Amy E. Cyr

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer

Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

Positive margin rates following breast-conserving surgery for stage I–III breast cancer: palpable versus nonpalpable tumors

BACKGROUND Margin status is a significant risk factor for local recurrence. We sought to examine whether the method of tumor localization predicted the margin status and the need for re-excision for both nonpalpable and palpable breast cancer. METHODS We identified 358 consecutive breast cancer patients who were treated with breast-conserving therapy (BCT) from 1999 to 2006. Data included patient and tumor characteristics, method of localization (needle versus palpation), and pathologic outcomes. Descriptive statistics were used for data summary and data were compared using χ(2). RESULTS Of 358 patients undergoing BCT, 234 (65%) underwent needle localization for a nonpalpable tumor and 124 (35%) underwent a palpation-guided procedure. Patients undergoing palpation-guided procedures were younger and had larger tumors at a more advanced pathologic stage of disease than those undergoing needle localization procedures (P < 0.05 for each). Patient race, tumor grade, presence of lymphovascular invasion, biomarker profile, and nodal status were not significantly different between the two groups (P > 0.05). Overall, 137 patients (38%) had one or more positive margins: 90 of 234 (38%) who had a needle localization procedure and 47 of 124 (38%) who had a palpation-guided procedure (P > 0.05). The number of margins affected did not differ significantly between the two groups. CONCLUSION Although patients with palpable breast cancer had larger tumors than those with nonpalpable breast cancer, the incidence and number of positive margins was similar to those who had needle localization for nonpalpable tumors. Improved methods of localization are needed to reduce the rate of positive margins and the need for re-excision.

Breast cancer in elderly women (≥80 years): variation in standard of care?

The study aim was to investigate the methods of breast cancer diagnosis and treatment for women at advanced ages.

A Prospective Longitudinal Clinical Trial Evaluating Quality of Life After Breast-Conserving Surgery and High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer

PURPOSE To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. METHODS AND MATERIALS Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring ≤3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. RESULTS The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. CONCLUSIONS HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment.

Successful Completion of the Pilot Phase of a Randomized Controlled Trial Comparing Sentinel Lymph Node Biopsy to No Further Axillary Staging in Patients with Clinical T1-T2 N0 Breast Cancer and Normal Axillary Ultrasound

BACKGROUND Axillary surgery is not considered therapeutic in patients with clinical T1-T2 N0 breast cancer. The importance of axillary staging is eroding in an era in which tumor biology, as defined by biomarker and gene expression profile, is increasingly important in medical decision making. We hypothesized that axillary ultrasound (AUS) is a noninvasive alternative to sentinel lymph node biopsy (SLNB), and AUS could replace SLNB without compromising patient care. STUDY DESIGN Patients with clinical T1-T2 N0 breast cancer and normal AUS were eligible for enrollment. Subjects were randomized to no further axillary staging (arm 1) vs SLNB (arm 2). Descriptive statistics were used to describe the results of the pilot phase of the randomized controlled trial. RESULTS Sixty-eight subjects were enrolled in the pilot phase of the trial (34 subjects in arm 1, no further staging; 32 subjects in arm 2, SLNB; and 2 subjects voluntarily withdrew from the trial). The median age was 61 years (range 40 to 80 years) in arm 1 and 59 years (range 31 to 81 years) in arm 2, and there were no significant clinical or pathologic differences between the arms. Median follow-up was 17 months (range 1 to 32 months). The negative predictive value (NPV) of AUS for identification of clinically significant axillary disease (>2.0 mm) was 96.9%. No axillary recurrences have been observed in either arm. CONCLUSIONS Successful completion of the pilot phase of the randomized controlled trial confirms the feasibility of the study design, and provides prospective evidence supporting the ability of AUS to exclude clinically significant disease in the axilla. The results provide strong support for a phase 2 randomized controlled trial.

Screening breast magnetic resonance imaging in women with atypia or lobular carcinoma in situ

BACKGROUND Atypical lesions and lobular carcinoma in situ (LCIS) are associated with an increased risk of breast malignancy. The utility of breast magnetic resonance imaging (MRI) screening in this cohort of women after excision of a high-risk lesion has not been previously established. The objective of this study was to investigate outcomes of breast MRI surveillance in this subgroup of high-risk patients. MATERIALS AND METHODS We performed a retrospective review of women who required excision of an atypical lesion or LCIS who underwent at least one screening breast MRI from April 2005-December 2011. We collected information on demographics, number of second-look imaging studies recommended, number of biopsies performed and pathologic outcomes. RESULTS A total of 179 patients met the inclusion criteria, including 131 (73%) with atypical lesions and 48 (27%) with LCIS. Second-look imaging was recommended for 31 of 131 (23.7%) patients with atypical lesions and 8 of 48 (16.7%) with LCIS. Ten biopsies were performed in the atypical cohort (7.6%) with two revealing a malignancy (Positive Predictive Value [PPV] of 20%). In the LCIS cohort, five biopsies were performed (10.4%) with one revealing a malignancy (PPV of 20%). CONCLUSIONS The benefit of breast MRI surveillance in patients after excision of atypical lesions or LCIS has not been clearly delineated previously. Our data demonstrate that the use of screening breast MRI in this cohort results in additional work-up in one-fifth of patients, but a PPV of only 20%. Large, prospective studies would be needed to determine whether breast cancer outcomes differ between patients undergoing conventional breast screening and those undergoing conventional breast screening plus breast MRI surveillance.

