Sandra Swain

ObjectivesClinical study reports (CSRs) are highly detailed documents that play a pivotal role in medicine approval processes. Though not historically publicly available, in recent years, major entities including the European Medicines Agency (EMA), Health Canada, and the US Food and Drug Administration (FDA) have highlighted the importance of CSR accessibility. The primary objective herein was to determine the proportion of CSRs that support medicine approvals available for public download as well as the proportion eligible for independent researcher request via the study sponsor.Study Design and SettingThis cross-sectional study examined the accessibility of CSRs from industry-sponsored clinical trials whose results were reported in the FDA-authorized drug labels of the top 30 highest-revenue medicines of 2021. We determined (1) whether the CSRs were available for download from a public …

Background: The ability to predict and identify ovarian function loss accurately after anticancer treatment is important for appropriate oncofertility counseling and to aid in therapy decision making for young women with early breast cancer (eBC). Anti-Müllerian hormone (AMH) has been proposed as both a pre- and post-treatment predictor of subsequent permanent loss of ovarian function. The present biomarker analysis conducted within two randomized controlled trials (RCTs) in a large and well-characterized patient population with HER2+ eBC receiving homogeneous treatment aimed to assess AMH use, alone and in combination with other hormonal biomarkers, for predicting loss of ovarian function at 36 months from randomization, i.e. approximately 2 years after end of therapy. Methods: BETH (NCT00625898) and KAITLIN (NCT01966471) were RCTs investigating adjuvant chemotherapy (CT) plus anti-HER2 …

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with …

Background: In early breast cancer, the optimal management of the axilla is uncertain. To better understand the long-term benefits and risks of different approaches, we undertook an individual patient data meta-analysis of randomised trials comparing varying types of axillary treatment. Methods: Information was available on 20,273 women in 29 trials of axillary surgery or axillary radiotherapy. The trial comparisons included in this overview are summarised in Table 1. Randomisation took place during 1958–2009. Median follow-up was 10.0 years (IQR 7.4–11.5). Findings: In the trials of more extensive versus less extensive axillary treatment, the rate ratios (RR) for locoregional recurrence varied by site (p=0.003), however, 82% of these locoregional recurrences (552/670) occurred either in the breast or were of unspecified location (Table 2). Considering locoregional recurrence at any site, there was little …

In 2018, the predicted number of new breast cancers in 28 European Union (EU) countries was 404 920, with estimated age-adjusted annual incidence of breast cancer of 144.9/100 000 and mortality of 32.9/100 000, with 98 755 predicted deaths [1]. Worldwide, there was about 2.1 million newly diagnosed female breast cancer cases in 2018, accounting for almost one in four cancer cases among women, and 630 000 died of it [2]. Breast cancer incidence has increased since the introduction of mammography screening and continues to grow with the ageing of the population.The most important risk factors include: genetic predisposition, exposure to oestrogens [endogenous and exogenous, including long-term hormone replacement therapy (HRT)], ionising radiation, low parity, high breast density and a history of atypical hyperplasia. The Western-style diet, obesity and the consumption of alcohol also contribute to …

Purpose BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. Experimental Design A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. Results The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR …

Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design …

ImportanceBiologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plusERBB2/HER2blockade inERBB2/HER2-positive early breast cancer (EBC).ObjectiveTo define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41.Design, Setting, and ParticipantsIn this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023.Main Outcomes and MeasuresThe …

Background: Identifying pts with HR-positive/HER2-negative breast cancer (BC) who benefit from adjuvant chemotherapy (ACT) has been a major research focus over the past 20 years. Development and clinical application of genomic classifiers such as the 21-gene recurrence score (RS) has contributed to the biologic understanding of BC and has refined pt selection for ACT. The TAILORx and RxPONDER clinical trials demonstrated that RS identifies many postmenopausal pts with node-negative and node-positive BC and RS < 25, who do not benefit from the addition of ACT to endocrine therapy (ET). However, both trials also showed that certain subsets of premenopausal pts (node-negative/high clinical risk/RS 16-20, node-negative/RS 21-25, and node-positive/RS < 25) benefited from the addition of ACT to ET. Most premenopausal pts in these two trials did not receive ovarian function suppression (OFS) as …

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS …

Title Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in HER2+ early-breast cancer (EBC). Background In HER2+ EBC, neoadjuvant trastuzumab-based therapy is the standard of care, with adjuvant therapy determined by whether residual disease (RD) is present. Patients (pts) with RD have significantly higher relapse rates than pts with pathologic complete response. Differences in tumor and immune biology between pre-treated and post-treated tumors after HER2-blockade have been described, but little is known about how these changes can affect long-term outcomes or can be leveraged to tailor adjuvant treatment. Here we evaluate the biology of RD using gene expression analyses of pre- and post-treated HER2+ tumors, and their prognostic value to predict event-free survival (EFS) in a pooled analysis of 4 neoadjuvant studies in which …

BackgroundRadiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.MethodsIn this meta-analysis of individual patient data, we sought data from all randomised trials of regional lymph node radiotherapy versus no regional lymph node radiotherapy in women with early breast cancer (including one study that irradiated lymph nodes only if the cancer was right-sided). Trials were identified through the EBCTCG's regular systematic searches of databases including MEDLINE, Embase, the Cochrane Library, and meeting abstracts. Trials were eligible if they began before Jan 1, 2009. The only systematic …

AimTo characterise risk of anaphylaxis/hypersensitivity with intravenous pertuzumab plus trastuzumab (PH IV), the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) or concomitant chemotherapy to support potential administration of PH FDC SC by healthcare professionals outside clinics.MethodsA cumulative search for anaphylaxis/hypersensitivity (Roche Standard Adverse Event Group Terms) was performed for all pivotal trials cited in the current EMA P IV/PH FDC SC summaries of product characteristics: MBC: NCT00567190, NCT02402712; EBC: NCT01358877, NCT00545688, NCT00976989, NCT02132949, NCT03493854 and NCT03674112. Occurrence, incidence and severity of events were analysed and a time–trend analysis (by cycle) was performed.ResultsThis analysis includes 4772 patients who received PH IV and/or PH FDC SC. Incidence of all-grade …

Simple Summary CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are the established first-line treatment for metastatic and advanced hormone receptor-positive breast cancer (mBC). Recently, there has been an expansion in available next lines of therapy; however, optimal sequencing remains unclear. This paper reviews data on the efficacy and response rates of approved therapeutic options, and when possible, discusses their efficacy in the setting of prior exposure to CDK4/6i. This paper also seeks to review emerging targets and therapeutics that may be approved in the future for this patient population. Abstract Front-line therapy for advanced and metastatic hormone receptor positive (HR+), HER2 negative (HER−) advanced or metastatic breast cancer (mBC) is endocrine therapy with a CDK4/6 inhibitor (CDK4/6i). The introduction of CDK4/6i has dramatically improved progression-free survival and, in some cases, overall survival. The optimal sequencing of post-front-line therapy must be personalized to patients’ overall health and tumor biology. This paper reviews approved next lines of therapy for mBC and available data on efficacy post-progression on CDK4/6i. Given the success of endocrine front-line therapy, there has been an expansion in therapies under clinical investigation targeting the estrogen receptor in novel ways. There are also clinical trials ongoing attempting to overcome CDK4/6i resistance. This paper will review these drugs under investigation, review efficacy data when possible, and provide descriptions of the adverse events reported.

503Background: Suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual cancer, particularly for pre-menopausal women with estrogen receptor (ER)-positive tumors. We report a collaborative meta-analysis of individual participant data from randomized trials of ovarian ablation or suppression. Methods: Data were sought from randomized trials that compared ovarian ablation or suppression versus not. Primary analyses included only premenopausal women age < 55 with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained. Standard log-rank methods estimated ER-weighted annual event rate ratios (RR). Results: Individual patient data were provided for 25 of 27 …

Background The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)–based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. Methods In this double-blind, phase III trial, patients with stage I-IIIA hormone receptor–positive breast cancer, disease free after 5 years of an AI or tamoxifen followed by an AI, were randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. Results Between September 2006 and January 2010, 3966 …

BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest. METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT …

BackgroundThe primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS).MethodsAll patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up …

The opportunity to detect pancreatic cancer (PC) when potentially curable depends on early diagnosis and an ability to identify and screen high-risk populations before symptoms arise. Identification of a high-risk population is challenging and optimal screening tools remain unclear. 1 Older age is the strongest risk factor; incidence peaks at 65-69 years in males and 75-79 years in females. 2 A pooled analysis of 117 meta-analyses assigned a relative risk to a number of common risk factors (Supplementary Table S1, available at Annals of Oncology online). 3The vast majority (> 80%) of PCs arise due to sporadically occurring somatic mutations. Only a small proportion are due to inherited deleterious germline mutations. 1 Familial PC, defined as at least two first-degree relatives with PC, accounts for only 4%-10% of all cases. Variants in BRCA2 are the most common genetic abnormalities seen in familial PC. Other …

The analysis of heart failure (HF) associated with human epidermal growth factor receptor 2 (HER2)-targeted agents by Wailiany et al 1 used the World Health Organization pharmacovigilance (VigiBase) database. This analysis compared the odds of HF between several cancer-directed regimens containing HER2-targeted therapies. A total of 78,028 patients from over 130 countries were included in the study. The analyses included patients who developed adverse drug reactions to monotherapy or combination therapies to either HER2-directed monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), or tyrosine kinase inhibitors (TKIs) with or without chemotherapy.Pharmacovigilance aims to detect, assess, understand, and ultimately prevent treatment-related adverse events, and several large databases have been established. 2 Pharmacovigilance plays a role in monitoring patients receiving …