Tumor Mutational Burden a New Pan Cancer Marker for Immuno-Oncology?

By Anthony M Magliocco MD

A new molecular marker “Tumor Mutational Burden” is rapidly emerging in the immuno-oncology world. New trials are showing that TMB may be superior to PDL1 IHC analysis to determine a patients probability of responding to costly and potentially toxic immuno-therapy treatments such as immune checkpoint inhibitors.

Tumor Mutational Burden

The Cancer Genome Atlas (TCGA) has shown that cancers have significant variation in the burden of genomic mutations they carry.  Some tumors such as melanoma have extremely high burdens whereas others such as thyroid cancer have very low loads.

 

04_Frequency_Chart

FREQUENCY OF TMB ACROSS TUMOR HISTOLOGY TYPES

 

Some tumors have exceptionally high mutational loads which probably represents an underlying DNA repair deficiency such as POLE or MSI abnormalities. It may also reflect the mechanism of oncogenesis as UV induced tumors such as melanoma have very high burdens.

 

05_Pan-Cancer-Chart

THE NEOANTIGEN BURDEN IS DIRECTLY RELATED TO TMB

It is thought that TMB actually results in the development of neo-antigens, which are essentially immunogenic.  The probability of neo-antigens emerging is proportional to the total tumor mutational burden. However, this is still a probability measurement, its possible that tumors with even low mutational loads might still generate neo-antigens of interest to the immune system.

210-neoantigens-mobile

CANCER CELL WITH NEOANTIGENS STIMULATE IMMUNE CELLS

 

Recent Clinical Trials Point to TMB as an important pan-cancer marker

There have recently been three interesting trials in advanced lung cancer reported with a significant association between tumor mutational burden (TMB) and response to the PD-L1 inhibitor nivolumab (Opdivo).  CheckMate 012 trial, was a single-arm evaluation of the combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy), reveled benefit in patients with high TMB independent of PDL-1 expression.

At AACR The CheckMate 568 trial,   used a TMB cutoff of ≥10 mutations per megabase of DNA (mut/Mb) as the definition of high TMB. Comparing TMB and response rate in 98 patients with untreated stage IV non-small cell lung cancer (NSCLC), investigators found a 44% response rate in association with TMB ≥10 mut/Mb and no further improvement in response with a higher TMB. The response rate fell dramatically with TMB <10 mut/Mb.  This finding is interesting as it may there is a “shelf” or a bimodal distribution of TMB

According to Dr Ramalingam  of Emory “PD-L1 and TMB identify distinct and independent populations of non-small cell lung cancer that independently are associated with enhanced objective response rate and progression-free survival.”

Investigators in the randomized CheckMate 227 trial prospectively applied the TMB cutoff of ≥10 mut/Mb.  There was aa threefold improvement in 12-month PFS (42.6% versus 13.2%) in the subgroup of patients with TMB ≥10 mut/Mb.

The PFS difference persisted across analyses of high and low PD-L1 expression and squamous versus nonsquamous histology.

“CheckMate 227 validates TMB as an important and independent biomarker to be routinely tested in treatment-naive, advanced non-small cell lung cancer,” said Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center in New York City

“TMB should be a standard of care in the initial evaluation of the patient with non-small cell lung cancer,” said Naiyer Rizvi, MD, of Columbia University Medical Center in New York City. “PD-L1 as a biomarker remains as a standard of care in concert with TMB. a validated TMB platform needs to be used.”

Problems with TMB

TMB is definitely showing promise, but what are the drawbacks?

NGS is required

First, TMB calculations require that a significant portion of DNA be sequenced, to generate enough sequence information to determine the tumor mutational load. However, some recent studies suggest that even targeted sequencing panels may provide enough sequence information to determine if the load is high. Access to NGS sequencing remains a challenge. Due to low reimbursements and difficulty of implementing the technology many oncologists may have difficulty  accessing the technology

The calculation of TMB is currently non-standardized and non-trivial

Second, TMB calculation is not standardized. It is not a trivial bioinformatics process as the bioinformatifcs process needs to determine if a  DNA variation is “real” or an artifact of sequencing- this is non-trivial as filters need to be defined to define the criteria to make a “call” ie what the confidence of the read is, what the alleic fraction is and whether the mutation is somatic or germline. In addition it must be determined if the sequence affects the coding region of a gene.  Further complicating this is what the denominator might be in an assay- ie does the NGS sequence only coding regions or are there significant non-coding regions. If the non-coding regions are included in the calculation the number may be artifactually low.

