Kerry Lynn Reynolds

Neoadjuvant Endocrine Therapy for Estrogen Receptor–Positive Breast Cancer: A Systematic Review and Meta-analysis

Importance Estrogen receptor-positive (ER+) tumors of the breast are generally highly responsive to endocrine treatment. Although endocrine therapy is the mainstay of adjuvant treatment for ER+ breast cancer, the role of endocrine therapy in the neoadjuvant setting is unclear. Objective To evaluate the effect of neoadjuvant endocrine therapy (NET) on the response rate and the rate of breast conservation surgery (BCS) for ER+ breast cancer. Data Sources Based on PRISMA guidelines, a librarian-led search of PubMed and Ovid MEDLINE was performed to identify eligible trials published from inception to May 15, 2015. The search was performed in May 2015. Study Selection Inclusion criteria were prospective, randomized, neoadjuvant clinical trials that reported response rates with at least 1 arm incorporating NET (n = 20). Two authors independently analyzed the studies for inclusion. Data Extraction and Synthesis Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using the fixed- and random-effects statistical model. Results The analysis included 20 studies with 3490 unique patients. Compared with combination chemotherapy, NET as monotherapy with aromatase inhibitors had a similar clinical response rate (OR, 1.08; 95% CI, 0.50-2.35; P = .85; n = 378), radiological response rate (OR, 1.38; 95% CI, 0.92-2.07; P = .12; n = 378), and BCS rate (OR, 0.65; 95% CI, 0.41-1.03; P = .07; n = 334) but with lower toxicity. Aromatase inhibitors were associated with a significantly higher clinical response rate (OR, 1.69; 95% CI, 1.36-2.10; P < .001; n = 1352), radiological response rate (OR, 1.49; 95% CI, 1.18-1.89; P < .001; n = 1418), and BCS rate (OR, 1.62; 95% CI, 1.24-2.12; P < .001; n = 918) compared with tamoxifen. Dual combination therapy with growth factor pathway inhibitors was associated with a higher radiological response rate (OR, 1.59; 95% CI, 1.04-2.43; P = .03; n = 355), but not clinical response rate (OR, 0.76; 95% CI, 0.54-1.07; P = .11; n = 537), compared with endocrine monotherapy. The incidence of pathologic complete response was low (<10%). Conclusions and Relevance Neoadjuvant endocrine therapy, even as monotherapy, is associated with similar response rates as neoadjuvant combination chemotherapy but with significantly lower toxicity, suggesting that NET needs to be reconsidered as a potential option in the appropriate setting. Additional research is needed to develop rational NET combinations and predictive biomarkers to personalize the optimal neoadjuvant strategy for ER+ breast cancer.

Endocrine therapy for breast cancer: a tough pill to swallow.

