostic indicators. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6034.

Abstract S2-06: DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer

Background: The PARP inhibitor veliparib in combination with carboplatin (VC) was one of the experimental regimens evaluated in the phase 2 neoadjuvant I-SPY 2 standing trial for high risk breast cancer patients. VC graduated in the triple negative (TN) signature. However, not all TN patients achieved pathologic complete response (pCR) and some HR+HER2- patients responded. The I-SPY 2 biomarker component provides a platform for rigorous evaluation of mechanism-of-action-based markers in the context of established biomarkers (HR, HER2, MammaPrint) within the trial. Here, we report results from 5 investigator-submitted biomarker proposals and the MammaPrint High1/High 2 (MP1/2) classification as specific predictors of VC response. Methods: Data from 116 HER2- patients (VC: 72 and concurrent controls: 44) were available. BRCA1/2 germline mutation was assessed by Myriad Genetics. 3 expression signatures relating to DNA damage repair deficiency (PARPi-7, BRCAness and CIN70) and MP1/2 classification were evaluated on Agilent 44K arrays. PARP1 levels were measured using reverse phase protein arrays. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of VC response if it associates with response in the V/C arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p Results: BRCA1/2 germline mutation status associates with VC response, but its low prevalence in the control arm precludes further evaluation. Of the biomarkers evaluated, three (PARPi-7, BRCAness, and MP1/2) associate with response in the VC arm but not the control arm, and have biomarker x treatment interactions with p Conclusion: If verified in a larger trial, PARPi7, BRCAness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care. Evaluation of the combined signature for patients treated with platinum-based chemotherapy is ongoing. Citation Format: Wolf DM, Yau C, Sanil A, Glas A, Petricoin C, Wulfkuhle J, Brown-Swigart L, Hirst G, I-SPY 2 TRIAL Investigators, Buxton M, DeMichele A, Hylton N, Symmans F, Yee D, Paoloni M, Esserman L, Berry D, Rugo H, Olapade O, van 9t Veer L. DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk 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 S2-06.

P5-15-01: Words Matter: Influence of DCIS Diagnosis Terminology on Patient Treatment Decisions.

Background: Treatment of ductal carcinoma in-situ (DCIS) poses significant challenges. Although retrospective studies suggest that most cases of low grade DCIS will never progress to invasive disease, it remains difficult to accurately identify those patients at greatest risk. In this situation where many diagnosed tumors could follow an indolent course for the patient9s lifetime, both systemic therapy and watchful waiting could be reasonable options, similar to those currently offered to patients with early prostate cancer. One strategy that has been suggested to reduce overtreatment is to use terms other than “ductal carcinoma in situ” when explaining a diagnosis of DCIS to a patient. In the current study, we have investigated the effect of terminology on women9s stated treatment preference for DCIS. Methods: Women 40–65 years of age were recruited from a database of volunteers at an academic hospital. Subjects with a personal history of breast cancer were excluded. Endpoints were gathered from a web-based survey. Each subject was presented with three different scenarios, each of which used a different terminology for DCIS: non-invasive breast cancer, breast lesion, and abnormal cells. The scenarios included a detailed explanation of the risks and benefits of three treatment options: surgery, systemic treatment only and active surveillance. After reading each scenario, the subject was asked to choose among the treatment options and to explain her choice. Results: 187 subjects completed the survey. More women chose active surveillance when DCIS was described using the terms “abnormal cells” or “breast lesion” than using the term “non-invasive cancer” (Table 1). The majority of women (97/187, 52%) changed their treatment preference when a different term was used to describe DCIS. Of the 97 women who changed their treatment preference, 47 (48%) chose surgery when the term “non-invasive cancer” was used to describe DCIS, but chose a less invasive treatment when “cancer” was not used in the diagnosis. Of 90 people who did not change their treatment preference, 39 (43%) chose active surveillance. Among the three treatments, the percent of women who chose surgery was the highest (84/187; 46%) when the term “non-invasive cancer” was used. 47/84 (56%) of the women who chose surgery when using the term “non-invasive breast cancer” changed their treatment preference when a different term was used. 36/84 (43%) switched to active surveillance while 11/84 (13%) switched to medication. Conclusion: These results support that the specific terminology used to explain a diagnosis of DCIS influences patients’ treatment preference. Moreover, we found that women may entertain treatment preferences other than surgery for DCIS when the tradeoffs of each choice are clearly explained. Avoiding the word “cancer” in the diagnosis may offer a strategy that reduces fear-based treatment decisions and may reduce the burden of overtreatment for DCIS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-01.