Third, thinking from a biological and mechanistic approach, it may matter whether the mutation actually produces a neo-antigen. Again this cannot be easily measured. It involves factors such as whehter the mutation is actually transcribed into protein, and whether the protein conformation is actually altered and neo-antigenic. Further issues include whether the sequence is secreted or made available when the cells degenerate.

TMB are not the only source of neo-antigens

DNA mutations may only account for some of the neo-antigens that a cancer can create. Other sources of neo-antigens in neoplasia include microbes (ie HPV virus in HPV driven cancers such as cervical or head and neck cancer. Other sources include post-translational modifications in cancer such as glycosolation events etc.

cgi-viruses

HPV VIRUSES ADD ANTIGENS TO TUMORS

 

Host Factors

Further complicating the impact of neo-antigens include the condition of the host immune system and its capacity to recognize and react to neo-antigens. For example in immune deficiency conditions, neo-antigens may be present but ignored by the immune systems. Or genetic variants in cellular receptors or MHC may affect how neo-antigens are presented to the immune system

patient-family

Neo-Antigens may be induced in tumors as a therapeutic strategy

Another interesting angle affecting therapy is the possibility that neo-antigens could be induced in a cancer to trigger immune response. This effect may be a side effect of some therapies such as temozolamide or radiation therapy.

Intraoperative-Radiation-Therapy-For-Breast-Cancer-1-550x330

RADIATION THERAPY MAY INDUCE NEO-ANTIGENS

 

Dr Magliocco is Chair of Pathology and director of the Morsani Molecular Laboratories at the Moffitt Cancer Center

 

 

 

Hormone Replacement Therapy does not Increase Risk of Breast Cancer in Women with BRCA Mutation after BSO Treatment

By Anthony M Magliocco MD

In a large multicenter international prospective study reported in JAMA Oncology, Kotsopoulos et al found that use of hormone replacement therapy overall did not appear to increase risk the of breast cancer among women with BRCA1-mutation after prophylactic bilateral salpingo-oophorectomy; however, use of estrogen-progesterone hormone replacement therapy appeared to be associated with increased risk vs estrogen alone.

Study Specifics

The study was a prospective, longitudinal cohort study of BRCA1- and BRCA2-mutation carriers from 80 centers in 17 countries which was conducted between 1995 and 2017. There was a mean follow-up of 7.6 years. The study participants had undergone BRCA1 or BRCA2 testing for familial or other reasions.

The current study included a total of 872 BRCA1-mutation carriers with no personal history of cancer with a mean postoophorectomy follow-up of 7.6 years. Patients had a mean age of 43.4 years. the questionnaires were administered every 2 years for information on hormone replacement therapy use.

The investigators concluded,

“These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that [hormone replacement therapy] is safe. The possible adverse effect of progesterone-containing [hormone replacement therapy] warrants further study.”

However the study also revealed that use of estrogen plus progesterone was associated with higher risk vs use of estrogen-alone hormone replacement therapy.

BRCA Mutation Predicts Carboplatinum Response in Women with TNBC

Anthony M Magliocco MD

 

A recent study published in Nature Medicine reports that women with triple negative breast cancer with a BRCA mutation were much more likely to respond to treatment with carboplatin compared to treatment with docetaxel, which is the current treatment recommendation for these patients.

https://www.nature.com/articles/s41591-018-0009-7

Triple negative breast cancer remains a difficult disease to treat as standard anti-estrogen or anti-HER2 treatments are not considered.

In this study there were 376 women with advanced triple-negative breast cancer across the trial, regardless of BRCA gene status, the researchers found the 2 drugs worked similarly well. But among the 43 women in the study who also had BRCA gene mutations those who received carboplatin were twice as likely to respond to therapy as those given docetaxel.

The researchers have reported an observed resesponse of 68% of the patients treated with carboplatin, but only in 33% of the women on docetaxel.