M edical oncologists are often cited for spending large sums of money on expensive therapies, with only minimal impact on life expectancy. However, one of the first and most cost-effective targeted therapies of all time, tamoxifen, has been available for decades and has saved countless lives. Most women with early breast cancer are candidates for oral adjuvant endocrine therapy (OAET), usually with the selective estrogen receptor modulator tamoxifen (if premenopausal) or, more recently, with an aromatase inhibitor (AI; eg, anastrozole, letrozole, or exemestane); if postmenopausal. These medications are extremely effective in preventing disease relapse and death from breast cancer, but their full benefit is often unrealized because women are unable to take their antiestrogen therapy as prescribed. In clinical trials, tamoxifen decreases the annual odds of recurrence and death by 39% and 31%, respectively, whereas anastrozole has been shown to increase disease-free survival and to reduce the risk of distant metastasis by an additional 13% and 14% in postmenopausal women, respectively. Trial participants represent a particularly motivated patient group who undergo frequent visits and rigorous follow-up, yet compliance is incomplete even among this group. The adjuvant trial National Surgical Adjuvant Breast and Bowel Project B-14 included 2,818 women with early breast cancer and observed decreased adherence over time, with 23% of women on tamoxifen having discontinued therapy at 5 years of follow-up. Time and again, clinical studies have demonstrated that adherence to therapy is associated with improved patient outcomes, and yet the rates of nonadherence to treatment outside a trial can be as high as 50%. Medication adherence is the act of filling new prescriptions or refilling prescriptions on time. Medication compliance is the act of taking medication on schedule or taking medication as prescribed. The article by Bell et al, published in this issue of Menopause, highlights the fact that there is room for improvement in compliance with OAET. This was a large study in which 1,076 women completed questionnaires that directly asked them about their medication compliance at baseline and annually for at least 5 years. They have previously reported in Menopause that, by the third year after diagnosis, 18% of affected women were not adherent to their OAET. In the current publication, they report that 19.7% received treatment for at least 5 years, and an additional 46.7% received treatment for at least 4 years. By year 4, the nonadherence rate had risen to an unsettling 33%, which included 7.8% of the cohort who did not take the medicines at all. The impact of compliance (and noncompliance) on outcomes is more important in 2013 than ever, given the evolution toward extended adjuvant therapy. Motivated by the long-term follow-up results of the National Cancer Institute of Canada Clinical Trials Group MA.17 and the Adjuvant Tamoxifen: Longer Against Shorter trial, many providers now recommend up to 10 years of adjuvant endocrine therapy. Given the rate of decline in compliance over time, how many women can be expected to make it to 10 years of therapy? Interestingly, this patient population seems to display relatively preserved compliance over time, presumably because it is a select population that has already tolerated 5 years of anti-estrogen therapy. In one study cohort, 28% of women were nonadherent to extended therapy, similar to the rate (26%) of nonadherence found in a female cohort treated with sequential therapy (AI after 2-3 y of tamoxifen). What are the hurdles to compliance, and how can we creatively help women to keep taking their pills? The single most common patient-reported reason for discontinuation of antiestrogen therapy is the development of intolerable adverse effects. Tamoxifen may induce hot flashes, decreased libido, mild arthritis, vaginal discharge, abdominal bloating, and, rarely, blood clots and endometrial cancer, whereas AIs are associated with hot flashes, joint aches, and loss of bone density. Recent data suggest that there may be a genomic explanation for why some women experience musculoskeletal pain with AIs. Liu et al performed functional genomic experiments on patient samples and identified four single nucleotide polymorphisms near the 3¶ terminus of the T-cell leukemia 1A (TCL1A) gene, which altered the expression of interleukin (IL)-17, IL-17RA, IL-12, IL-12RB2, and IL-1R2, and the transcription of nuclear factor JB (NF-JB). This suggests that estrogen withdrawal in certain individuals could alter cytokine production and increase NF-JB pathway activation. This may explain AI-induced musculoskeletal pain, considering that NF-JB controls many genes involved in inflammatory cascade. Understanding the mechanisms of adverse events may ultimately allow for the development of strategies to sufficiently ameliorate them, allowing women to remain on antiestrogen therapy. Age seems to be a consistent predictive factor in nonadherence. One of five women younger than 40 years does not initiate endocrine therapy or stops taking it within the first few months. In addition, 42% of women skip at least two consecutive months within the first 2 years of treatment. The effect of such intermittent use on outcome is unclear. When looking at factors associated with reduced adherence, the

Diagnosis and Management of Hepatitis in Patients on Checkpoint Blockade

Immunotherapy for cancer holds great promise, but immune dysregulation of checkpoint blockade has resulted in new autoimmune adverse events. Hepatic toxicity occurs in 1%–17% of patients on immune checkpoint inhibitors. Hepatitis is usually a low‐grade toxicity, but grade 3 and 4 hepatotoxicity does occur. This article answers frequently asked questions about immune‐related hepatitis to assist in the recognition and management of this important condition.

Abstract 1439: Pathological complete response after neoadjuvant chemotherapy predicts improved survival in all major subtypes of breast cancer: systematic review and meta-analyses of over 18,000 patients

