The importance of cancer clinical trials as illustrated by HER2+ breast cancer

Cancer Clinical Trials

Clinical trials are fundamental to advances in healthcare. COVID 19 and the development of effective vaccines have helped shine an important spotlight on the importance of clinical trials. The recent ‘Just Ask 2022’ survey conducted by Cancer Trials Ireland (CTI) showed 78% of the the public surveyed agreed the pandemic has highlighted the importance of clinical trials.

The oncology community was one of many groups that celebrated International Clinical Trials Day “Then and Now” on the 20th May 2022. International Clinical Trials Day (ICTD) is held on/ around the 20th May of each year to commemorate the day when James Lind started his clinical trial on scurvy in 1747. This laid the foundation for modern clinical research and is the bedrock on which clinical medicine advancements are made.

Why cancer trials are important

Clinical trials are the backbone of all progress seen in treatment of cancer. Medical oncology in particular, along with radiation oncology has helped to unite the disciplines of biology, basic research, genetics, immunology, pathology and pharmacology. The collective input of these diverse disciplines has seen the development of systemic treatments that has resulted in dramatically improved outcomes for patients. This is a dynamic and ever evolving field as shown by the recent ground breaking DESTINY 04 breast cancer trial results presented at the international American Society of Clinical Oncology (ASCO) annual meeting.

The National Cancer Control Program (NCCP) was established by the HSE in 2007 to lead in the development and implementation of cancer policies with the aim of standardising and improving national cancer care and patient outcomes.

In June 2022, the NCCP launched the Systemic Anti-Cancer Therapy (SACT) Model of Care. The report highlighted the growing incidence and prevalence of cancer in Ireland, with the number of cancers expected to double from 2015 to 2045. This will result in a projected 58-81% increase in the number of patients receiving SACT for cancer during this period. It has set out twenty five key recommendations to optimise SACT services.

One of its key recommendations is that ‘all patients should have access to a clinical trial where clinically appropriate’ and that ‘clinical trial services should be enhanced/developed in SACT services to support the availability of trials to all patients undergoing SACT.’ This recommendation is supported by the evidence that treatment on a clinical trial is regarded internationally as the gold standard of care. The report also notes there is evidence to suggest that outcomes for patients treated within the context of clinical trials are superior to those outside formal trials. The central role of clinical trials in cancer care has also being noted in the NCCP Cancer Strategy 2017-2026. One of its key performance indicators (KPI) is to increase patient participation in cancer therapeutic trials from 3% to 6% by 2020.

How cancer trials are conducted in Ireland

Cancer Trials Ireland (CTI), established in 1996 (formally known as ICORG) is the leading cancer research trials organisation in Ireland. More than 15,000 Irish patients have particiapted in over 350 cancer trials. It is a not for profit registered charity and is partly funded by the Health Research Board (HRB) and Irish Cancer Society. It has developed strong links with international cancer research groups and has facilitated Irish patients being able to participate in internationally, practice changing clinical trials. It serves as the key link for strategic and coordinated support for the dedicated on site cancer trials units in hospitals across Ireland and the recently formed six cancer clinical trials groups. In 2021, the HRB invested ¤22 million to support the delivery of high quality cancer care in these six cancer trials groups (Children’s Health Ireland Cancer Trials Group, Beaumont Hospital – RCSI University of Medicine and Health Sciences Cancer Trials Group, Irish Research Radiation Oncology Trials Group, UCC Cancer Trials Group, Ireland East Hospital Cancer Trials Group, Trinity Academic Cancer Trials Group.)

Regulation of Clinical Trials

The conduct of clinical trials is strictly regulated ensuring the fundamental importance of safety for all trial participants. All clinical trials must be conducted within strict national regulations and are underpinned by Good Clinical Practice (GCP). GCP is an international ethical and scientific quality standard for the designing, conducting and reporting of trials that involve human participants.

Before a clinical trial can be conducted, it must receive approval by a national ethics committee and/or the Ethics Committee of the hospital in which it is taking place. The recent establishment of the National Ethics Committee aims to streamline this process. Furthermore, a clinical trial involving an investigational medicinal product (IMP) must be approved by the Health Products Regulatory Authority (HPRA). The HPRA ensures that trials are conducted in line with current Irish & EU legislation and standards for clinical research.

Clinical trials are subject to continuous data monitoring with strict criteria for reporting serious adverse events. Pharmacovigilance compliance is monitored by HPRA.

Study personnel

All study personnel involved in the conduct of a study must have up to date GCP training and must receive specific training in relation to the particular study in which they are involved. Compliance with this standard provides public assurance that the rights, safety and wellbeing of people participating in cancer trials are protected and that the resulting clincal trial data is trustworthy.

Patient participation

Patient participation in clinical trials is entirely voluntarily. It involves a detailed consent process. This involves dicussing both standard of care options in addition to the clinical trial. Armed with this knowledge, a patient can determine what the best treatment plan is for them.

Why Cancer Trials are Important – review of 30 years of progress in treating HER2+ breast cancer 15-20% of breast cancers overexpress the HER2 protein and are referred to as HER2+ breast cancer. Before HER2 directed therapy, this subset of breast cancer was recognised for its aggressive biology and poorer outcomes in comparison to hormone sensitive breast cancer. Targeting HER2+ breast cancer has dramatically changed the natural history of this disease and is no longer associated with the dismal outcome of the past.

Identifying HER2 as an oncogene

The discovery of the protooncogene HER2 as a driver of cancer, is a prime example of how this sparked a revolution in the management of cancers which overexpress this protein. It highlights the essential ecosystem that is bench to bedside/clinical research. Understanding this process is important for all health professionals and is critical to be able to evaluate and critically appraise trial results.