 

 

 

Furthermore Carboplatin also appeared to cause fewer side effects along with prolonged tumor progression for longer in women with BRCA mutations—with a progression free survival of  7 months compared with 4 months for those treated with standard docetaxel.

The researchers believe carboplatin is more effective for this patient group because it works by damaging tumor DNA, and BRCA mutations impair the ability of cancer cells to repair the type of DNA damage created by this kind of platinum drug.

This study further highlights the need for availability of BRCA gene testing in women with breast cancer.

This study further highlights the need for NGS gene testing in women with breast cancer for the purpose of appropriate therapy selection

 

One curious feature of the study was women with BRCA1 gene methylation, low BRCA1 mRNA expression, or Myriad HRD analysis was not clearly associated with benefit of treatment with platinum based agents.

 

A study at the Moffitt Cancer Center recently showed many triple negative breast cancers may actually be misclassified due to errors in primary pathology biomarker analysis.

Second opinion analysis should be considered for women diagnosed with triple negative breast cancer as the original biomarker analysis may frequently be flawed and an actionable target such as estrogen receptor or HER2 is identified on reanalysis

 

TRIPLE NEGATIVE BREAST CANCER IS OVER DIAGNOSED

 

Morsani Molecular Lab at Moffitt Cancer Center is Central to its Personalized Oncology Mission

By Anthony M Magliocco MD

Moffitt Cancer Center, the largest and only NCI designated comprehensive cancer center in Florida and one of the largest in the country has been rapidly expanding its capabilities in molecular diagnostics with a clear focus on supporting its burgeoning personalized oncology programs which are led by internationally recognized expert Dr Howard McLeod.

It became clear several years ago that a huge revolution was coming in the area of personalized oncology and cancer treatments. That revolution is now here.

Explosive advances and numerous FDA approvals for new targeted therapies have emerged for treating and controlling once universal killers such as metastatic melanoma and advanced lung cancer.

These targeted therapy medicines, include vemurafenib targeting mutant BRAF, Erlotinib for EGFR mutant lung cancer, and crizontinib targeting ALK translocations. Further truly dramatic results have been seen with immunotherapy treatments such as the anti PDL-1 immune checkpoint inhibitor pembrolizumab for treatment of a variety of advanced cancers that over express the protein PDL-1 or carry MSI. More recently approvals of NTRK inibitors Larotrectinib and the PARP inhibitor Olaparib for BRCA mutant cancer have further increased demand for specialized testing as both of these treatments have companion diagnostic requirements

 

Immune cells (red and blue) surround a invasive cancer cells (green)

The approval of many new targeted treatments requiring companion biomarker evaluation is providing impetus to develop more advanced diagnostic technology including new cellular imaging methods

These rapid advances in treatment options hinge on the availability of routine, high quality, clinical grade, molecular analysis and diagnosis to properly identify patients who will be most likely to benefit from these costly and frequently toxic treatments.

The Morsani Molecular Laboratories were created to facilitate the rapid development and implementation of new molecular diagnostic assays into the routine CLIA laboratory at Moffitt

Moffitt leadership and its generous philanthropic doners and foundation laid the important cornerstone of the Moffitt Morsani Molecular Laboratories. Under the direction of Dr Magliocco, the laboratories had a singular mission to rapidly develop and deploy the advanced clinical grade diagnostic services necessary to support Moffitts rapidly maturing personalized medicine program.

The Laboratories were initially opened in 2012 and were first equipped with Mass array instruments and conventional Sanger sequencing, pyrosequencing and routine PCR ability. The decision was made to recruit PhD scientists who would help develop the new assays to a CLIA standard and then launch them into a “routine” production laboratory.

The demand from the Moffitt clincal services was high, especially from thoracic oncology, a ground breaking team offering a multitude of clinical trail options for Moffitt patients. This demand required that the assays be CLIA grade, complex and delivered in a rapid way.

This was very challenging. Launching a highly multiplex assay into a CLIA lab is not a trivial matter. The assay must be calibrated to show sensitivity, specificity, analytical performance, range, precision, accuracy and many other technical components. Further, any new assay must also be put through its paces to show its robustness and reproducibility when handled by different scientists and technologists.