Introduction: Several randomized clinical trials have shown that neoadjuvant chemotherapy has similar long-term survival outcomes as compared to adjuvant chemotherapy. However, the prognostic significance of pathological complete response (pCR) after neoadjuvant chemotherapy remains unclear, particularly for HR+ (Hormone Receptor positive) and HER2+ (Human Epidermal growth factor Receptor-2 positive) breast cancer where adjuvant therapy after surgery could also have an impact on survival. The primary objective of this study was to conduct a systematic review of published neoadjuvant chemotherapy studies to comprehensively evaluate the association between pCR with subsequent breast cancer recurrence (BCR) and mortality. Methods: Based on PRISMA guidelines, a librarian-led search of PubMed from inception until November 2015 was performed to identify potentially eligible studies. Inclusion criteria were clinical trials or retrospective studies with at least one arm featuring neoadjuvant chemotherapy that reported pCR results as well as recurrence and/or survival stratified by the presence or absence of pCR. A total of 1,171 citations with associated abstracts were reviewed. Pooled odds ratios (ORs), 95% confidence intervals (CI), and p values were estimated for endpoints using the fixed and random effects statistical model. Results: 18,772 patients from 49 studies met inclusion criteria. The majority of studies featured patients with stage II-III breast cancer and defined pCR as no residual invasive cancer in breast or nodes with residual noninvasive breast cancer allowed (ypT0/is ypN0). The overall pCR rate was 21.5% (range: 5.7-62%), with the highest pCR rates seen in HER2+ (range: 16.7-76%) and triple negative tumors (range: 14.3-67%). Achievement of pCR, as compared to absence of pCR, was associated with significantly reduced BCR (OR 0.33, CI: 0.28-0.39, p = Conclusions: Achieving pCR following neoadjuvant chemotherapy is associated with significantly improved disease recurrence and survival across the various breast cancer subtypes, including HR+ and HER2+ breast cancer. These results provide further support for using pCR as a surrogate marker for survival outcomes as newer targeted therapies are evaluated in the neoadjuvant setting and might provide an efficient model for drug development in early breast cancer, but impact of adjuvant therapy needs to be carefully weighed in the analytical interpretation. Citation Format: Laura Spring, Rachel Greenup, Kerry Reynolds, Barbara L. Smith, Beverly Moy, Aditya Bardia. Pathological complete response after neoadjuvant chemotherapy predicts improved survival in all major subtypes of breast cancer: systematic review and meta-analyses of over 18,000 patients. [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 1439.

Abstract P1-13-03: Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer

Background: Phosphatidylinositol 3-kinase (PI3K) gene (PIK3CA) mutations are the most common somatic mutations in breast cancer. Preclinical models suggest that activating mutations in PIK3CA may mediate resistance to endocrine therapy in breast cancer, and multiple clinical trials testing combinations of endocrine therapy with PI3K inhibitors are ongoing. However, the role of PIK3CA in modulating the clinical response to endocrine therapies is less clear, with some studies suggesting that PIK3CA mutations are associated with improved prognosis in HR+ breast cancer. The primary objective of this study was to evaluate the association of PIK3CA mutation with clinical response to endocrine therapies in metastatic HR+ breast cancer. Methods: We identified patients with metastatic HR+ /HER2 negative breast cancer, including ER+/PR+ (estrogen receptor/progesterone receptor) and ER+/PR-, to determine the time to progression (TTP) on first-line endocrine therapy for metastatic disease. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a robust, high-throughput tumor genotyping assay (Snapshot), developed at our institution, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Actuarial analysis of TTP was performed using Cox proportional hazard method to compute Hazard Ratio (HR) and 95% Confidence Intervals (CI). Results: Between 2009 and 2012, we identified 188 patients with HR+ metastatic breast cancer who had tumor genotyping performed. PIK3CA mutations were identified in 32.2% of tumors, including mutations in both helical (exon 9) and kinase (exon 20) domains (60% and 40%, respectively). The PIK3CA mutant and wild type patients had a similar median age at diagnosis of metastatic disease (55.8 and 56.7 years; p=0.2), ER+/PR+ tumors (75.0% vs 76.4%; p=0.8), and median TTP (8.2 versus 11.4 months; p=0.6). After adjusting for age at diagnosis and ER+/PR+ versus ER+/PR-, the TTP on first-line endocrine therapy did not vary among patients with PIK3CA mutations versus wild type (HR: 0.94; 95% CI:0.62-1.43; p=0.8), but did vary by type of endocrine therapy. Patients with PIK3CA mutations, as compared to wild type patients, had shorter TTP with fulvestrant (HR: 3.6; 95% CI:1.2-11.0; p=0.03), but not with aromatase inhibitors (AIs) (HR: 0.70; 95% CI:0.44-1.1; p=0.1), suggesting that mutant PIK3CA may specifically modulate the response to fulvestrant therapy. We did not observe any difference in TTP for exon 9 versus 20 PIK3CA mutations, though numbers were small resulting in limited statistical power. Conclusion: Among patients with metastatic HR+ breast cancer in this study, PIK3CA mutations are associated with decreased time to progression with fulvestrant, but not with AIs, suggesting that the these mutations may mediate resistance to specific endocrine therapies. Further studies are needed to confirm these findings and provide mechanistic insights to help guide optimal selection of endocrine therapy and combination with PI3K directed therapy in metastatic HR+ breast cancer. Citation Format: Douglas S Micalizzi, Dejan Juric, Andrzej Niemierko, Kerry L Reynolds, Darrell Borger, Sadhna R Vora, Steven J Isakoff, Beverly Moy, Leif W Ellisen, Aditya Bardia. Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-03.

Neoadjuvant single and dual HER2 blockade among patients with localized HER2-positive breast cancer.

