The government hopes genome sequencing technology will improve the treatment of cancer
A series of NHS and healthcare events are taking place over the coming weeks to spark a conversation among healthcare professionals about genomics.
They will help educate healthcare professionals about the benefits of genomics – the practice of using people’s DNA and genetic information to inform their clinical care – in improving diagnosis and treatment for patients.
Health Education England (HEE) held its second annual #GenomicsConversation this week to increase health professionals’ familiarity about genomics. HEE’s campaign involves panel events, online courses, the launch of new podcasts and educational resources.
In December last year, health secretary Matt Hancock announced that the 100,000 Genomes Project, led by Genomics England in partnership with NHS England, reached its goal of sequencing 100,000 whole genomes from NHS patients.
The programme was launched in 2012 by then prime minister David Cameron, with the goal of harnessing whole genome sequencing technology to improve diagnosis and treatments for people with rare inherited diseases and cancer. The project laid the foundations for a NHS Genomic Medicine Service, which will provide genomic testing to patients across the NHS from 2019.
HEE wants to make healthcare professionals aware of the roll-out of the new service and whole genome sequencing so that they feel more comfortable discussing genomic testing with patients, and can signpost them to relevant information and services.
Meanwhile, the University of Cambridge will be holding an event on genomics on 13 March as part of Cambridge Science Festival to celebrate the sequencing of all 100,000 genomes and the UK becoming the first nation in the world to apply genome sequencing at scale in healthcare.
Genomics England interim chief executive and chief scientist Mark Caulfield said: ‘The Genomic Medicine Service is the first of its kind where genomics will be embedded into a national health system and transform routine healthcare in the UK.’
Four regional events organised by NHS England in partnership with Macmillan Cancer Support, Cancer Research UK and NHS Horizons will take place in London, Birmingham, Bristol and Leeds, starting from 12 April. Entitled Genomics and Personalisation of Cancer Care, they will explore how genomics can be embedded into personalised cancer care.
They will also enable those working in NHS Genomic Medicine Centres to engage with the public and other healthcare professionals to reflect on the transformation that has already taken place, and consider the changes that will be needed in the future.
Cancer Nursing Practice conference
Genomics will also be among the topics presented at Cancer Nursing Practice’s annual conference on 1 May, where Barts Cancer Institute and Genomics England specialty trainee and clinical research fellow in medical oncology Alison May Berner will present on the implications of genomics for people with cancer and nursing. She will also discuss some of the findings of the 100,000 Genomes Project by drawing on patient case studies.
The overall theme of the conference is patient experience. Topics include dementia and cancer, social prescribing, pain management, managing a large systemic anti-cancer therapy unit and supporting patients with recovery.
Royal Wolverhampton NHS Trust matron for oncology and haematology Doreen Black, who won the top leadership category in NHS England’s 2018 Windrush Awards, will make a keynote address.
The early bird rate for registration expires on 15 March and you can book here
THOUSANDS of pounds have been donated within just two days to help a young Co Donegal mother-of-five access life saving cancer treatment.
Sonya Hamilton McCloskey (35) – who is originally from St Johnston close to the Derry border but lives with husband Michael in Ballybofey – has been fighting cancer for the past two years.
The businesswoman, who gave up work to look after her children who are aged from three to 15, first thought she had pulled a muscle.
Following various treatments for the pain, it was confirmed in April this year that she had cancer. It was later discovered that the disease had spread to her pancreas, lungs and liver.
Following a number of weeks separated from her four youngest children in an oncology ward, Mrs Hamilton McCloskey was transferred to Galway Hospital last Tuesday to have a stent inserted into her liver.
Unable to undergo chemotherapy she now hopes that UK-based specialists Oncologica will be able to provide a course of treatment which will give her a “fighting chance” against her illness.
The Donegal woman’s family set up a GoFundMe page last Wednesday hoping to raise the €2,000 (£1,785) necessary to cover the cost of having biopsies sent to Oncologica for analysis.
However, nothing could have prepared them for the public reaction to her appeal. Within just two days, a massive €36,000 (£32,139) was raised through the GoFundMe page and other donations.
The family has been overwhelmed by the support shown by the public. One man alone donated €5,000 (£4,464).
In a message issued from her hospital bed in Galway, Mrs Hamilton McCloskey and her husband thanked everyone who had donated, giving her some hope.
Her parents also took to social media to thank those who have donated.
In a post on the Sonya’s Struggle Facebook page, they wrote: “From the Hamilton family we would like to thank everyone for their support in these hard times. Sonya is one that brings our family together.”
They said their daughter had a heart of gold.
“We couldn’t ask for a better daughter. Keep on fighting dear,” they said.
Mrs Hamilton McCloskey’s Gofundme page can be accessed at https://www.gofundme.com/qap9y-sonyas-battle
Medicine has always been personal to some extent – a doctor looks for the best way to help the patient sitting in front of them.
But with advances in technology, it is becoming possible to use the most unique of characteristics – our genomes – to tailor treatments for individuals.
Genomes are made up of a complete set of our DNA, including all of our genes, and are the instruction manual on how to build and maintain the 37 trillion cells in our bodies.
Any two people share more than 99% of their DNA. It’s the remaining less than 1% that makes us unique, and can affect the severity of a disease and effectiveness of treatments.
Looking at these small differences can also help us understand the best way to treat a patient for a range of diseases – from cancer and heart disease to depression.