Launching new assays into CLIA labs is not trivial and requires extensive expertise and investments

We initially chose to launch the LungCarta (TM) Mass Array Panel from Sequenom. This was very challenging to validate as it contained individual assays run in multiplex to assay over 213 distinct mutations. as these were separate mutations and assays, the decision was made to only validate the most clinically important ones, namely BRAF V600E, KRAS, EGFR, and PIK3CA. The next issue was obtaining appropriate clinical reference materials to validate these assays. Fortunately with Moffitt’s very high clinical volume, previous experience with single-plex testing, and availability of Total Cancer Care Protocol tumor bank which houses data and specimens from over 400,000 patients it was possible to obtain the necessary control and case materials to validate and launch the assays into clinical service.

The development of a CLIA assay requires access to appropriately characterized reference materials to enable clinical validation of the process and assay results.

Although the complete 213 mutation panel was run, only the CLIA validated assay results were reported to the treating physician. The remaining results were ported into Moffitt’s data warehouse for storage and use in properly approved research studies. Following the launch of the LungCarta assay, the Morsani Molecular laboratory also launched assays for melanoma, and a specially constructed Glioma panel assay.

 

In 2014, clinical demands for even more complex sequencing arose for proper management of Myelodysplastic Syndrome (MDS) mounted. The hematology team needed access to over 30 genes and potentially thousands of mutations. It was time for the big guns, time for next generation sequencing. At the same time Moffitt molecular pathologists also saw increasing needs for more complex sequencing for solid tumors as well. After careful discussions and further evaluations it was decided to begin next generation sequencing. Following some debate, the consensus was to start with Illumina, given their long history in next gen sequencing and also the experience with the technology in Moffitt’s core genetic research laboratory. It was decided to develop an off the shelf 26 gene panel TST26 that covered most of the key mutations in lung cancer and in melanoma. In addition Moffitt CLIA scientists, molecular pathologists, and clinicians worked with Illumina to design a 32 gene myeloid NGS panel.

Bringing on NGS brought new challenges of a complex wet lab and also a very complex bioinformatics dry lab. At Moffitt we worked with PierianDx who helped design bioinformatics pipelines and an efficient validation program for both the wet and dry lab as well as an information system – a genome workbench- which allows molecular pathologists to rapidly review cases and access a knowledge database to enable rapid sign out. We also required access to numerous control samples to validate the assays. Again these came from Moffitts vast biospecimen resources and also Horizon Discovery, a company specializing the the provision of reference materials for clinical validations. To date Moffitt has run over 10,000 NGS assays.

By 2017, clinical demands continued to mount for even more complex testing. There were new drugs approved that needed to evaluate fusions, “exon skipping” mutations, and even MSI and tumor mutational burden. With these demands, we turned to illuminas TST170 assay, a new type of sequencing assay that had both DNA and RNA. In addition the assay was designed with “actionable targets” in mind. Meaning, that targeted agents in clinical trials were scrutinized to determine the collection of genes and mutations that would likely be most informative for treatment selection in solid tumor oncology. This approach makes the assay very useful and practical for deployment in a busy cancer center where multiple trials are underway and complex patients with unusual cancers are presenting. Moffitts Morsani molecular team worked hard and spent several months validating the assay to bring it to acceptable CLIA standard finally launching it as “Moffitt STAR” an assay to screen for actionable mutations.

Since its launch, demand has been exceptionally high with hundreds of physician orders in the first week alone.

 

Moffitt laboratories continue to work closely with the worlds leading oncologists and pharma and technology companies to ensure that Moffitt Patients always have access to the latest diagnostic tools to enable them access to the most current treatment options.

That is what makes Moffitt an exceptional hospital for cancer patients seeking innovative treatments and explains why Moffitt has some of the best cancer outcome response rates in the country.

 

Loxo Oncology work with Illumina to develop Cdx NGS assay for Larotrectinib (NTRK) and LOXO-292 (RET)

Anthony Magliocco MD

In an important announcement Industry sequencing leader Illumina and LOXO Oncology, released that they are working on developing a companion diagnostic for larotrectinib, a NTRK inhibitor and LOXO-292 which targets ret.

