Clonal evolutionary analysis during HER2 blockade in HER2-positive inflammatory breast cancer: A phase II open-label clinical trial of afatinib plus /- vinorelbine

Background Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy. Methods and Findings HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m(2) weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naIve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naive patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naIve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. Conclusions Afatinib, with or without vinorelbine, showed activity in trastuzumab-naive HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease

Establishment of the First Comprehensive Adult and Pediatric Hematopoietic Stem Cell Transplant Unit in the United Arab Emirates: Rising to the Challenge

Hematopoietic stem cell transplantation (HSCT) is increasingly indicated for various malignant and non-malignant diseases. In the United Arab Emirates (UAE), patients that could benefit from the procedure commonly need to seek medical care abroad in view of the lack of a comprehensive HSCT facility that could offer the full spectrum of interventions and monitoring protocols. This comes with considerable challenges related to coverage and logistics of travel. It also limits the continuity of clinical care, and presents inconvenience to patients who come from a different cultural background. In this article, we share our experiences and lessons learned during the establishment of the first comprehensive adult and pediatric HSCT unit in the UAE that is designed to cater for local citizens and residents, as well as neighboring countries facing similar availability challenges

Breast Cancer in the Arabian Gulf Countries

Breast cancer stands as the prevailing malignancy across all six Gulf Cooperation Council (GCC) nations. In this literature review, we highlighted the incidence and trend of breast cancer in the GCC. Most of the studies reported a consistent increase in breast cancer incidence over the past decades, which was particularly attributed to the adoption of a Westernized lifestyle in the region and the implications of emerging risk factors and other environmental and societal factors, the increase in screening uptake, as well as the improvement in data collection and reporting in the GCC. The data on breast cancer risk factors in the GCC were limited. In this geographic region, breast cancer frequently manifests with distinctive characteristics, including an early onset, typically occurring before the age of 50; an advanced stage at presentation; and a higher pathological grade. Additionally, it often exhibits more aggressive features such as human epidermal growth factor receptor 2 (HER2) positivity or the presence of triple-negative (TN) attributes, particularly among younger patients. Despite the growing body of literature on breast cancer in the GCC, data pertaining to survival rates are, regrettably, meager. Reports on breast cancer survival rates emanating from the GCC region are largely confined to Saudi Arabia and the United Arab Emirates (UAE). In the UAE, predictive modeling reveals 2-year and 5-year survival rates of 97% and 89%, respectively, for the same period under scrutiny. These rates, when compared to Western counterparts such as Australia (89.5%) and Canada (88.2%), fall within the expected range. Conversely, Saudi Arabia reports a notably lower 5-year survival rate, standing at 72%. This disparity in survival rates underscores the need for further research directed toward elucidating risk factors and barriers that hinder early detection and screening. Additionally, there is a pressing need for expanded data reporting on survival outcomes within the GCC. In sum, a more comprehensive and nuanced understanding of breast cancer dynamics in this region is imperative to inform effective strategies for prevention, early detection, and improved patient outcomes

Study flow and patient disposition.

<p>This figure describes the study and number of patients in each part of the clinical trial (blue outline), reasons for patients being excluded or discontinuing treatment (purple outline), and number of patients with genomic analysis performed (green outline). PD, progressive disease.</p

Genomic analysis of tumour biopsies before treatment and following disease progression on afatinib monotherapy.

<p>(A) Somatic mutations (SNVs and indels) identified in pre- and post-treatment biopsies. Green, mutations identified in pre-treatment only; yellow, mutations identified in both pre- and post-treatment; blue, mutations identified in post-treatment only. Data tracks below denote: if patient derived confirmed clinical benefit from afatinib monotherapy (red); amplifications (≥2x ploidy), gains (≥1 copy number relative to ploidy), and losses (≤1 copy number relative to ploidy) in <i>ERBB2</i> (<i>HER2</i>), <i>EGFR</i>, <i>PIK3CA</i>, and <i>PTEN</i> are indicated by red, pink, and blue, respectively. NEV, not evaluated; NA, no information available. (B) Two main patterns of clonal evolution following afatinib monotherapy observed, either branched evolution or shifting clonal structure. Numbers refer to mutation clusters from PyClone results, also in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002136#pmed.1002136.s011" target="_blank">S10 Fig</a>. T1, pre-treatment biopsy; T2, post-treatment biopsy; CCF, cancer cell fraction.</p

Most common treatment-related adverse events reported in ≥10% of patients.

<p>Most common treatment-related adverse events reported in ≥10% of patients.</p

Somatic mutations in HER2-positive IBC.

<p>(A) Top panel shows number of somatic mutations (SNVs and indels) identified across the 22 IBC patients. Data tracks below indicate if patient was: treated with trastuzumab prior to afatinib monotherapy (orange); oestrogen-receptor (ER) or progesterone-receptor (PgR) positive (yellow); derived confirmed clinical benefit from afatinib monotherapy (red); tumour underwent whole-genome doubling (WGD) (pink). Mutational signatures identified in IBC tumours were predominantly age-related (Signatures 1A and 1B) (blue), APOBEC-related (Signatures 2 and 13) (salmon), and others (grey). NEV, not evaluated; NA, no information available. (B) <i>TP53</i>, <i>PIK3CA</i>, <i>AKT1</i>, and <i>ERBB2</i> mutations identified in samples are indicated if present (blue) or absent (grey). Gain-of-function mutations (<i>TP53</i> p.R248, <i>PIK3CA</i> p.H1047R, <i>AKT1</i> p.E17K, <i>ERBB2</i> p.V777L) are indicated by a yellow dot. Clonal and subclonal mutations are indicated by dark blue and yellow outlines, respectively. Amplifications (≥2x ploidy), gains (≥1 copy number relative to ploidy), and losses (≤1 copy number relative to ploidy) in <i>ERBB2</i> (<i>HER2</i>), <i>PIK3CA</i>, <i>EGFR</i>, and <i>PTEN</i> are indicated by red, pink, and dark blue, respectively. Somatic activation of PI3K/AKT/mTOR pathway (defined as <i>PIK3CA</i> activating mutation or gain, <i>PTEN</i> deletion, <i>AKT1</i> mutation) indicated in orange. (C) Plots showing results of GISTIC analysis identifying recurrent focal gains (left panel in red) and losses (right panel in blue); <i>y</i>-axis is genomic position and <i>x</i>-axis is GISTIC q-value; green line represents significance threshold (q-value = 0.25). Gene names are indicated where significantly mutated cancer driver genes were previously associated with the GISTIC peak in a pan-cancer analysis of SCNAs [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002136#pmed.1002136.ref038" target="_blank">38</a>]. (D) Box plot showing higher numbers of somatic nonsynonymous (NS) mutations identified in IBC patients compared to non-IBC patients. The band inside the box denotes median. (E) Bar plot showing an enrichment of <i>TP53</i> mutations in IBC patients versus non-IBC patients. Yellow bar is proportion of gain-of-function <i>TP53</i> p.R248 mutations. (F) Boxplot showing higher numbers of neoantigens predicted in IBC patients compared to non-IBC patients. Asterisk (*) denotes significant <i>p</i>-value <0.05.</p