Cancer is the most advanced area of medicine in terms of developing personalised treatments. In the UK, differences in the DNA sequence are being used by the NHS to help doctors prevent and predict cancer. For example, women with an increased risk of developing breast or ovarian cancer have been identified by screening for changes to the BRCA1 or BRCA2 genes.
Mutations in these genes increase a woman’s risk of breast cancer by four-to-eightfold and can explain why some families see many relatives with the disease. A BRCA1 mutation gives women a lifetime risk of ovarian cancer of 40-50%.
Screening has helped women make informed choices about treatment and prevention – for example, whether to have a mastectomy.
It is steps like these – splitting patients into ever smaller groups to identify the best treatments – that is taking us towards personalisation.
- ‘New era’ of personalised cancer drugs
- ‘Dismantling cancer’ reveals weak spots
- Targeted checks ‘prevent 10% of heart attacks’
For certain cancers, measuring gene activity is becoming commonplace. Gene activity is a little like the dimmer switch on a light – it can be set to low, high or anywhere in between.
Measuring this allows us to see how active a particular gene is in a tissue or cell.
In breast cancer, a test measuring the activity of 50 genes in tumours can be used to guide decisions about whether the patient will benefit from chemotherapy.
To extend this approach to other cancers, researchers are switching off all of the genes in hundreds of tumours grown in the laboratory. In doing so, scientists are looking for cancer’s weaknesses – to try to produce a detailed rule book for precision treatment.
The development of personalised medicine
- Genome sequencing is being offered in England to children with rare diseases – and has led to a change of treatment for some
- An 11-year-old became the first patient to use a leukaemia drug called CAR-T, which re-programmes the immune system to fight cancer
- The entire genetic code of women diagnosed with breast cancer is being mapped by scientists in Cambridge
- There are plans to sequence one million genomes in the UK in the next five years
The development of such techniques raises the question: how far can personalisation go?
For illnesses like heart disease, diabetes and infectious diseases, a combination of genetic, lifestyle and life events also play a part. This means that information about small differences in the DNA sequence alone will not be enough to predict susceptibility and outcome.
Measuring the activity of our genes also captures information about current stresses to the body. For example, certain genes will have a higher or lower activity depending on the type of infection.
Yuvan Thakkar, 11, is the first to receive a drug called CAR-T.
His mother, Sapna, said: ‘This new therapy is our last hope’
Looking at gene activity could also provide important clues as to how to best treat a patient.
One life-threatening illness where these techniques could help is sepsis.
It is a condition in which the immune system damages its own organs when trying to fight an infection. Anyone can develop sepsis and it kills 52,000 people each year in the UK – more than breast, bowel and prostate cancer combined. Worldwide, a third of patients who develop sepsis die.
To save lives, general antibiotics are given first to reduce the infection. A blood test is done to find out which particular bacteria have caused the sepsis, so a more targeted antibiotic can be given. But these blood tests take precious time and cannot always identify the bacterium causing the infection.
In our research, we are looking at gene activity in sepsis patients’ immune systems, to give us clues as to why different people respond in different ways.
We hope to pinpoint which part of their immune systems are not working properly – helping doctors decide how other drugs could be used.
This demonstrates how personalised medicine could be used for short-term treatment in intensive care, as well as for longer-term illnesses like cancer.
About this piece
This analysis piece was commissioned by the BBC from an expert working for an outside organisation.
Note: In order to respect the privacy of the patient, his/her identity will not be revealed.
I was diagnosed with terminal bowel cancer in March 2018. I started radiotherapy, which worked well. The tumour then started to cause a build up of fluid in my abdomen, which chemotherapy helped to reduce. However, when the first line chemotherapy stopped working after 5 months and then the second line chemotherapy failed to work at all, the fluid returned and I had two stays in hospital to help drain it.
Having exhausted standard therapy and become bedbound, I found out about the Oncofocus Test from an online search. The overall process from submitting the form to Test results was easy and rapid. The company called to talk me through the process and to explain the results of the Test, and also took care of the logistics of collecting the sample from the hospital. It turned out that I have a rare cancer mutation and was lucky to have had a response at all to the initial chemotherapy.
I had a remarkably effective and rapid response to the drugs that the Test recommended for my cancer mutation. After just 2 weeks of treatment, my abdomen returned to normal size. After 4 weeks of treatment, I was swimming, walking and fully enjoying all that life has to offer again. I am truly grateful for the significant improvement in quality of life I experienced, especially as I had no side effects from the new drugs. The extra months that this gave me meant that I had further quality time with my family and could prepare them better for life without me.
The results of a new study, underscoring the value of precision medicine in advanced sarcoma, showed that patients with heavily pretreated sarcoma who received treatment in accord with their mutational profile attained better outcomes than patients who did not (Abstract 11018). Most notably, median overall survival reached 22.1 months for patients treated with agents targeting mutations identified by genomic profiling, compared with 15.5 months for patients who received treatment unguided by genomic profiling (HR 0.70, 95% CI [0.50, 0.98]; p = 0.031).
“Drug development in sarcomas remains challenging, with few effective U.S. Food and Drug Administration–approved therapies,” lead investigator Shiraj Sen, MD, PhD, of the Sarah Cannon Research Institute, said. “Fortunately, recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear, and whether patients enrolled on genomically matched early-phase trials have improved outcomes over patients enrolled on nongenomically matched trials remains unknown.”
To clarify the value of genomic profiling in sarcoma, the investigators leveraged clinical data and next-generation sequencing information for 406 patients with advanced disease who were treated within phase I trials at The University of Texas MD Anderson Cancer Center over a 12-year period (2006 to 2018). Patients had received a median of three prior lines of therapy (range, 0 to 9) before being enrolled in a phase I trial, and collectively they featured a diverse array of soft tissue sarcomas (e.g., leiomyosarcoma, 16%; liposarcoma, 13%; gastrointestinal stromal tumor, 11%; and synovial sarcoma, 3%) and bone sarcomas (e.g., osteosarcoma, 8%; chondrosarcoma, 7%; and Ewing sarcoma, 6%).
Within the 406-patient cohort, 23% of patients had potentially actionable alterations identified through next-generation sequencing and were enrolled in clinical trials of genomically matched therapies. The remaining 77% of patients who participated in nongenomically matched trials served as the comparator group.
The results revealed no difference in the objective response rate for patients who were and were not matched to treatment based on their genomic profile (11% vs. 6%, respectively; odds ratio [OR] 1.97, 95% CI [0.88, 4.44]; p = 0.10). However, significant differences favoring the genomically matched group over the unmatched group were observed for the clinical benefit rate (41% vs. 19%, respectively; OR 2.91, 95% CI [1.77, 4.80]; p < 0.0001), the median time to progression (3.7 vs. 2.7; HR 0.72, 95% CI [0.57, 0.91]; p = 0.0048), and median overall survival (22.1 vs. 15.5 months; HR 0.70, 95% CI [0.50, 0.98]; p = 0.031).
“In our study, while response rates in genomically matched trials were low (11%), occasional responses were seen with experimental therapies targeting alterations such as NTRK, LRRC15, cMET, mTOR, VEGF, MDM2, and FGFR. This suggests that molecular profiling should be considered in metastatic, refractory sarcomas and clinical trial enrollment should be considered for these patients,” Dr. Sen said.
Kara Nyberg, PhD
Immunotherapy is a burgeoning sector that heralds a breakthrough against the world’s second-most deadly disease. Dr Mike Tubbs explains how investors can benefit too.
Cancer is the world’s second-biggest killer. The disease is responsible for around one in six deaths globally; 9.6 million people succumbed to it in 2018, while 18.1 million new cases were diagnosed. In 2025 there will be more than 20 million new cases, according to the World Health Organisation’s International Agency for Research on Cancer, and 29.5 million in 2040. To reduce cancer deaths we need new treatments beyond the conventional options of surgery, radiotherapy, chemotherapy and drugs discovered years ago. Fortunately, the last few years have seen a breakthrough in cancer treatments as a new field of research has developed: immunotherapy.
A new approach
Cancer immunotherapy is a new method of fighting cancer that uses the body’s own immune system to kill cancer cells where they are growing. This doesn’t happen naturally. The immune system is wired to conduct safety checks that prevent it attacking normal body cells. Cancer cells cleverly use these checks to fool the immune system into thinking tumour cells are just like normal cells – in other words, the cancer cells make themselves invisible to the body’s T-cells (white cells tasked to deal with disease carriers). That means T-cells cannot recognise cancer cells and therefore cannot attack them. The techniques of immunotherapy are all based on various ways of removing this cloak of invisibility from cancer cells and helping the immune system work better at destroying them.
The first immunotherapy drug to consistently improve survival, Yervoy (from Bristol-Myers Squibb), was approved in 2010 for treating metastatic melanoma (one that has spread to other parts of the body) and there are now at least ten immunotherapies approved for treating cancer with several approved for many different cancers. The fast pace of research is clear from the 2,000 or so ongoing clinical trials of new immunotherapy drugs. That will drive growth of the global cancer immunotherapy market from $40bn in 2017 to $170bn by 2028.
Miraculous results with some cancers
Immunotherapy can have miraculous results for particular kinds of cancer. One famous case is Philadelphia’s Stefanie Joho. Her colon cancer was raging out of control, with a massive tumour appearing in her abdomen despite surgery and chemotherapy. Her oncologist said there were no more treatment options left. However, Stefanie’s sister Jess discovered a clinical trial at Johns Hopkins University and Stefanie joined it. It was a trial of Keytruda, a drug not then approved for colon cancer, but which had helped treat former president Jimmy Carter’s brain and liver cancer. The results on Stefanie were remarkable: her tumour shrank and then disappeared, leaving her free from all signs of cancer. Further investigation showed that Stefanie had a genetic glitch called MMR deficiency; her cancer had many more mutations than usual and it was therefore more likely her immune system would recognise it and attack it with the assistance of Keytruda. In 2017, America’s Food and Drug Administration (FDA) approved Keytruda to treat colon cancers of Stefanie’s type. There are many similar stories of patients with advanced cancer whose lives have been saved by immunotherapy drugs.
Three key types of immunotherapy
There are three important types of immunotherapy. The first is antibody checkpoint inhibitor therapy (ACIT). ACIT uses monoclonal antibodies (a type of protein produced in a laboratory) to target immune checkpoints, which regulate pathways in the immune system that stimulate or inhibit its action. Checkpoint therapy blocks checkpoints that tumours use to protect themselves from the immune system. This blocking flags up tumour cells so that the immune system can recognise and attack them. The second sort of immunotherapy is known as T-cell therapy, of which CAR-T cell TCR are the best known examples. T-cells are taken from the patient and genetically modified to add a chimeric antigen receptor (CAR), which specifically recognises cancer cells. The resulting modified CAR-T cells are multiplied outside the body and then reintroduced into the patient to attack tumours. CAR-T therapy in the US famously treated the leukaemia contracted by Zac Oliver, a young man from Shropshire, after a Daily Mail fund-raising campaign. He was declared cancer-free last month.
Mixing and matching
One of the frustrations of many early immuno-oncology drugs is that they work very well on only some patients and with only some types of cancer. This is why a lot of effort is now being put into the third approach: combination therapies (CT). They aim to enhance the immuno-stimulatory response by combining two different antibody therapies, or an antibody therapy with a conventional pharmaceutical one. Bristol-Myers Squibb’s mix of Opdivo and Yervoy, for instance, combines two ACIT antibody therapies, each targeting one of the body’s two main proteins critical to the immune system’s ability to control cancer growth. The Opdivo+Yervoy combination is the first treatment for metastatic melanoma with a better-than-50/50 chance of patients responding. Another example is the combination of Keytruda with chemotherapy for lung cancer, which is more effective than either alone.
New lines of enquiry
Two further categories of immunotherapy exist, but here drugs are only just beginning to emerge. Oncolytic virus therapies (OVT) are being pioneered by Amgen. A virus is injected into the tumour, enters the cancer cells (but not healthy ones) and makes copies of itself so the cancer cells burst and die. Amgen’s Imlygic uses modified herpes viruses to do this. Cancer vaccines, meanwhile, expose the immune system to an antigen that the immune system then recognises and destroys – in this case, cancer cells.
With more and more immuno-oncology drugs and other treatments for cancer being approved, doctors need to find out which drug is most suitable for a particular cancer in any specific patient. This is particularly important for certain cancers, such as Stephanie Joho’s, where immunotherapy can produce a miraculous cure. The answer lies in genomic testing, an area covering people’s genetic predispositions to certain types of cancer as well as the genetic make-up of tumours, which can help discern how they might develop.
There are now several genetic tests for tumours on the market that can indicate the most effective treatment. This helps to make targeted precision cancer treatment a reality. Examples of such tests are Oncofocus from Oncologica and FoundationOne from Roche. Given the range of cancers treatable with the checkpoint inhibitors Opdivo, Keytruda and Opdivo+Yervoy, a test called the Tumour Inflammation Signature (TIS) has been developed to help predict whether patients will respond to these drugs.
Since the first effective cancer immunotherapy was approved in 2010, many other single and combination immunotherapies from major biopharma companies have been approved for various types of cancer. Their 2018 sales vary from less than $100m to $7bn.
Opdivo: another miracle cure
The only two super-blockbusters – boasting sales of over $5bn – are Opdivo and Keytruda, which both have sales of around $7bn and have at least nine approvals each for different types of cancer. Stefanie Joho’s colon cancer was cured with Keytruda, and Opdivo has had similarly miraculous effects. The US Cancer Research Institute cites Maureen O’Grady, 62, who in 2009 was diagnosed with stage-four (the final stage) lung cancer that had spread to her liver and heart. She was given a year to live by her doctors. She tried chemotherapy, which had horrendous side effects and merely slowed the growth of the cancer, and also Tarceva, a conventional lung-cancer drug.
She stopped both chemotherapy and Tarceva after discovering a clinical trial of Opdivo at Yale. She joined the trial in early 2010 and found she had almost no side effects from Opdivo. Her first scan after eight weeks on Opdivo showed she was responding dramatically to treatment. The tumours shrank to almost nothing after two years and Maureen was alive and well six years after original diagnosis. Dr Herbst, chief of medical oncology at Yale, said: “In 25 years I’ve never seen anything like it.” The FDA approved Opdivo for lung cancer in 2015. The potential of these drugs, then, is enormous – and small biotechs as well as giant pharmaceuticals are getting in on the act. Below, we look at how investors can profit.
The stocks and funds to consider now
There are four main ways for investors to participate in the success of immunotherapies. The first is to back large biopharma companies that make a substantial proportion of sales from immunotherapies and have promising new ones in the pipeline. Two of these companies – Bristol-Myers Squibb (NYSE: BMY) and Merck (NYSE: MRK) – stand out, with super-blockbusters Opdivo and Keytruda. No other firms at present have even a blockbuster (sales more than $1bn a year) to their name.
The FDA approval history of Opdivo shows how its range of application has expanded following first approval for advanced melanoma in 2014. Approvals for lung cancer and kidney cancer followed in 2015, hepatocellular cancer in 2017 and expanded kidney and colorectal cancer indications in 2018. Opdivo/Yervoy combinations have been approved for melanoma (2015 and 2016) and for kidney and colorectal cancer in 2018. Keytruda has a comparable approval history to Opdivo.
Bristol-Myers Squibb had immunotherapy sales of more than $8bn in 2018, or 35.5% of total 2018 sales, making cancer immunotherapy a substantial proportion of revenue. It is taking over Celgene, a blood-cancer specialist, which in turn has bought Juno Therapeutics, a firm with a pipeline of CAR-T therapies. The combined companies would have had 2018 revenues of $37.9bn.
For Merck, Keytruda’s $7.2bn of 2018 sales made up 17% of total revenue (of $42.3bn). A small immunotherapy portfolio should therefore contain Bristol-Myers Squibb and Merck.
Many smaller firms have pipeline immunotherapies, but no approved drugs on the market; only a few, such as Tocagen (Nasdaq: TOCA) have Phase-III trials (the final stage of clinical tests) in progress. Most are based in the US, which has 30 of the top 46 immunotherapy start-ups; four are from the UK. Investment success depends on the smaller company either being acquired or partnering its key drug with a large biopharma. Brave investors willing to do a great deal of research may wish to explore this sub-sector.
Another approach to the immunotherapy boom is to invest in the industry’s suppliers: companies making things needed to diagnose or develop immunotherapies. Enter Illumina (Nasdaq: ILMN), a world leader in genomic testing used for deciding which drug is likely to be most effective for any particular combination of tumour and patient.
Grail, a company spun out of Illumina and soon to be floated, is developing a DNA-based blood test for the very early detection of cancer. Consider also MorphoSys (Frankfurt: MOR), a supplier of antibodies, many of which are used for cancer drugs.
A fourth way to gain exposure is through funds, although the main biotech and healthcare-orientated trusts do not have especially large proportions of their top-ten portfolio holdings in cancer immunotherapy companies. The Biotech Growth Trust (LSE: BIOG) has Celgene, Illumina, Gilead Sciences and Amgen accounting for 26.1% of its portfolio, while the BB Healthcare trust (LSE: BBH) contains Illumina, Celgene and Bristol-Myers Squibb, jointly contributing 32.6% of the overall portfolio’s value.
Given that most cancer immunotherapy companies are in the US, another option is to track the Nasdaq Biotech index directly. This can be done with the iShares Nasdaq US Biotech ETF (LSE: BTEC), which charges 0.35%. Illumina and immunotherapy groups Gilead Sciences, Amgen, Incyte and Celgene jointly comprise 30% of the index.
The WINTHER trial***, NCT01856296, led by investigators from Vall d’Hebron Institute of Oncology – VHIO (Spain), Chaim Sheba Medical Center (Israel) (Raanan Berger), Gustave Roussy (France) (Jean-Charles Soria), Centre Léon Bérard (France) (Pierre Saintigny), Segal Cancer Centre, McGill University (Canada) (Wilson H. Miller), UT MD Anderson Cancer Center (USA) (Jordi Rodon and Apostolia-Maria Tsimberidou) and University of California San Diego, Moores Cancer Center (USA) (Razelle Kurzrock), aimed to expand precision oncology to patients with advanced solid tumors that progressed after treatment with standard therapies.
For the first time in the clinic, the WINTHER trial applied transcriptomics (RNA expression testing) to tailor precision medicine in oncology to a greater number of patients based on the increased expression of RNA in tumors compared to normal tissues.
303 patients were enrolled in WINTHER; 107 of whom were ultimately treated according to recommendations made by a committee of cancer experts spanning five countries. These patients had been heavily pretreated, with one quarter having received five or more prior lines of therapy. Of the 107 patients treated, 69 received treatment based on DNA mutation profiling, and 38 based on RNA profiling. Overall, the WINTHER trial succeeded in matching personalized therapy to 35% of patients with advanced cancer.
“The strategy employed in WINTHER resulted in a higher proportion of patients treated than in many precision medicine trials. Previous studies have identified potential treatments for between 5% and 25 % of patients based on DNA profiling alone, our findings represent an important step toward delivering on the true promise of precision medicine in oncology,” said Richard L. Schilsky, Chairman WIN Consortium and Chief Medical Officer of ASCO.
In this trial, patients were first evaluated for targetable alterations in cancer driver genes. Those who were not matched to drugs based on DNA alterations received a treatment tailored to the differences in gene expression between patients’ tumors and normal tissues which were assessed using a patented algorithm developed by the WIN Consortium. Comparisons with normal tissues proved essential due to highly variable RNA expression between patients and across normal tissue types. The WINTHER researchers showed that RNA expression can be used to expand personalized therapy options for patients and that normal tissue biopsy is safe and accepted by patients.
Patients who received therapy optimally tailored to their respective DNA alterations, or consistent with the algorithm recommendation for RNA guided treatment, responded better. Patients with a good performance status and a high degree of matching had a significantly longer median overall survival of 25.8 months versus 4.5 months for others. There was also a correlation between degree of matching and progression-free survival independent of the number of prior therapies. “Importantly, our results show that patients treated with a drug or regimen more closely matched to the molecular profile of their tumor, do better,” observed Razelle Kurzrock, co-leader of the WINTHER trial and Director of UCSD Moores Center for Personalized Cancer Therapy.
“Assessing RNA is an important adjunct to DNA profiling for determining precision treatments. WINTHER rings in a new era for personalized medicine in oncology,” concluded Josep Tabernero, Vice-Chairman WIN Consortium, Director VHIO and President ESMO.
A new single-center report has found that the results of next-generation sequencing (NGS)–based molecular profiling for non–GI stromal tumor (non-GIST) sarcomas provided information used to effectively guide clinical management.
A team of authors led by Spandana Boddu, a research assistant at Moffitt Cancer Center in Tampa, Florida, analyzed data from 114 patients with a diagnosis of non-GIST sarcoma who underwent molecular profiling during treatment at the center between May 2013 and March 2017.
“We found that clinical management was affected by NGS results in a small but notable percentage of patients, including those with a diagnosis change (4.4%) and/or in whom therapeutic selection was altered by the treating physician because of findings
(13.2%),” the authors wrote in JCO Precision Oncology. “The genes most commonly affected by pathogenic mutations in our cohort mirror those most widely reported in sarcomas to date.”
Boddu et al used Moffitt’s Personalized Medicine Clinical Service (PMCS) database to identify all non-GIST sarcoma patients who underwent commercial genomic testing between May 2013 and March 2017. A PMCS review of all patients with solid or hematologic malignancies who undergo commercial genomic sequencing is standard at Moffitt.
Each patient’s genomic findings were also included in the Clinical Genomic Action Committee (Moffitt Molecular Tumor Board) database. The database included demographic, clinical, and histologic information, such as the type of genomic test and the source of biopsy specimen. Each gene, mutation, and allele frequency or copy number along with microsatellite status and mutation burden, if available, was also recorded in the molecular tumor board database.
Each patient underwent molecular profiling on the same comprehensive genomic panel on a commercial platform. The authors performed a chart review to retrospectively collect treatments and outcomes data and confirm pathology findings.
The authors identified “clinically actionable” genetic alterations on the basis of the assessment of the commercial testing company and the PMCS review. They also defined genetic alterations as clinically actionable if they had been previously documented as “providing diagnostic or prognostic information or to predict response or resistance to commercially available or investigational agents.”
Boddu et al defined actionability as “predicting response to approved drugs available for the patient’s diagnosis (on-label), for another diagnosis (off-label), or investigational drugs being studied in humans for whom the genetic alteration has been shown to serve as a suggested biomarker for response,” they wrote. “Assessment of clinical actionability was limited to mutations previously reported or likely to be driver mutations based on available literature and functional classification and did not consider analysis of variants of unknown significance.”
Of the 114 patients, slightly over half were female (n = 63, 55%). Patients’ median age at diagnosis was 55 (interquartile range [IQR], 38 to 65) years. Most patients had metastatic disease (85.1%) and had received prior systemic therapy (81.6%). A large majority of patients had soft tissue tumors (n = 94, 82.5%), while the remaining 20 patients had bone sarcomas (17.5%).
Patients’ histologies were consistent with the most common sarcoma subtypes, including leiomyosarcoma (16.7%), well-differentiated/dedifferentiated liposarcoma (12.2%), and undifferentiated pleomorphic sarcoma (10.5%). Chondrosarcoma (7.0%) and osteosarcoma (6.1%) were the most common types of bone tumors.
NGS detected 438 genetic variants among the collection of 114 tumors that were presumed to be oncogenic. Almost all tumors had at least one driver variant (96.7%), while the median number of driver variants per tumor was 3 (range, 0 to 19). Regardless of sarcoma subtype, the most common alterations were in TP53 (36.8%), CDKN2A/B (20.2%), CDK4/MDM2 (19.3%), ATRX (13.2%), and RB1 (13.2%). About 60% of alterations were structural, including 157 amplifications and 66 copy-number losses.
No patients displayed evidence of microsatellite instability. NGS was able to assess tumor mutational burden in 106 patients. The clear majority of these patients had <6 mutations (84.9%). Around 13% of patients were characterized as having intermediate tumor mutational burden (6 to 20 mutations), while less than 2% of patients had >20 mutations.
In 5 cases (4.4%) treating physicians viewed the genomic findings as either diagnosis-changing or diagnosis-modifying. Boddu et al described a “low grade spindle cell sarcoma” being reclassified as a desmoid tumor after the detection of a CTNNB1 mutation prompted additional pathologic review.
Additionally, the diagnosis of “poorly differentiated sarcoma, favor neurogenic tumor/MPNST [malignant peripheral nerve sheath tumor]” was revised to synovial sarcoma after NGS detected a typical SS18-SSX2 fusion. This mutation was then confirmed by conventional testing. “In the remaining three cases, novel or seminovel fusions that were felt to be disease-defining were detected in cases of ‘small round cell sarcoma, not otherwise specified’, including one each of EWSR1-PATZ1, BCOR-ZC3H7B, and PHF1-TFE3,” wrote Boddu et al.
NGS testing reports included a therapeutic treatment recommendation for 88 patients (77.2%). Following Moffitt review of the genomic findings, 56 patients (49.1%) were classified as having an actionable result. Most of these patients had options to pursue both off-label targeted therapy and molecularly matched clinical trial options. Nine of these patients found that their only significant alteration was already known or assumed. These findings included MDM2/CDK4 amplification in dedifferentiated liposarcoma or NF1 in malignant peripheral nerve sheath tumor.
NGS findings guided treatment management in 15 cases (13.2%). This includes patients for whom a standard treatment was preferred over an alternative treatment and patients for whom chosen therapies changed due to a change in diagnosis based on NGS findings. Boddu et al reported that 4 of 15 (26.7%) NGS-influenced treatment plans resulted in clinical benefit such as partial response or stable disease > 6 months.
Boddu et al concluded that clinical genomic profiling altered the disease course of “a sizeable minority” of sarcoma patients at Moffitt. “Looking forward, we expect the number of patients who have actionable NGS findings to steadily increase as more molecularly targeted therapies become available and as genomics becomes increasingly used as a biomarker for immunotherapy response,” they wrote. “At present, our experience is that patients with sarcoma who are most likely to benefit or at least have their clinical course altered by NGS are those with an unclear diagnosis or rarer sarcoma subtypes in which potential genomic targets are not well known, and patients in whom early-phase trials are being considered.”
At least half of patients with cholangiocarcinoma have mutations in their tumors that may be treatable with targeted drugs or immunotherapies that are either experimental or approved for other cancer types. These are available through clinical trials.
Yet when surveyed, half of patients with this diagnosis said their tumor tissue hadn’t undergone molecular profiling to determine if those mutations were present. Why not? Most said they hadn’t known about this kind of testing.
