Purpose To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. Recommendations The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.

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American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer

High quality protocols facilitate proper conduct, reporting, and external review
 of clinical trials. However, the completeness of trial protocols is often
 inadequate. To help improve the content and quality of protocols, an
 international group of stakeholders developed the SPIRIT 2013 Statement
 (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT
 Statement provides guidance in the form of a checklist of recommended items to
 include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important
 information to promote full understanding of the checklist recommendations. For
 each checklist item, we provide a rationale and detailed description; a model
 example from an actual protocol; and relevant references supporting its
 importance. We strongly recommend that this explanatory paper be used in
 conjunction with the SPIRIT Statement. A website of resources is also available
 (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement,
 should help with the drafting of trial protocols. Complete documentation of key
 trial elements can facilitate transparency and protocol review for the benefit
 of all stakeholders.

https://www.bmj.com/content/bmj/346/bmj.e7586.full.pdf

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Background Unresectable locally advanced or metastatic triple-negative (hormone-receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab. Methods In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1–positive subgroup) and ov...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1809615

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Validating prognostic or predictive candidate genes in appropriately powered breast cancer cohorts are of utmost interest. Our aim was to develop an online tool to draw survival plots, which can be used to assess the relevance of the expression levels of various genes on the clinical outcome both in untreated and treated breast cancer patients. A background database was established using gene expression data and survival information of 1,809 patients downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays). The median relapse free survival is 6.43 years, 968/1,231 patients are estrogen-receptor (ER) positive, and 190/1,369 are lymph-node positive. After quality control and normalization only probes present on both Affymetrix platforms were retained (n = 22,277). In order to analyze the prognostic value of a particular gene, the cohorts are divided into two groups according to the median (or upper/lower quartile) expression of the gene. The two groups can be compared in terms of relapse free survival, overall survival, and distant metastasis free survival. A survival curve is displayed, and the hazard ratio with 95% confidence intervals and logrank P value are calculated and displayed. Additionally, three subgroups of patients can be assessed: systematically untreated patients, endocrine-treated ER positive patients, and patients with a distribution of clinical characteristics representative of those seen in general clinical practice in the US. Web address: www.kmplot.com . We used this integrative data analysis tool to confirm the prognostic power of the proliferation-related genes TOP2A and TOP2B, MKI67, CCND2, CCND3, CCNDE2, as well as CDKN1A, and TK2. We also validated the capability of microarrays to determine estrogen receptor status in 1,231 patients. The tool is highly valuable for the preliminary assessment of biomarkers, especially for research groups with limited bioinformatic resources.

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An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients.

Purpose Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected. Methods Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression. Results Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most ...

Metastatic Behavior of Breast Cancer Subtypes

Purpose Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated. Methods Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer–specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared. Results Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and E...

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2005.06.178

Population-Based Validation of the Prognostic Model ADJUVANT! for Early Breast Cancer

BACKGROUND. Over the past decade, a number of new therapeutic agents have become available in the treatment of metastatic breast cancer (MBC). This study characterized the use and assessed the impact on survival of population-based access to new agents for the treatment of MBC. METHODS. The dates of release in British Columbia of 7 new systemic agents for MBC during the 1990s were used to construct 4 time cohorts. All patients with a first diagnosis of distant metastases in each of the time cohorts were identified and characterized, and their survival was compared. Cox proportional regression modeling was used to assess for predictors of survival. RESULTS. In total, 2150 patients with a first distant metastases diagnosed during 1 of the 4 cohort intervals were identified. Baseline characteristics between cohorts were similar, except a greater proportion of the later cohorts received adjuvant chemotherapy (P < .001), had positive estrogen receptor status (P 5 .01), and had a longer median time from initial diagnosis to MBC (P < .001). Survival in Cohort 1 (1991–1992) and Cohort 2 (1994–1995; median, 438 days and 450 days, respectively) was similar. Survival was longer in Cohort 3 (1997–1998; median, 564 days; P 5 .002) and improved further in Cohort 4 (1999–2001; median, 667 days; P 5 .05). In multivariate analysis, the later cohorts were associated independently with improved survival (P 5 .01 and P < .001, respectively).

The impact of new chemotherapeutic and hormone agents on survival in a population‐based cohort of women with metastatic breast cancer

Purpose To determine if time to start of adjuvant chemotherapy after curative surgery influences survival in early-stage breast cancer. Patients and Methods A retrospective review was conducted of 2,594 patients receiving adjuvant chemotherapy for stage I and II breast cancer between 1989 and 1998 at the British Columbia Cancer Agency. Relapse-free survival (RFS) and overall survival (OS) were compared among patients grouped by time from definitive curative surgery to start of adjuvant chemotherapy (≤ 4 weeks, > 4 to 8 weeks, > 8 to 12 weeks, and >12 to 24 weeks). Results RFS and OS were similar for women starting chemotherapy up to 12 weeks after surgery. OS hazard ratio (univariate) for initiation of chemotherapy more than 12 weeks compared with 12 weeks or less after surgery was 1.5 (95% CI, 1.07 to 2.10; P = .017). Five-year OS rates were 84%, 85%, 89%, and 78%, (log-rank P = .013); RFS rates were 74%, 79%, 82%, and 69% (log-rank P = .004) for patients starting chemotherapy 4 weeks or fewer, more than...

https://ascopubs.org/doi/pdf/10.1200/JCO.2005.01.6089

Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer

Purpose Human epidermal growth factor receptor 2 gene (HER2) is associated with a poorer outcome in node-positive breast cancer, but the results are conflicting in node-negative disease. This study assessed the prognostic impact of HER2 overexpression/amplification in a large series of node-negative breast cancers. Patients and Methods A tissue microarray (TMA) series was constructed consisting of 4,444 invasive breast cancers diagnosed in British Columbia from 1986 to 1992. Within this series, 2,026 patients were node negative, of whom 70% did not receive adjuvant systemic therapy. The TMA series was assessed for estrogen receptor (ER) and HER2. Logistic regression modeling was used to estimate odds ratios at the 10-year follow-up. Results HER2 was positive in 10.2% of the node-negative cohort. In this cohort, an inferior outcome was seen in patients with HER2-positive tumors compared with HER2-negative tumors for 10-year relapse-free survival (RFS; 65.9% v 75.5%, respectively; P = .01), distant RFS (71....

https://ascopubs.org/doi/pdf/10.1200/JCO.2007.15.8659

Caroline Speers

Papers

Metastatic Behavior of Breast Cancer Subtypes

Population-Based Validation of the Prognostic Model ADJUVANT! for Early Breast Cancer

The impact of new chemotherapeutic and hormone agents on survival in a population‐based cohort of women with metastatic breast cancer

Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer

Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers.