Genetic Testing in Cancer

About the author

Assoc. Prof. Mirette Saad

MBBS (Hons), MD, MAACB, FRCPA, PhD Lab: Clayton VIC Speciality: Chemical pathology and molecular genetics Areas Of Interest: Cancer genetics, antenatal genetic screening and fertility, medical research and teaching Phone: (03) 9538 6777 Email: mirette.saad@clinicallabs.com.au Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Clinical Director of Molecular Genetic Pathology at Australian Clinical Labs. At Clinical Labs, A/Prof Mirette Saad leads the Molecular Genetic testing for Non-Invasive Prenatal Testing (NIPT), genetic carrier screening, personalised drug therapy and cancer. She is a Chair of the RCPA Chemical Pathology Advisory Committee, Member of the RCPA Genetic Advisory Committee and a Chair of the Precision Medicine Services at Australian Clinical Labs.

Cancer, a leading cause of mortality, is associated with aberrant genes. The world of molecular profiling in cancer has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumours. New agents have been approved based on molecular testing instead of tumour site of origin.

Driver Mutations Guide Treatment Decisions The introduction of targeted therapies in lung, colon, melanoma and breast cancer have contributed to a significant increase in overall survival (OS) related to these diseases.

Genetic variants identified in cancer are known to be associated with increased or decreased sensitivity to targeted therapy. For example, while PIK3CA and EGFR mutations are sensitive to tyrosine kinase inhibitors (TKIs), RAS and BRAF are known to be resistant. Crizotinib is an ALK/ROS1/MET inhibitor that is already FDA approved in ALK-positive or ROS1-positive NSCLC but also has proven clinical activity in cases of MET exon 14 alterations and MET amplification. PD-L1 expression in metastatic NSCLC can benefit from FDA approved pembrolizumab monotherapy under specific criteria.

Recently, a third-generation EGFR TKI, which is effective in tumours harbouring the p.T790M EGFR mutation was approved in Australia for patients with NSCLC following progression on an EGFR TKI. In breast cancer, mutated PIK3CA has become an attractive therapeutic target. While anti-BRAF inhibitors (BRAFi) remains the first-line treatment for melanoma tumours that harbour a BRAF mutation, particularly in Australia, other oncogenic driver mutations such as cKIT mutations may guide the selection of KIT TKIs (imatinib and sunitinib) for the melanoma treatment.

New Guidelines; Broadening Molecular Profiling Boundaries Recent NCCN guidelines recommended additional genetic biomarkers for different types of cancer tissues.

In lung cancer, the new NCCN guidelines recommend testing for EGFR, ALK, ROS1, BRAF, and PD-L1 for all patients with NSCLC at baseline before treatment. Universal Microsatellite instability (MSI)/DNA mismatch repair (MMR) testing at the time of initial diagnosis for all stages of colorectal tumours is now recommended to determine whether patients have a germline mutation indicative of Lynch syndrome. For additional treatment options, testing for KRAS/NRAS/BRAF in un-resectable left-sided stage IV metastatic colorectal cancer (mCRC) tumours is also recommended.

In addition to breast and ovarian cancers, germline mutations, mainly BRCA1/2, along with somatic mutation testing are recently recommended by NCCN guidelines for both pancreatic and prostate cancers. In prostate cancer, BRCA1/BRCA2 can occur in 20-25% of all advanced prostate cancer. Although ATM testing is not yet recommended by the NCCN as a predictive measure, Na et al., showed that germline BRCA2 and ATM mutations distinguish lethal from indolent prostate cancers and are associated with shorter survival times and earlier age at death. While tumour mutation burden (TMB) is certainly an interesting emerging biomarker, evidence of its importance is growing. ctDNA identified the emergence of polyclonal and heterogeneous patterns of mutation in KRAS, NRAS, BRAF, or EGFR with mutations found in 96% of panitumumab- or cetuximab refractory patients. Subsequently, Misale et al., were able to illustrate a way to use this information to overcome treatment resistance.

Furthermore, studies demonstrate better outcomes when no tumour-derived DNA is found in patients following surgery or chemotherapy in colorectal cancer patients, whereas those with whom tumour DNA is still present do better with the addition of more aggressive targeted treatment or chemotherapy.

In melanoma, several studies showed the utility of ctDNA as a diagnostic, predictive and prognostic biomarker for patients on anti-BRAF treatment.

Liquid Biopsy: Circulating Tumour DNA (ctDNA) Testing The variety of validated technologies emerging enables more precise and robust analysis of circulating tumour-derived DNA (ctDNA) extracted from blood with sufficient sensitivity and specificity to accurately detect cancer biomarkers.

It is clear today that a single biopsy from a single metastatic site does not seem to be representative of the metastatic cancer. The advent of molecular profiling overcame the limitations of traditional solid tumour classification methods, which relied on the morphology of tumour cells and the surrounding tissue.

While considered the gold standard, tissue biopsy-based tumour diagnosis has many limitations. For instance, tumour heterogeneity, the detection of early-stage tumour or residual lesions is unsatisfactory, and its application in the evaluation of treatment efficacy, resistance, relapse and prognosis is also limited.

The use of liquid biopsy profiling has proven useful in selected clinical scenarios. The first ctDNA liquid biopsy approved for use in clinical settings was in lung cancer patients for the identification of EGFR mutations for first line therapy or identifying resistance mutations that will allow for treatment with third generation EGFR inhibitors.

In colorectal cancer, ctDNA could also be used to track clonal evolution and targeted drug responses. In patients with metastatic colorectal cancer who developed resistance to EGFR antibodies, analysis of Moreover, ctDNA can also ease the decision in the daily clinical practice when radiological evaluation is problematic especially for patients receiving PD-1 inhibitor immunotherapy. In this context, an important advantage of ctDNA is the possibility of non-invasive serial testing for monitoring treatment response and resistance to therapy.

Finally, precision medicine in cancer is moving that quickly specially in the malignant heme space and is now a part of our standard practice. While with new challenges, it will continue to move forward with more discoveries to come.

References on request

Contact a local pathologist near you

Dr Shona Hendry MBBS (Hons), FRCPA Lab: Subiaco Speciality: Anatomical pathology

Areas Of Interest: Molecular pathology, Gastrointestinal pathology, cytology, bone and soft tissue and urology. Phone: (08) 9213 2173 Email: shona.hendry@clinicallabs.com.au

Dr Hendry is an Anatomical Pathologist with special interests in molecular pathology, gastrointestinal pathology, cytology, bone and soft tissue and urology. She is an Honours graduate of the University of Western Australia medical school who completed much of her pathology registrar training in Perth, gaining her FRCPA in 2016.

Care – for the Whole Person

Busselton GP and educator Dr Sarah Moore takes a journey around mindful medicine.

In October 2019, I was fortunate enough to travel to Montreal to spend two weeks on sabbatical at McGill University, based in the Programs in Whole Person Care in the Faculty of Medicine. This was as a consequence of my successful application for a Fay Gale Fellowship, which the University of WA awards annually to an early career academic.

While there, I attended the third International Congress in Whole Person Care, chaired by my sabbatical supervisor, Dr Tom Hutchinson, and the program included inspiring keynote speakers, practical workshops and presentations focussing on whole person care approaches to addiction, compassionate health care and culture change in health care.

One of the most powerful speakers was Dr Rana Awdish, who is a critical care physician and faculty member of Wayne State University School of Medicine in Detroit, Michigan. She completed her medical degree at Wayne State in 2002, her residency at Mount Sinai Beth Israel in New York, and her fellowship training at Henry Ford Hospital where she currently serves as the Director of the Pulmonary Hypertension Program. She also serves as Medical Director of Care Experience for the entire health system.

At the conference, she shared her experience of being seven months pregnant and finishing her critical care fellowship, only to experience a life-threatening intra-abdominal haemorrhage.

She described in detail her experience of arriving on the obstetric ward at the hospital where she worked and being greeted by a resident who admitted he didn’t have much experience with ultrasound. She reassured him she would help.

When she told him there was no fetal heart beat to be seen, he asked her “can you show me where you see that?”.

Next, she was rushed to theatre for emergency surgery, and she remembers hearing the anaesthetist say, “We’re losing her, she’s circulating the drain”. Then she arrested and the next thing she remembers is waking up very debilitated in ICU, having had a cerebellar stroke.

Her first thought was getting hold of a pen so she could ask, “am I dying?”. Her family wouldn’t give her one because they thought she was going to ask “is the baby alive?” and they feared that if they told her the baby had died it might impair her healing.

Later, she recalled overhearing her medical team discussing her management, and the resident said “she’s been trying to die on us” to which she thought, “I am not! Why do we have to be on different sides – I’m part of the team too!”

She then had an experience of bleeding into her legs and had to ask her treating medical team to examine her because not once had they done so, relying instead on blood tests and CT scans to determine her management. She went on to endure 12 months of slow recovery, experiencing further episodes of discoordination of care, inability of her treating doctors to attend to human suffering and poor communication.

However, she was able to report one positive interaction with her surgeon. He could see she was anxious about having a residual abdominal hernia, so invited her in for a consultation. He asked her “what are you most afraid of?” to which she responded “having an ostomy bag”. He replied, “I’ll do everything I can to avoid that”. There was no data he could give her to reduce her fear, but he could demonstrate rapport and trust, which is what she needed.

As a consequence of her experience, Dr Awdish has become passionate about improving the patient experience across the health system.

Dr Awdish has also developed a model for healing, which she shared with us. It is simple yet powerful. • Mutuality Doctors, patients and their families working together as a team, not in opposition

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Sarah strolls the grounds of McGill with her children.

• Proximity Getting close to what makes us uncomfortable and sharing this, exposing our vulnerabilities in order to build rapport and trust Resilience Putting time and effort into the “rewards” of medicine, including meaning, healing, autonomy and gratitude, to allow us to endure and bounce back from the impact of the many stressors, including suffering, monotony, responsibility and blame. Humility Understanding that we do not know it all, but if we are open to different perspectives we can learn from others and deepen our wisdom.

CLEAR conversations When eventually Dr Awdish returned to work, she sought training in Vital Talk, a communications training program for health professionals. She then established a workshop program to train faculty and trainees in relationship-based communication skills. These workshops are run in small groups of eight physicians who take turns in giving bad news to a patient-actor following which doctors receive feedback from the actors. The aim is mastery through experiential and transformational learning. The values are CLEAR – Connect, Listen without judgement, Empathise, Align with patient values and Respect.

Coaching Dr Awdish believes that every doctor needs a coach, even after they complete their fellowship training. Atul Gawande has written a lot on this topic and much of the training that has been developed at Henry Ford Hospital is based on his work. One example of how coaching can be provided is encouraging medical staff to use reflective statements when talking to their patients and to each other. For example, It sounds like what you value most is… What I hear you saying is… It seems you may feel… What appears to be most important to you is…

What is Whole Person Care?

Dr Hutchinson has written a number of books on the subject, and below is his definition, paraphrased from his most recent publication MD Aware: A Mindful Medical Practice Course Guide.

Whole person care is about being a doctor who will provide competent medical care and relate to the patient a whole person, who has preferences and needs that need to be considered as part of their treatment. Whole person care contrasts the reductionist view of medicine that sees doctors as technicians who repair broken bodies. Whole Person Care focuses on the fact that even though a patient may not be cured, they may still be healed. In summary, whole person care requires that the doctor recognises their own whole personhood, including their valuable medical knowledge, skills and attitudes but also their own human limitations, ignorance, lack of skill and unhelpful attitudes.

Visual thinking strategies At Henry Ford Hospital, all multidisciplinary teams go to the art museum together at the beginning of a new rotation. A trained facilitator takes them to a painting and asks the following questions: What do you think is happening here? What do you see that makes you say that? What else could you see?

All members of the team share their insights and through this process realise that everyone sees things slightly differently, illustrating the importance of shared decisionmaking. The purpose of the exercise is to demonstrate implicit bias and the importance of mutuality with the intention of building a positive team structure. Narrative writing Henry Ford Hospital runs practical workshops where medical staff read literature and poetry and watch films then share what they notice, either verbally or in writing. These reflective exercises encourage doctors to get in touch with their emotional responses and the value that comes with communicating these responses.

In closing, Dr Awdish stated that she set out to change herself but ended up transforming the culture of her hospital. A powerful and inspiring message for us all.

Now that I am back in Australia and reflecting on my learnings from Montreal, there are a number of actions I intend to take.

I already have an (almost) daily meditation and yoga practice, which I will continue. I have read MD Aware: A Mindful Medical Practice Course Guide and will be facilitating this seven-week course with my 10 Rural Clinical School (RCS) medical students in Busselton in 2020 under the guidance of Dr Hutchinson. I plan to establish a “Whole Person Care” interest group with academic colleagues from the RCS. I also anticipate facilitating regular debriefing sessions with my medical students to discuss the challenges they face, both personally and professionally. I hope that each of these actions will allow me to strengthen my ability to provide whole person care and inspire my students to master this essential clinical skill.