The Cholangiocarcinoma Foundation (cholangiocarcinoma.org) — which supports and advocates for those with this rare cancer that affects the bile ducts — is determined to make sure everyone with the disease learns about and has access to genetic profiling and clinical trial participation. The foundation is working toward that goal through its new program called Mutations Matter, funded with a $125,000 grant from Bayer Pharmaceuticals.
Through a new website (mutationsmatter.org), educational videos and targeted email campaigns, the foundation plans to tell both patients and doctors why this testing should be done as soon as possible after a cholangiocarcinoma diagnosis.
“Profiling needs to be done immediately, so you can plan what you want to do next if it progresses,” Stacie Lindsey, president of the foundation, said in a presentation at the organization’s annual conference, held Jan. 30 in Salt Lake City, Utah. “Cholangiocarcinoma is the most highly targetable among gastrointestinal cancers,” she added — it expresses the most mutations that are potentially treatable with drugs already approved to treat other types of cancer.
The gap in knowledge on this topic lies mainly in the fact that 85 percent of patients with cholangiocarcinoma are treated outside major academic cancer centers, where both tumor profiling and access to clinical trials are standard, Lindsey said. In community treatment settings, she said, oncologists who treat cholangiocarcinoma tend to be generalists rather than gastrointestinal specialists, tumor profiling may be limited or discouraged, and access to clinical trials may be restricted or not offered.
When it comes to a rare cancer like cholangiocarcinoma, the fact that just 5 percent of adults with cancer participate in clinical trials is “tricky,” she said, because insufficient enrollment can lead to studies being canceled or pharmaceutical companies and academia failing to invest in them.
The foundation conducted its survey of 132 patients and their profiling histories a year and a half ago, when the immunotherapy Keytruda (pembrolizumab) was approved for all solid tumors that are considered microsatellite instability-high, meaning that they have trouble repairing their own DNA when it’s damaged. About 3 percent of patients with cholangiocarcinoma have that status and are eligible for the treatment, but they can’t know that unless their tumor tissue is profiled, Lindsey said.
Of the half of respondents who said that their tumors had been profiled, 62 percent noted that the test results had influenced their treatment decisions.
Lindsey cited 51-year-old survivor Matt Reidy as an example. He had his tumor profiled, and when Keytruda was approved two years later, it turned out he was eligible to take the drug.
“I started Keytruda, and within four months I had a complete response,” Reidy is quoted as saying on the Mutations Matter website. “I continued the therapy for 18 months total, and three years after starting, I remain cancer-free and consider myself cured.”
Lindsey said the foundation is running Mutations Matter with help from a variety of partners.
Komodo Health gathers data on where patients are being treated and how, to pinpoint where education is most needed. If hot spots are found at sites within the country, the foundation can wage email campaigns targeted to community oncologists there. Digital communications company DMD is in charge of those targeted email efforts, and public relations experts at EIN Communications created a communications plan and are reaching out to media.
It was D2 Creative that made the simple, digestible videos — called “illuminations” — that are available in six languages and aimed at patients and doctors. The Cholangiocarcinoma Foundation has established a blueprint for outreach to other nonprofit organizations that might benefit from sharing the videos with their members, Lindsey said.
Finally, Perthera Inc., a health care artificial intelligence company, is acting as a concierge for patients, facilitating genetic profiling for each and then generating a free report, including a list of potentially relevant clinical trials and how to contact them. Perthera is offering its services at no cost during the program’s first year, which began in June 2018.
Between the 24th and 28th of June, Oncologica will participate in two relevant Cancer Conferences to be held in Cyprus.
The 36th International Conference on the Advances in the Applications of Monoclonal Antibodies in Clinical Oncology and Symposium on Cancer Stem Cells.
Date: June 24-26, 2019. Venue: Grecian Park Hotel, Konnos Bay, Cyprus
One of the longest-running conferences in the field, the meeting will include presentations by leading researchers on scientific and clinical aspects of monoclonal antibodies in clinical oncology, including open-air workshops in a truly international setting conducive to networking.
The 9TH International Conference on Notch Targeting in Cancer.
Date: June 26-28, 2019. Venue: Grecian Park Hotel, Konnos Bay, Cyprus
This annual international conference, devoted to Notch Biology and related Cancer Therapeutics will address basic and translational research, preclinical and clinical studies, including open-air workshops in a truly international setting conducive to networking.
Atezolizumab for Triple-Negative Disease
March 08, 2019
The US Food and Drug Administration today granted accelerated approval to atezolizumab (Tecentriq, Genentech/Roche) plus the chemotherapy nab-paclitaxel (Abraxane, Celgene) for the first-line treatment of unresectable locally advanced or metastatic, PD-L1-positive triple-negative breast cancer (TNBC).
Atezolizumab is the first immunotherapy to be approved for breast cancer.
The approval is based on progression-free survival results and continued approval may be contingent upon confirmatory trial data.
The new approval of the combination is based on safety and efficacy results from the multicenter IMpassion130 trial, which were presented at the European Society for Medical Oncology (ESMO) 2018 Congress and simultaneously published in the New England Journal of Medicine.
The trial randomly assigned 451 patients with locally advanced or metastatic triple-negative breast cancer patients to atezolizumab and 451 to placebo. All 902 patients also received nab-paclitaxel.
In this intention-to-treat (ITT) population, atezolizumab significantly reduced the risk of disease progression or death (progression-free survival; PFS) compared with placebo (median PFS = 7.2 vs. 5.5 months; hazard ratio [HR] = 0.80, 95% confidence interval [CI], 0.69 – 0.92, P = .0025).