Axillary Ultrasound Accurately Excludes Clinically Significant Lymph Node Disease in Patients With Early Stage Breast Cancer

Objective: Assess the performance characteristics of axillary ultrasound (AUS) for accurate exclusion of clinically significant axillary lymph node (ALN) disease. Background: Sentinel lymph node biopsy (SLNB) is currently the standard of care for staging the axilla in patients with clinical T1-T2, N0 breast cancer. AUS is a noninvasive alternative to SLNB for staging the axilla. Methods: Patients were identified using a prospectively maintained database. Sensitivity, specificity, and negative predictive value (NPV) were calculated by comparing AUS findings to pathology results. Multivariate analyses were performed to identify patient and/or tumor characteristics associated with false negative (FN) AUS. A blinded review of FN and matched true negative cases was performed by 2 independent medical oncologists to compare treatment recommendations and actual treatment received. Recurrence-free survival was described using Kaplan-Meier product limit methods. Results: A total of 647 patients with clinical T1-T2, N0 breast cancer underwent AUS between January 2008 and March 2013. AUS had a sensitivity of 70%, NPV of 84%, and PPV of 56% for the detection of ALN disease. For detection of clinically significant disease (>2.0 mm), AUS had a sensitivity of 76% and NPV of 89%. FN AUS did not significantly impact adjuvant medical decision making. Patients with FN AUS had recurrence-free survival equivalent to patients with pathologic N0 disease. Conclusions: AUS accurately excludes clinically significant ALN disease in patients with clinical T1-T2, N0 breast cancer. AUS may be an alternative to SLNB in these patients, where axillary surgery is no longer considered therapeutic, and predictors of tumor biology are increasingly used to make adjuvant therapy decisions.

Abstract S6-05: A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC)

Background ER+ BC is associated with activated CDK4/6. The CDK4/6 inhibitor palbociclib (P) markedly improves time to progression in advanced ER+HER2- BC. We conducted a neoadjuvant phase II trial to determine the activity of P in primary breast cancer as a prelude to adjuvant studies. Methods To assess molecular changes induced by anastrozole (A) or P+A, patients (pts) were treated initially with A alone (1mg PO daily) for 28 days in cycle 0 (C0) before the addition of P (125mg PO daily on D1-21 each cycle) on C1D1. P+A was administered for 4 28-day cycles followed by C5 with A alone for 2-4 weeks (wks) before surgery. P was added in C5 for 10-12 days immediately prior to surgery in the last 20 pts enrolled to assess molecular changes induced by A, either alone or in combination with P immediately prior to surgery, in resected tumor. Goserelin was added in premenopausal pts. Research tumor biopsies were obtained at baseline, C1D1, and C1D15. Central Ki67 analysis was performed at all timepoints, those with Ki67 >10% at C1D15 went off study treatment. The primary endpoint was complete cell cycle arrest (CCA), defined as Ki67 50% improvement over A in CCA rate on C1D15 biopsy (44% with A alone based on historical data, vs 66% with P+A, power = 0.8, alpha=0.05). The primary endpoint is met if >20 pts achieved CCA in this cohort. Correlative endpoints included assessment of markers of proliferation, apoptosis, senescence, Rb, gene expression microarray, intrinsic subtype, and next generation sequencing of 83-gene panels, which will be reported at the meeting. Results Between 4/23/2013 and 4/24/2015, 50 pts (33 PIK3CA WT, 11 PIK3CA Mut, 2 pending, 4 tissue quantity or quality not sufficient for sequencing (QNS)) were enrolled to the study. Median age was 57.5 (range: 34.1–79.6) years. Four pts, all with WT PIK3CA, went off study due to Ki67 >10% on C1D15 biopsy, 26 pts completed treatment and surgery, 1 refused surgery, 3 withdrew study treatment in C1, and 16 continued to receive study drug (2 in C0, 3 in C1, 4 in C2, 5 in C3, 1 in C4, and 1 in C5). Among the 40 pts currently evaluable for the primary endpoint (C1D15 Ki67), CCA occurred in 34 (85%) pts, including 9 of 9 (100%) PIK3CA Mut, 22 of 28 (78.5%) WT, and 3 of 3 QNS pts. Preliminary analysis of available data indicated a significantly lower Ki67 value after 2 wks of P+A (C1D15) compared to that on A alone (C1D1) (p=0.034, n=18). Conclusion This study met the primary endpoint demonstrating that P+A is a highly effective anti-proliferative combination. The sequential biopsy design clearly demonstrated that P+A increased cell cycle control over A alone. P+A was effective regardless of PIK3CA mutation status and these results support the evaluation of this combination in the adjuvant setting for ER+HER2- BC. Citation Format: Ma CX, Gao F, Northfelt D, Goetz M, Forero A, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras H, Hoog J, Han J, Guo Z, Vij K, Mardis E, Al-Kateb H, Sanati S, Ellis MJ. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). [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 S6-05.

Sentinel lymph node biopsy during prophylactic mastectomy: Is there a role?

We investigated rates of occult malignancy in the breast and sentinel lymph nodes (SLNs) in patients undergoing prophylactic mastectomy (PM) and whether routine sentinel lymph node biopsy (SLNB) is justified.

Molecular Profiling of Breast Cancer

Breast cancer is now considered a heterogeneous and phenotypically diverse disease. Molecular profiling is used in clinical practice in 2 broad categories: (1) characterization of breast cancers beyond the standard histopathologic features such as tumor grade, histologic subtype, and biomarker profile for prognostic information; and (2) prediction of response to therapy and clinical outcome. This article addresses the importance and application of molecular subtype analysis, and provides an in-depth analysis of the clinical application of the molecular prognostic indices for ductal carcinoma in situ, node-negative invasive breast cancer, and node-positive invasive breast cancer.