Comparison of MRI endpoints for assessing breast cancer response to neoadjuvant treatment: preliminary findings of the American College of Radiology Imaging Network (ACRIN) trial 6657.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6043 Background: ACRIN 6657, the imaging component of the I-SPY trial (CALGB 150007/150012), is a multi-center study testing the ability of MRI to provide in-vivo quantification of breast tumor response to neoadjuvant chemotherapy, for early prediction of response and stratification of risk-of-recurrence following treatment. We report results from preliminary analysis comparing MRI variables for correlation with pathologic response and disease progression. Methods: Women with ≥3 cm invasive breast cancer receiving an anthracycline-cyclophosphamide (AC) neoadjuvant chemotherapy regimen followed by a taxane (T) were enrolled between May 2002 and March 2006. Contrast-enhanced MRI was performed prior to start of treatment (baseline), following 1 cycle of AC chemotherapy (t2), between AC and T regimens (t3), and after all chemotherapy but prior to surgery (t4). MRI assessments included tumor longest diameter (MRLD), tumor volume (MRVol), and signal enhancement ratio (SER), a measure of contrast enhancement kinetics. Clinical size (cSize) and mammographic longest diameter (MGLD) were also recorded. Linear dimension was measured by the radiologist for MGLD and MRLD; MRVol was calculated by computer using SER thresholds. Pathologic residual disease size (pSize) and residual cancer burden (RCB) index were evaluated following surgery. Results: 237 patients were enrolled at 9 institutions. 216 patients with complete imaging formed the preliminary analysis set. At time of analysis 42 patients had progressed or died with mean time-to-progression of 21 months; 174 patients were progression-free with mean follow-up time of 42 months. At t4, MRVol was more strongly correlated with pSize than MRLD, SER or cSize (r=.61 vs .28, .24 and .43), while SER showed a stronger correlation with RCB than MRLD, MRVol or cSize (r = .45 vs .30, .31 and .37). MGLD at t4 did not show a significant correlation with either pSize or RCB. Early measurements of tumor size change from baseline by MRVol at t2, and MRVol, MRLD and SER at t3, all showed significant correlation with RCB. In univariate logistic regressions, all t4 measurements were found to be predictive of disease progression. Conclusion: Among clinical and imaging measurements of residual breast tumor size, MRI appears to most accurately reflect pathologic extent of disease following neoadjuvant treatment. Preliminary findings also suggest that tumor size and contrast kinetics measured by MRI may be useful early predictors of treatment response. ACRIN 6657 is continuing to collect follow-up data toward the primary aim testing MRI for stratification of post-treatment risk groups according to 3-year disease-free survival. This work is funded by NIH/ACRIN Grant U01 CA79778S2, CALGB Grants CA31946 and CA33601, and NCI SPORE Grant CA58207. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6043.

Abstract P2-12-11: Use of the DigniCap™ System to Prevent Hair Loss in Women Receiving Chemotherapy (CTX) for Stage I Breast Cancer (BC)

Background: Alopecia is a non-life threatening complication of adjuvant CTX for early stage BC. CTX induced hair loss affects quality of life and potentially impacts decisions regarding the risks and benefits of treatment. Scalp cooling (SC), used internationally by thousands of patients (pts) including a growing number in the U.S., is thought to prevent hair loss through decreased follicular metabolic rate and vasoconstriction resulting in reduced delivery and cellular uptake of drugs. The DigniCap™ System is a self-contained SC system with circulating coolant. We sought to evaluate feasibility and efficacy of the DigniCap™ System in pts with stage I BC. Methods: We performed an initial prospective feasibility study before a planned pivotal trial. The primary endpoint was feasibility, defined as 75% HL). Pts assessed their own HL using the Dean9s scale, and pt-assessed quality of life, time to and quality of hair re-growth, and impact of HL on treatment decisions were also evaluated. Successful prevention of alopecia was defined as Results: 20 pts were enrolled. CTX regimens included: docetaxel and cyclophosphamide (TC) × 4–6 cycles (n = 16), weekly paclitaxel and trastuzumab × 12 (n = 2), and docetaxel, carboplatin, and trastuzumab (TCH) × 6 (n = 2). 19 of 20 pts (95%) completed all CTX using the DigniCap™ System. By IP assessment, 15 pts (75%) had a maximum of ≤ grade 2 HL; 2 pts (10%) and 3 pts (15%) had a maximum grade 3 or 4 HL respectively. By pt assessment, 11 pts (55%) reported ≤ grade 2 HL. 68% and 32% of pts reported grade 1 or 2 toxicity, respectively, including head/scalp pain, feeling chilled, and rash. 85% of pts reported that SC made decisions about CTX easier. At a median follow-up of 15.4 months, no scalp metastases have been observed. Conclusions: Use of the DigniCap™ System is feasible, effective in preventing CTX-induced alopecia in the majority of users, and safe with short-term follow-up in pts with stage I BC. Additional studies should help to define potential causes for cap failure. This is the first prospective US trial to evaluate the effect of SC using an expert IP and blinded photographs to assess extent of alopecia. A larger trial is planned to confirm these results in pts with stage I/II disease. Support for this trial was provided by the Tauber Foundation (UCSF), the Madonia and Cooper Funds (WFBH), and Dignitana. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-11.