Atezolizumab also improved median overall survival (OS), but statistical significance was not met at the time of the interim analysis (21.3 vs. 17.6 months; HR = 0.84, 95% CI, 0.69 – 1.02, P = .0840).
These co-primary endpoints were investigator assessed; median follow-up was 12.9 months.
The trialists also performed a subgroup analysis among patients who were PD-L1+, defined as expression ≥ 1% on tumor-infiltrating immune cells. In this analysis, the atezolizumab group consisted of 185 patients and the placebo group 184 patients.
In this PD-L1+ population, atezolizumab significantly reduced the risk of disease progression or death (median PFS = 7.5 vs. 5.0 months; HR = 0.62, 95% CI, 0.49 – 0.78, P < .0001). The immunotherapy also improved median OS (25.0 vs. 15.5 months; HR = 0.62, 95% CI, 0.45 – 0.86).
Presenting these results last year, lead study author Peter Schmid, MD, PhD, St. Bartholomew’s Breast Cancer Centre, Barts Health NHS Trust, London, United Kingdom, said that, in the PD-L1+ subgroup, “we see a nearly 10-month overall survival difference, which I think is a key encouragement to see this drug as a new standard.”
However, Kathy Miller, MD, of the IU Simon Cancer Center at Indiana University, Indianapolis, was uncertain about that conclusion because the OS findings were not final. In a Medscape commentary about this trial, she said: “The authors of IMpassion130 conclude that atezolizumab plus nab-paclitaxel is a new standard of care in the PD-L1-positive subgroup. At this point, I have to say I disagree. What they’ve reported so far is a very modest improvement in progression-free survival. We honestly don’t yet know whether there is an improvement in overall survival.”
In the pivotal trial, atezolizumab was administered at a fixed dose of 840 mg via intravenous (IV) infusion on days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity. Nab-paclitaxel was administered at a starting dose of 100 mg/m2 via IV infusion on days 1, 8, and 15 of each 28-day cycle.
The median duration of atezolizumab and nab-paclitaxel treatment in the atezolizumab group was 24.1 weeks and 22.1 weeks, respectively, and the median duration of placebo and nab-paclitaxel in the placebo group was 22.1 weeks and 21.8 weeks, respectively.
Over the study period, 358 (79.4%) patients in the atezolizumab group and 378 (83.8%) of those in the placebo group had disease progression or died.
The investigators reported that adverse events (AEs) were consistent with the safety profiles of the study drugs; no new safety signals were identified with the combination of atezolizumab plus nab-paclitaxel.
Severe adverse events (SAEs) were reported in 23% of the atezolizumab group vs 18% of the placebo group.
Grade 3-4 AEs occurred in 49% of the atezolizumab group vs 42% of the placebo group. The most common were neutropenia (8%); peripheral neuropathy (6%); decreased neutrophil count (5%); fatigue (4%); and anemia (3%).
Following signature of an agreement between Oncologica UK Ltd and another UK private medical insurer, all the leading UK health insurers’ customers now have access to the Oncofocus Cancer Test.
The Oncofocus Cancer Test is the world’s most comprehensive genomic profiling platform test that enables oncologists to select precisely the most effective targeted therapies and immunotherapies for their patients when certain clinical criteria are met.
London, UK, 8th March 2019
Today Oncologica UK Ltd. announces the signature of a commercial relationship with a leading UK private medical insurer that allows funding of the Oncofocus Cancer Test. The relationship will enable the insurer’s customers, meeting strict clinical criteria, access to the world’s most comprehensive precision oncology test that enables them to be matched precisely to the most relevant targeted therapies and immunotherapies, improving day-to-day care and delivering the best outcomes.
The insurer will fund the Oncofocus Cancer Test when the following clinical criteria are met:
Advanced common cancers not responding to standard treatment
Cancers for which there is no standard therapy
Carcinoma of unknown origin
The Oncofocus Cancer Test analyses the DNA and RNA extracted from the routine biopsy sample. Oncofocus currently profiles 505 genes with linkage to around 700 targeted therapies and immunotherapies. It detects thousands of genetic variants across the most clinically relevant cancer driver genes. All the variants detected are “actionable”, and therefore, treatable by targeted therapies either on-market FDA or EMA approved, carrying ESMO and NCCN guideline references, or currently in clinical trials (phases I to IV) worldwide.
Oncofocus is a dynamic test and is updated on a 12 weekly basis to reflect changes in approval status of drugs and progress of clinical trials worldwide.
About Oncologica UK Ltd
Oncologica UK Ltd. is an internationally recognised, leading precision oncology profiling company that delivers personalised medicine solutions for people with cancer. Oncologica is focused on addressing the growing demand for molecular profiling of cancer patients for targeted therapies by using its in-depth expertise and knowledge of molecular diagnostics. It established the first laboratory in Europe with state-of-the-art diagnostic platforms that enable comprehensive linkage of specific cancer genetic alterations to the most appropriate targeted therapy.
Oncologica also functions as a Contract Research Organization to support biomarker and drug development programmes worldwide. Using their extensive knowledge in anatomical and molecular oncopathology, Oncologica can provide high quality and cost-effective Contract Research Services to support theranostic programmes at all stages of the development pipeline. In addition, Oncologica runs its own in-house R&D programmes that focus on development of novel diagnostic and therapeutic intervention strategies targeting the cell cycle machinery.
Oncologica UK ltd www.oncologica.com
Telephone: 01223 785327
Telephone: 01223 789148