147 Background: Dual neoadjuvant HER2 directed therapy is offered only in a clinical trial setting and is not standard of care, but emerging data suggests targeting multiple mechanisms may be more effective. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), and on pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, as well as the impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ breast cancer. METHODS MEDLINE, EMBASE, and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and p values were estimated for endpoints using the random effects statistical model. RESULTS We identified 36 trials (N = 4130). High pCR rates (> 40%) were seen with anthracycline-based chemotherapy and trastuzumab alone, and non-anthracycline based dual HER2 blockade. The addition of trastuzumab to chemotherapy did not improve BCS rate (RR 1.40, p = 0.15), but significantly increased rates of pCR (RR 1.91, p = 0.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, p = 0.84), but significantly increased rates of pCR overall (RR 1.39, p < 0.00001), in both ER+ (RR 1.72, p = 0.01) and ER- subsets (RR 1.91, p = 0.0001), with no increase in grade 3/4 toxicity (RR:1.13, p = 0.16). Dual HER-2 blockade without chemotherapy was associated with pCR in a subset (11.2% - 27%) with minimal toxicity (incidence of grade 3/4 toxicity:1-5%). Higher pCR was associated with improved DFS (RR 2.29, p = 0.006) and OS (RR 4.61, p = 0.009). CONCLUSIONS Neither the addition of trastuzumab to chemotherapy, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS. However,both significantly improve rates of pCR, which is associated with improved DFS and OS. Dual HER2 blockade,with endocrine therapy for ER+, could potentially lessen or even obviate the use of chemotherapy.

Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience

BACKGROUND The use of immune checkpoint inhibition (ICI) has revolutionized cancer treatment. However, these medications are associated with significant and potentially debilitating immune-related adverse events (irAEs). While certain toxicities have been well studied, rheumatic complications have been less widely recognized and characterized. METHODS We report our experience of patients who were evaluated by rheumatology after the development of a suspected rheumatic irAE following ICI treatment. Cases of rheumatic irAEs were included if active rheumatic signs or symptoms developed during or after ICI treatment and were confirmed by a treating rheumatologist. RESULTS Twenty-nine patients were evaluated by rheumatology for suspected rheumatic irAEs. Eighteen patients had confirmed toxicity including inflammatory arthritis (n = 12) and PMR (n = 6). Twelve patients had de novo toxicity and six had a flare of a pre-existing rheumatic condition. The onset of de novo toxicity occurred late into treatment (median 38 weeks), while patients with pre-existing rheumatic disease flared soon after initiation of ICI treatment (median 4.6 weeks). Management often required systemic or intra-articular steroids, with initiation of disease modifying anti-rheumatic drug (DMARD) therapy in those unable to wean off steroids. CONCLUSION De novo rheumatic irAEs are generally delayed in onset after ICI initiation, while flares of pre-existing rheumatic conditions occur shortly after ICI initiation. Effective management often requires systemic corticosteroids as well as DMARDs in a subset of patients. Future prospective studies are needed to accurately describe the incidence and spectrum of rheumatic irAEs and to identify the most effective management strategies.

Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: Checkpoint Inhibitors for MSI-H/dMMR mCRC

Patients with microsatellite instability–high (MSI‐H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC) show a significant response to checkpoint inhibitor therapies, but the economic impact of these therapies is unknown. A decision analytic model was used to explore the effectiveness and cost burden of MSI‐H/dMMR mCRC treatment.

Abstract P5-13-02: Neoadjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer: Comprehensive systematic review and meta-analysis