PD02-01: Impact of Contralateral Prophylactic Mastectomy on Surgical Outcomes.

Background: Among women with unilateral cancer, rates of contralateral prophylactic mastectomy (CPM) are continuing to increase. However, little is known about whether rates and types of complications differ between patients undergoing unilateral mastectomy or bilateral mastectomy, limiting the surgical outcomes evidence that can be presented in pre-surgical decision making for women considering CPM. This study was undertaken to determine whether surgical complications are increased in women undergoing CPM compared to those without CPM. Methods: Between the years 2005–2010, all patients at UCSF undergoing mastectomy with immediate reconstruction were entered into a prospective database. This database was queried for patients with unilateral cancer who had mastectomy and immediate reconstruction with or without CPM. Surgical outcomes, including implant loss, admission for IV antibiotics, and return to OR were evaluated and compared between patients who did and did not undergo CPM. Patients with bilateral cancer or bilateral prophylactic surgery were excluded; analyses were limited to patients with a minimum of 1 year follow-up. Results: 468 patients were identified who met study criteria, totaling 667 breasts. Mean follow-up time was 22 months (range 12 - 69 months). 269 of the 468 (57.5%) patients had unilateral mastectomy only, while 199 of 468 (42.5%) patients also had CPM. There were no differences in tumor grade, stage, follow-up time, smoking history, or radiation (prior or post-surgery) between the two groups. The only significant differences between the unilateral and bilateral groups were median age at diagnosis (50.7 vs. 45.9 respectively; p In patients undergoing bilateral mastectomy, overall complication rates were comparable between the index breast and the CPM breast; however, there was a higher implant loss rate in the index breast (22/177 vs. 11/188; p=0.05). Conclusions: While CPM is an increasingly common procedure, it is associated with an increased risk of major post-operative surgical complications. In this cohort, patients undergoing bilateral mastectomy for unilateral cancer had higher rates of overall complications, greater use of IV antibiotics, and more frequent return to the operating room. Since the majority of CPM cases are not at sufficiently high risk for a second breast cancer to meet clinical criteria for prophylactic surgery, guidelines and clinical recommendations should consider these increased complication rates when counseling women contemplating CPM. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD02-01.

PD02-06: Outcomes after Total-Skin Sparing Mastectomy and Immediate Reconstruction in 657 Breasts.

Background Total skin-sparing mastectomy (TSSM), a technique comprising removal of all breast and nipple tissue while preserving the entire skin envelope, is increasingly offered to women for therapeutic and prophylactic indications. However, standard use of the procedure remains controversial as a result oft concerns regarding oncologic safety and risk of complications.

Abstract P6-09-08: Patient Preference for Intra-Operative (TARGIT) or External Beam Radiotherapy Following Breast Conservation

Background: Recently published data for the TARGIT Trial (a randomized trial comparing Intraoperative Radiotherapy [IORT] for equivalence to External Beam Radiotherapy [EBRT] following lumpectomy for invasive breast cancer for selected low risk patients) shows equivalence for the IORT and EBRT arms at 4 years follow-up[1]. The TARGIT steering committee originally used a 2.5% non-inferiority margin for statistical considerations at trial initiation. We hypothesized that patients would indeed choose IORT even with the possible 2.5% inferior local recurrence rate and can now compare recently published data to patient preference. Methods: We used a validated tradeoff technique to quantify any additional risk patients would accept to receive either treatment. Subjects who were candidates for breast conserving radiation were presented with a slideshow comparing EBRT with IORT, and then asked their preference given hypothetical recurrence risks. Two initial Tradeoff Slides were used to assess whether the initial risk comparison had an effect on patients’ switch points. The first stated both forms of radiotherapy lead to a 10% 10 year risk of local recurrence, while the second stated EBRT leads to a 10% risk versus an IORT risk of 20%. Subsequent tradeoff slides incrementally increased or decreased the rate of recurrence associated with IORT until the subject preference changed. Results: Data from 81 patients were analyzed. The median additional accepted risk to have IORT was 2% (-9% to 39%). There were two outliers who accepted 34% and 39% additional risk with IORT. Only 7 patients chose to accept additional risk for EBRT; 22 accepted IORT at no additional risk, and the remaining 52 chose IORT with some additional risk. Patients who were grade 2 or 3 (versus 1) were more likely to accept a higher additional risk for IORT. No other factors studied correlated with a higher additional tolerated risk for IORT. Conclusions: Some patients chose to consider IORT even if experimental and with a higher risk for 10 year local recurrence compared to EBRT. The recetly published results from the TARGIT Trial at 4 years reported a 1.2% (95%CI 0.53-2.71) local recurrence rate for TARGIT and a 0.95% (95%CI 0.39-2.3) local recurrence for EBRT, clearly within the projected margin of 2.5% inferiority. Thus, it may be appropriate to consider offering TARGIT as an informed option on registry trial to selected low-risk patients. 1. Vaidya, J et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial), Lancet available online June 4, 2010 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-08.