Finding the Receptor: Cell signalling & Nomeclature

Neu refers to the oncogene that was isolated by Weinberg et al

in rat neuroblastomas in 1984. It was noted to be similar in overall structure to EGF receptors. This was soon followed in 1985 by the cloning of the human neu counterpart by Ullrich’s group, which was called HER2 (Human E(GFR) Receptor 2) based on the similarity with EGFR receptor. ERBB2 refers to the gene across both human and rodent species. HER2 is one of the four members of the ERBB family of receptor tyrosine kinase inhibitors, which include EGFR (HER1), HER3 and HER4. HER2 mediates signalling pathways including PI3K/AKT/ mTOR and MAPK pathways, which regulate cellular processes of proliferation, motility and survival.

Discovering the role of HER2 in human cancer

In 1987, Dr Dennis Slamon, a physician/scientist at UCLA discovered that the HER2 gene was amplified in approximately 30% of breast cancers. This major breakthrough was achieved with the interrogation of tumour cells provided from a human breast cancer tumour bank rather than cell lines. The Slamon group furthermore, idenitifed HER2 as a prognositic biomarker showing that women with overpression of HER2 in their tumours had a more aggressive phenotype with a substantially worse progress. This provided strong evidence that HER2 was likely to play a role in driving tumorigenesis.

Defining HER2 positive breast cancer: IHC & ISH

Assessment of HER2 overexpression is with immunohistochemistry (IHC) and in situ hybridization (ISH) testing. Correct pathological assessment of HER2 status is of the utmost importance, as it is the sole predictive marker for response to HER2 directed therapy. Reporting of IHC and ISH results is in accordance with the updated 2018 ASCO/CAP guidelines. Since 2007, ASCO/CAP guidelines recommend initial assessment of HER2 status using IHC and a semi quantitative scoring system, followed by reflex ISH testing in all IHC score 2+ cases.

Understanding the nuances of this testing has become even more important in the context of the recent DESTINY 04 trial publication. Prior to this trial, predictive HER status has been reported in a binary fashion (positive versus negative). DESTINY 04 results defined a new predictive group called HER2 low expression.

Hitting the bull’s-eye: HER2 as a predictive biomarker in breast cancer

Preclinical research by Drs’ Shepard and Ullrich led to the development of HER2 mouse monoclonal antibodies called ‘MoAb 4D5’ followed by the humanised monoclonal antibody 4D5, now known as trastuzumab. In 2019, a New England of Medicine editorial by Professor Daniel Hayes stated – “the terms ‘game changer’ and ‘blockbuster’ are worn, but in this case the ingenuity, vision and persistence of these collaborators justify these superlatives.” In 2019, Drs’ Slamon, Shepard and Ullrich were awarded the prestigious Lasker DeBakey Clinical Medical Research Award for their invention of Herceptin.

The discovery of trastuzumab led to a flurry of clinical trials which demonstrated not only its dramatic benefit in the advanced setting but also in the neo/adjuvant setting. For instance, the HERA trial reported in 2005, showed the addition of adjuvant Herceptin in HER2+ breast cancers halved the risk of cancer returning when it was added to chemotherapy. Irish patients had the benefit of participating in this trial ensuring they had the earliest access to treatment which ultimately proved to dramatically improve survival. There is no better example of how access to clinical trials can be truly life changing for patients.

Since those initial studies, the treatment landscape for HER2+ positive breast cancer has exploded, with 3 classes of HER2 targeted therapy now available.

Beyond HER2+ Breast Cancer:

In 2009, the TOGA (Trastuzumab for Gastric Cancer) Trial, showed a benefit of trastuzumab beyond breast cancer. The results of this phase III trial led to approval of trastuzumab for patients with HER2+ metastatic gastric or gastroesophageal cancer.

HER2 also represents a potential opportunity for seeking tissue agnostic approval. These umbrella trials or basket trials enroll patients based on the genetic biomarkers of their tumours as determined with genomic sequencing, regardless of the pathological tissue of origin. Examples of these trials include the TAPUR (Targeted Agent and Profiling Utilisation Registry), MATCH and MyPathway.

2022 – HER2+ Low Breast Cancer: A new predictive biomarker & treatment paradigm

DESTINY 04 results which were presented at the plenary session at the annual ASCO congress in June 2022 were met with rapturous standing ovation by the packed audience. It is the first randomized trial to demonstrate that targeting HER2 for patients with metastatic HER2-low (IHC 1+ or IHC2+ and ISH negative) breast cancer had meaningful benefit. This phase three randomised trial, demonstrated that heavily pre-treated patients with advanced HER2 low expressing breast cancers as defined by conventional HER2 testing (previously defined as HER2 negative) had a 50% reduction in the risk of disease progression or death when treated with trastuzumab-deruxtecan as compared with treatment of physicians choice. With approximately 60% of HER2 negative breast cancers assessing low levels of HER2 expression; this represents a significant advancement for a large cohort of patients. Further refinement and discussion regarding inter pathological variability in detecting HER2 low (IHC 1+) will be of even greater importance given this new therapeutic option, in addition to assessing risks and management of treatment related toxicities including pneumonitis.

Clinical trials are integral to providing the very best care for patients. One in two people will develop cancer in their lifetime. It is imperative that we strive to cure as many people as possible. This can only be achieved with access to high quality clinical trials that is embedded in health care planning.

*See www.cancertrials.ie for more information.

References available upon request

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