Background: ER positive tumors are generally highly responsive to endocrine treatment. However, the specific indications for neoadjuvant endocrine therapy, both as monotherapy and in combination with other therapies, in early breast cancer remain unclear. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant endocrine therapy on response rate (RR), based on clinical response or imaging, and pathological complete response rate (pCR) for ER positive breast cancer. Methods: Based on QUORUM guidelines, a librarian-led search of PubMed, Ovid, and EMBASE was performed to identify eligible trials published prior to May 15, 2015. Inclusion criteria were prospective, randomized neoadjuvant trials that had at least one arm with neoadjuvant endocrine therapy and reported RR. Pooled odds ratios (ORs), 95% confidence intervals (CI), and p values were estimated for endpoints using the fixed and random effects statistical model. Results: We identified 477 citations initially with 277 remaining after duplications were removed. Twenty trials ultimately met inclusion criteria, with a total sample size of 3,493. The majority of studies (90%) focused on post-menopausal women and compared chemotherapy to endocrine therapy, different durations and types of endocrine therapies, or combinations with growth factor pathway inhibitors. Overall, as compared to chemotherapy, neoadjuvant endocrine therapy had a similar clinical RR (OR 0.93, CI: 0.43-2.02, p = 0.85) and radiological RR (OR 0.73, CI: 0.48-1.09, p = 0.12), but lower rate of toxicity (febrile neutropenia, mucositis). Aromatase inhibitors were associated with significantly higher clinical RR (OR 1.69, CI: 1.36-2.10, p = Conclusion: Neoadjuvant endocrine therapy is associated with similar response rates as neoadjuvant chemotherapy but with lower toxicity, and neoadjuvant AIs are superior to tamoxifen for ER-positive tumors. Compared to endocrine monotherapy, dual combination therapy may have superior response rates by imaging, but the low number of trials limits strong conclusions. Additional studies and more predictive biomarkers are needed to personalize the optimal neoadjuvant endocrine combination for an individual patient with ER positive breast cancer. Citation Format: Spring L, Gupta A, Reynolds KL, Gadd MA, Isakoff SJ, Ellisen LW, Moy B, Bardia A. Neoadjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer: Comprehensive systematic review and meta-analysis. [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 P5-13-02.

Abstract P4-12-02: High HER2 gene amplification and clinical outcomes in localized HER2-positive breast cancer

BACKGROUND Anti-HER2 therapy with trastuzumab is associated with a significant improvement in disease-free survival as compared to chemotherapy alone, and is considered the standard of care for localized HER2 positive breast cancer. However, a subset of HER2 positive breast cancers do not respond to trastuzumab. While various mechanisms have been proposed for trastuzumab resistance, one potential contributor could be very high level of HER2 gene amplification. Since trastuzumab is a HER2 receptor antagonist, it is possible that single agent trastuzumab might be unable to block HER2 downstream signaling thresholds efficiently in the presence of very high HER2. The clinical outcomes for tumors with high HER2 gene amplification treated with trastuzumab have not been well studied. METHODS With IRB approval, we reviewed the clinical records of all Stage I-III breast cancer patients with HER2+ breast cancer at our institution from 2008-2012. HER-2 to Chromosome 17 FISH ratio was determined by two pathologists with high inter-person reliability using the PathVysion dual color probe (Abbott Laboratories). We abstracted data on demographics, tumor characteristics including tumor size (T), lymph node involvement, grade, DCIS, HER2 amplification levels, and clinical outcomes from the clinical charts. We defined high HER2 amplification as FISH ratio > 8.0, as used in the HERA trial. Categorical data are summarized by frequency and percentage and comparisons between groups are performed by chi-square tests. In addition, we conducted a meta-analyses and systematic review to evaluate the association between high HER2 gene amplification and clinical outcome with/without trastuzumab in the large adjuvant HER2 clinical trials. RESULTS A total of 503 patients with HER2+ breast cancer were seen between the years of 2008-2012, and 16% (N = 82) had tumors with high HER2 levels. The median age was 50.5 years (range 29-89). The majority of tumors were T1 (56.79%) or T2 (34.57%), and had HER2 IHC staining of 3+ (94.37%). Tumors with high HER2 levels were more likely to be ER-/PR- (48.4%) than ER+/PR+ (32.8%) or ER+/PR- (18.8%), and likely to have concomitant DCIS (82.5%) and high grade (grade 3 = 74%). Women (n = 16) with high HER2+ breast cancer treated with standard neoadjuvant therapy with single agent trastuzumab (AC-TH or TCH) had a low pathological complete response (pCR) rate of 7.14%. In addition, this group had a high recurrence risk of 42.9%. Two patients with recurrence had mutation profiling by multiplexed genotyping platform (SNaPshot) and mutations in PIK3CA and TP53 oncogene were identified.One patient with grade 3, high HER2+ (FISH 8.2) microinvasive DCIS, treated with mastectomy, developed pulmonary metastases 3 years after original diagnosis. The meta-analysis revealed adjuvant trastuzumab with chemotherapy did not result in improved disease free survival as compared to chemotherapy alone among tumors with high FISH ratio (Hazard Ratio: 0.89, 95% CI: 0.57, 1.38; p = 0.60). CONCLUSIONS: Our results suggest that tumors with high HER2 amplification, including small tumors, have an aggressive biology, are less likely to respond to standard trastuzumab based therapy, and more likely to have a recurrence, compared with historical HER2 controls. High FISH may predict a clone of cells that have resistance to single agent trastuzumab warranting more aggressive HER2 directed therapy such as dual HER2 or combined HER2 and PI3K/Akt/mTOR blockade. These findings need confirmation in additional studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-02.