Amy Jo Chien

Aromatase Inhibitors and Bone Health in Women With Breast Cancer

The role of aromatase (estrogen synthetase) inhibitors (AIs) in breast cancer has expanded since their introduction in the mid-1990s. They are superior to tamoxifen in the treatment of postmenopausal women with estrogen-dependent tumors in the metastatic, neoadjuvant, and adjuvant settings. The profound estrogen depletion with AIs is responsible for improved antitumor effect but has led to concerns about healthy organs such as bone. This is particularly important in postmenopausal patients already at risk of osteoporosis and bone fracture because of premature menopause and toxic effects from chemotherapy and steroids. Compounding this, 80% of metastases develop in bone, which increase the risk of fracture through osteoclast-mediated destruction of surrounding bone. The American Society of Clinical Oncology (ASCO) currently recommends an AI as adjuvant therapy in postmenopausal women with hormone receptor–positive early breast cancer, either as initial monotherapy or after tamoxifen therapy. Trials examining their use beyond 5 years and their role as preventatives in healthy women are underway. Therefore, it is imperative that oncologists are familiar with long-term toxicities associated with AI therapy. This review summarizes emerging preclinical and clinical data related to the effects of AIs on bone mineral density, markers of bone turnover, and clinical fracture rates, and offers surveillance and clinical management recommendations with respect to bone health in women receiving chronic AI therapy.

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.

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies

Purpose: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach. Experimental Design: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m2) was conducted in patients with advanced solid tumors. Results: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory. Conclusion: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models. (Clin Cancer Res 2009;15(17):5569–75)

Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer: A Randomized Clinical Trial

Importance Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance. Objective To evaluate safety of intravaginal testosterone cream (IVT) or an estradiol-releasing vaginal ring (7.5 &mgr;g/d) in patients with early-stage breast cancer (BC) receiving an AI. Intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (E2), defined as E2 greater than 10 pg/mL (to convert to pmol/L, multiply by 3.671) and at least 10 pg/mL above baseline after treatment initiation on 2 consecutive tests at least 2 weeks apart. Design, Setting, and Participants Postmenopausal (PM) women with hormone receptor (HR)–positive stage I to III BC taking AIs with self-reported vaginal dryness, dyspareunia, or decreased libido were randomized to 12 weeks of IVT or an estradiol vaginal ring. Estradiol was measured at baseline and weeks 4 and 12 using a commercially available liquid chromatography and tandem mass spectrometry assay; follicle-stimulating hormone levels were measured at baseline and week 4. Gynecologic examinations and sexual quality-of-life questionnaires were completed at baseline and week 12. This randomized noncomparative design allowed safety evaluation of 2 interventions concurrently in the same population of patients, reducing the possibility of E2 assay variability over time and between the 2 interventions. Main Outcomes and Measures The primary objective of this trial was to evaluate safety of IVT or an estradiol vaginal ring in patients with early-stage BC receiving an AI; secondary objectives included evaluation of adverse events, changes in sexual quality of life using the Cancer Rehabilitation Evaluation System sexuality subscales, changes in vaginal atrophy using a validated 4-point scale, and comparison of E2 levels. Results Overall, 76 women signed consent (mean [range] age, 56 [37-78] years), 75 started treatment, and 69 completed 12 weeks of treatment. Mean (range) baseline E2 was 20 (<2 to 127) pg/mL. At baseline, E2 was above the postmenopausal range (>10 pg/mL) in 28 of 76 women (37%). Persistent E2 elevation was observed in none with a vaginal ring and in 4 of 34 women (12%) with IVT. Transient E2 elevation was seen in 4 of 35 (11%) with a vaginal ring and in 4 of 34 (12%) with IVT. Vaginal atrophy and sexual interest and dysfunction improved for all patients. Conclusions and Relevance In PM women with early-stage BC receiving AIs, treatment with a vaginal ring or IVT over 12 weeks met the primary safety end point. Baseline elevation in E2 was common and complicates this assessment. Vaginal atrophy, sexual interest, and sexual dysfunction were improved. Further study is required to understand E2 variability in this setting. Trial Registration clinicaltrials.gov Identifier: NCT00698035

Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2s dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy. Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (ESBC): Predictors of cognitive decline.

104 Background: Cog complaints are common among women receiving adjuvant therapy (Rx) for ESBC. Longitudinal prospective data is needed to help identify predictors of cog decline. We conducted a prospective trial to evaluate the effects of chemo- (CTX) and hormone therapy (HRx) on brain and cog fcn in pts with ESBC using multiple objective and subjective tests as well as MRI/PET imaging. Here we report evaluation of clinical characteristics that predict decline in cog fcn. METHODS Eligibility included female patients (pts) planning to receive adjuvant Rx for ESBC. Pts were enrolled in 3 Rx groups (grps): CTX, CTX and HRx, and HRx, with a 4th no Rx age/education matched control grp. All pts underwent a battery of objective and subjective cog tests before start of Rx, 1 mo after CTX or 5 mo after start of HRx (FU1), then 9 mo (FU2) and 18 mo (FU3) after CTX. Brain MRI, PET and serum estradiol (E) were performed at baseline, FU1 and FU2. RESULTS 81 pts were enrolled as follows, 14 CTX, 33 CTX and HRx, 22 HRx, 12 control. 90% completed FU1, 72% FU2, and 62% FU3, with 29 pts waiting to complete testing. Demographics were similar between grps, median age 54, 78% Caucasian. At each FU, ~25% of pts showed decline in cog fcn compared to the prior time point using a reliable change index; 51% showed decline at > 1 time point, primarily in tests measuring executive function and verbal memory. 62% of pts who declined from baseline to FU1 later stabilized or improved; 77% of pts who declined from FU1 to FU2 later stabilized or improved. Compared to controls, receipt of CTX and HRx (OR 3.15, p=.008), or HRx overall (OR 4.94, p=.004) but not serum E, menopausal status, or CTX, were significant predictors of decline at any time point. Rx group did not predict poorer perceived cog fcn (FACT-COG); depression and fatigue did not predict decline in objective cog fcn. CONCLUSIONS Decline in cog fcn is common in pts receiving adjuvant Rx for ESBC. Predictors included CTX and HRx, or HRx overall but not other treatment and pt related factors. Ongoing HRx, particularly after CTX, appears to be a risk factor for worse cog fcn. Pts should be aware that HRx may be a risk factor for cog deficits, and intervention studies should be designed to focus on this group of pts. FUNDING NIH R01 1AG025303-01A2. CLINICAL TRIAL INFORMATION 00755313.

Dedicated Breast Positron Emission Tomography for the Evaluation of Early Response to Neoadjuvant Chemotherapy in Breast Cancer

Neoadjuvant chemotherapy provides an opportunity to assess tumor response to targeted therapies in vivo, and imaging plays a critical role in assessing the effectiveness of such therapies. Currently no clinical standard exists for evaluating response to neoadjuvant chemotherapy, although positron emission tomography (PET) and contrastenhanced magnetic resonance imaging (MRI) are promising candidate technologies. Positron emission tomography with fluorodeoxyglucose provides information about tumor metabolism that can powerfully predict treatment response early in the course of therapy, before anatomic changes become evident on MRI scans. The recent development of a high-resolution, breastspecific PET imaging system allows more detailed characterization of the primary breast tumor than conventional whole body PET systems. We report on the usage of dedicated breast PET to provide early assessment of treatment response in a patient with bilateral synchronous breast cancers.

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

Background: Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods: Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m 2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results: Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. Conclusion: The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen9s likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van9t Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-02.

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

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