Genomic Profiling in Sarcoma Shows Potential in Guiding Clinical Management

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.”

Source: targetedonc.com

Dr David Fenelly

MD FRCPI ESMO

Former: Consultant Medical Oncologyst St Vincent’s University Hospital (SVUH); St Luke’s Hospital, National Maternity Hospital; St. Vincent’s Private Hospital; and Blackrock Clinic, Dublin; Member of International Advisory Board of Oneview Ltd. and Oneview Healthcare PLC; Member Director Centre for Colorectal Disease of SVUH;

Member of American Society of Clinical Oncology, European Society of Medical Oncology and Irish Society of Medical Oncology; Fellow of Royal College of Physicians; Formerly: Member of Breast and Gynaecological Cancer; Post Graduate Training from Memorial Sloan Kettering Cancer Centre.

Prof Umberto Tirelli

MD

Former: Consultant Medical Oncologyst National Cancer Institute Aviano; Specialist in Oncology, Hematology and Infectious Diseases; “Commendatore” of the Italian Republic, awarded by the President of the Republic for scientific merit; co-founder and VP of the Associazione Scientifica Galileo 2001; Member of the Technical Scientific Board (CTS) at Centro di Riferimento Oncologico (CRO) in Aviano, Istituto Nazionale Tumori; Assigned to the Scientific Council of AIN (Associazione Italiana Nucleare) on nuclear power; Former President of AIMAC (Cancer Patients Italian Association) and now part of the Scientific Council;

Formerly appointed by the Italian Minister of Health as member of the National Oncology Commission; Member of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the American Society of Hematology (ASH),and the International Immune-compromised Host Society (IHS); Member of the Scientific Committee of the AIOTE (Italian Association of oncology of the elderly);

Task Force Member (EORTC – European Org for Research and Treatment of Cancer) – Cancer in the elderly; Member of National Academy of Medicine for medical oncology (AIOM);  Environmental Comm. Committee mmber appointed by the Minister of the Environment.

Prof Daniele Generali

MD

Former: Consultant Medical Oncologyst, Azienda Istituti Ospitalieri, Cremona and Prof of Medical Oncology, Trieste Univ; Former Prof of Molecular Oncology, Institute of Molecular Medicine, Oxford Univ. Member of the Board of European Commission for initiative on Breast Cancer; Director of the Unit of Molecular Therapy and Pharmacogenomics, Azienda Istituti Ospitalieri, Cremona; Clinical Director of the Italian Red Cross, Cremona Section; Scientific Director of the Association of Research in Oncology Onlus, Cremona.

I would just like to thank you all for your help, support and professionalism this year, I contacted you after my recurrence of breast cancer, everything was explained to me in detail and I decided to go ahead with the test, I am so glad I did, every one I dealt with was so kind and encouraging, I was very scared about the journey ahead of me. The promptness of all the team was amazing my biopsy was collected quickly and I was contacted by Sarah constantly with updates on what was happening. As soon as the tests were completed I was sent the report with a follow up telephone call from the Doctor who talked me through it, he said he would be available to answer any further questions.

I showed the report to my hospital. Doctors and they were impressed with the information gathered and I am on the drugs recommended in my report and I have been really well with no side effects. Thank you all again.

I would like to pass not only my, but my father’s, gran’s and entire family and friends appreciation to not only Oncologica® but to you directly. Sarah, you went above and beyond what was expected, you took a personal interest and gave huge support. Your tone was always polite and you helped to listen to myself during the emotional moments when speaking. The hope you as a person gave and the encouragement, helped when I had to mount the challenge on behalf of my mother and father. Myself and my father agreed before taking to Oncologica® that as long as we tried all avenues and did everything we could for my late mother, this would be the only way we could coped.

Without yourself and Oncologica® we would not have been able to achieve the goal. My late mother took hope, encouragement and huge amounts of mental positively from the work but more importantly the personal touch you gave. As a person your indirect support helped my late mother. A person who didn’t praise health professionals easily due to career in the NHS and private sector. She praised you from the information, hope and personal feel you gave. You helped to give her peace of mind and know all options were looked into. I can’t sum up our, my feelings as they hold you in the highest regard. Perhaps, to say you have our eternal gratitude summons it all.

I just wanted to get in touch to thank you and the whole team at Oncologica® for the reports you did for my Dad. Despite a very poor prognosis, following the advice in the Oncologica® reports he has been receiving an immunotherapy drug under Dr Fennelly in St Vincent’s Hospital, Dublin, since the early spring and is now in much better health. The latest scans show a significant reduction in the size of the main tumour and a stagnation in the growth of secondary tumours. He is no longer in significant pain and is able to enjoy day to day life again. Thank you all for your hard work, we really appreciate it.

After being diagnosed with stage 4 lung cancer my mothers only treatment option on the NHS was chemo therapy. The doctors gave her 6 months without treatment and only 9 with treatment but her quality of life would have been awful if undergoing chemo therapy.

After finding Oncologica® their help, advice and support have been second to none. Their ground breaking analysis and treatment options enabled my mother to undergo immunotherapy which has successfully reduced the size of her tumour and thankfully she is still with us over 2 years later. This would have not been possible without Oncologica®!

Without Oncologica® we do believe that my mother would no longer be with us but through them and their continued support she is still hear and enjoying her life with us and able to watch her grand children grow and play. We cannot thank Oncologica® enough for everything they have done and their continued support and cannot recommend them highly enough.” Many, many thanks from the whole family.

Karan Jensen was diagnosed in 2017, aged 48 with cervical cancer. Karan ordered the Oncofocus® Test to identify additional treatment options and shares her story here in the following Q&A.

How did your diagnosis come about?

I had been having regular smear tests, but then one came back with irregular cells and the doctor asked to see me in 6 months time. We were moving, so I delayed going back, but when I did get to the doctors, they ended up doing a biopsy. Within 2 weeks I was diagnosed with Stage 2B cervical cancer with lymph node involvement.

What happened after you were diagnosed?

Treatment was started to cure my cancer. I had four cycles of chemotherapy plus 32 sessions of radiotherapy.

Did this treatment work?

Unfortunately, the tumour did not change with this type of chemotherapy, so I then started on alternative therapies.

Did the second round of treatment work?

I was meant to have six sessions of this chemotherapy, but after three, I had a scan and found out that the tumour had grown. I was told that there was no point continuing treatment as my cancer was incurable, and to go home and get things in order.

Did you experience any side effects of chemotherapy?

During chemotherapy, I was hospitalised four times with infections and neutropenic sepsis. The chemotherapy also caused swelling of my legs (lymphoedema), and my kidneys had been damaged so that I had to have a nephrostomy bag attached to collect urine.

How did you feel when they told you that you cancer was incurable?

I have an 11-year-old son, so I was not going to give up and did some research online on the best treatments for my cancer.

What did you find searching online?

I found out about the Oncofocus®® cancer test by Oncologica® on their website and got in touch.

Was it easy getting the Oncofocus® test done?

It cost £2000 but it was an easy decision to make. I just had to fill in a few forms and Oncologica® did all the work to get the biopsy from my hospital.

What were the results of the Oncofocus® test?

The test quickly came back that my tumour was exceptionally high in a protein called PD-L1, so it would respond really well to immunotherapy, which works by boosting a person’s immune system to help it recognise and fight cancer cells.

What happened when you knew the results of the test?

The treatment that the test recommended was not available on the NHS so my oncologist contacted Christie Hospital in Manchester, which was part of the PROCLAIM-CX-072 clinical trial that is investigating an experimental drug that targets PD-L1.
I was very sick at this stage, and the doctors were not sure that I would be well enough to get into the trial. As my levels of PD-L1 were so high, however, they thought they had to give me the opportunity.

Was this new treatment successful?

I was meant to have four sessions of CX-072 plus ipilumumab every 3 weeks, plus CX-072 maintenance therapy for a year. Although the treatment was not as bad as chemotherapy and I did not lose any hair, it still made me feel very poorly. After the third session, I developed a bad reaction and the level of some of my white blood cells that fight infection, neutrophils, plummeted and could not be restored to normal. It was therefore too risky to continue the treatment.
The good news was that a scan in March this year showed that the new therapy had reduced the tumour by 50%.

Are you still receiving treatment?

Even though the treatment has stopped, my immune system has taken over and is fighting the tumour. I am scanned every 2 months, and every time my tumour reduces by a further 0.5% to 1%. Last week I had another scan, and it had reduced by 3% and I feel better today than I have over the past 3 years.

What are your thoughts on the Oncofocus® test?

If I had had the test before receiving chemotherapy, this would have saved the NHS a load of money giving me a treatment that did not work and putting me through so much. I continue to need a nephrostomy bag due to the damage done by chemotherapy, which needs changing once a week and the tubes replaced in hospital every 3 months.

What is happening now?

We are now at the ‘watch and wait’ stage. However, as I have had such a good response to the immunotherapy and feel so much better, I can have more treatment if needed in the future. The swelling in my leg has gone down and I can now wear my shoes and move around normally again. I was so sick that I did not think that I would see last Christmas. Now I will get to experience Christmas again this year.

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.

A father of two with terminal cancer has been given new hope after being offered a free pioneering test to help find alternative treatments.

Mick Weldon, 38, from Cambourne, has a rare form of stomach cancer which is resistant to conventional forms of treatment.

In April, the News reported on Mick’s efforts to crowdfund enough money to cover the cost of analysis of new treatments.

After reading his story, Cambridge-based research company Oncologica® approached Mick to offer a ground-breaking test for free.

Mick was first admitted to hospital in December 2015 with a suspected ruptured ulcer, only to be later diagnosed with a cancer that had spread to his abdomen, liver, and surrounding organs.

Doctors found that Mick had a rare subset of Stage 4 GIST stomach cancer called wild type SDH deficient, which is incurable, but could be held at bay by new drugs.

Normally costing around £1,500, Mick under went an Oncofocus® test, which has been developed to detect every mutation linked to every drug and applicable to all tumour types.

Oncologica® claim that the test can identify specific treatment options in 85 to 90 per cent of patients.

Mick’s results show that a certain protein, PDL-1, expressed by his tumours, was acting as a ‘cloaking agent’ and effectively hiding the tumour from his immune system.

He now hopes his crowdfunding efforts will help to finance three cycles of anti-PDL-1 drugs.

“I’ve gone from having no options to a lot of options,” he said. “I’m amazingly positive. I’ve gone from a place where I had no hope to where I have a viable option. We’re all really upbeat.”

Mick hopes new treatments will give him more time to spend with his wife Emma and daughters Charlie, 17, and Rebecca, 15.

He previously said: “No one prepares for their own death, no wife wants to stand by and watch her once proud strong husband slowly degrade, and I can’t even begin to imagine how hard it must be for two beautiful young ladies to watch the father they have looked up to for as long as they have known slowly slip away.”

If Mick is able to secure the funding for his three cycles of drugs he hopes the evidence gathered will benefit other cancer patients.

“The NHS needs evidence,” he said. “We have to prove these drugs are viable.”

“I’d like to be in a position to start up a database where people can find this information where people can look up their options.”

He also remains realistic about how any new drugs will help his condition, but very thankful to the support of Oncologica®.

“Even if this fails, at least something is being done and I’m not just waiting to die,” Mick said.

“[Oncologica®] are absolutely amazing people. It buoyed me up. Until that point I was coming to the end of conventional treatment.”

Dr Marco Loddo, co-founder and scientific director at Oncologica®, said: “We saw the article and learnt about Mick’s story and in particular that his tumour type was quite rare and found out that he had exhausted all treatment options on the NHS.

“We hoped that we might be able to help with our tests. We’re happy to help.”

Oncologica® is a precision oncology services laboratory and contract research organisation founded in 2014.

Its Oncofocus® test aims to help encourage a move away from toxic non-specific cancer treatments to the use of the new generation of biological anti-cancer agents called targeted therapies.

Targeted therapies specifically hit cancer cells and not the normal cells of the body. They are said to be more effective than chemotherapy because patients are spared severe toxic side effects such as hair loss, infections, anaemia, gut toxicity and fatigue.

Professor Gareth Williams, co-founder and medical director, said: “What we are doing is to optimise the treatment pathway to provide a roadmap and that can have huge benefits for patients. You can avoid all the toxicity issues.”