 

It appears that they intend to use the TST170 as a basis and perhaps a DX version of the Nexseq 500

This is an important development for 2 reasons. The first is the molecular alterations in question are relatively rare, but they can occur in any tumor type regardless of the tissue of origin. The second is the identification of a standard instrument platform and multi-gene assay panel that is already in clinical use (Moffitt has recently deployed a version of TST170 for patient care as Moffitt STAR) will undoubtedly expedite the capability to scale this test for widespread deployment accross laboratories

The fact that TST170 is so comprehensive potentially offers the opportunity for other oncology drug developers to consider using this versatile assay as a companion diagnostic as well.

https://ir.loxooncology.com/press-releases/loxo-oncology-and-illumina-to-partner-on-developing-next-generation-sequencing-based-pan-cancer-companion-diagnostics

STAMFORD, Conn. and SAN DIEGO, April 10, 2018 (GLOBE NEWSWIRE) —  Loxo Oncology (Nasdaq:LOXO) and Illumina, Inc. (Nasdaq:ILMN) today announced a global strategic partnership to develop and commercialize a multi-gene panel for broad tumor profiling, resulting in a distributable, next-generation sequencing (NGS) based companion diagnostic (CDx) with a pan-cancer indication. The co-development partnership will seek approval for a version of the Illumina TruSight Tumor 170 as a companion diagnostic (CDx) for Loxo Oncology’s larotrectinib, which targets NTRK gene fusions, and LOXO-292, which targets RET gene alterations, across tumor types.

TruSight Tumor 170 is a comprehensive, state-of-the-art, next-generation sequencing test that interrogates point mutations, fusions, amplifications and splice variants in 170 genes associated with common solid tumors. The CDx version of TruSight Tumor 170 will allow local laboratories to provide referring physicians with comprehensive genomic information, so that patients can be matched to the most appropriate therapeutic options. This version of TruSight Tumor 170 will run on the NextSeq 550Dx platform.

“We are leveraging our leadership in next-generation sequencing to deliver in-vitro diagnostic solutions to improve the management of cancer patients in the clinic,” said Garret Hampton, Ph.D., executive vice president of clinical genomics at Illumina. “To this end, we are partnering with leading biotechnology companies, such as Loxo Oncology, to develop companion diagnostics for best-in-class therapeutics. Distributable diagnostic solutions, such as a CDx version of TruSight Tumor 170, in combination with the NextSeq 550Dx platform, will enable labs to perform precision medicine testing in-house.”

Under the partnership, the companies will collaborate to validate a CDx version of TruSight Tumor 170 for NTRK fusions and RET fusions/mutations as a Class III FDA-approved diagnostic in conjunction with larotrectinib and LOXO-292, respectively. The companies are also planning to broaden the clinical utility of the full panel by obtaining regulatory approval for the other assay content, to be marketed as a tumor profiling test. Illumina will lead regulatory activities related to the Class III plans for NTRK and RET, the Class II plans for the tumor profiling content, and CE marking.

“We are very excited to announce this collaboration with Illumina, the world’s leader in NGS technology,” said Jacob Van Naarden, chief business officer of Loxo Oncology. “We have piloted numerous NGS assays, and the Illumina TruSight Tumor 170 assay has consistently demonstrated robust performance with its assessment of both DNA and RNA, including highly sensitive gene fusion detection. The broad 170-gene assay content has the potential to deliver meaningful insights from a single tumor specimen, identifying patients with NTRK fusions, RET fusions, RET mutations, and many other actionable tumor alterations. Furthermore, we believe that this collaboration will improve patient access to high-quality NGS testing because pathologists will be able to run TruSight Tumor 170 locally and receive reimbursement.”

FDA Approved PARP Inhibitor Rucaparib For Maintainance Treatment for Recurrent Ovarian Cancer Boosting Need for Clinical NGS Testing

By Anthony M Magliocco MD

On April 6, 2018, the Food and Drug Administration approved rucaparib (Rubraca®, Clovis Oncology Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.      

Approval was based on ARIEL3 (NCT01968213), a randomized, double-blind, placebo-controlled trial in 561 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with at least two prior treatments of platinum-based chemotherapy and were in complete or partial response to the most recent platinum-based chemotherapy. Patients were randomized (2:1) to rucaparib 600 mg orally twice daily (n=372) or placebo (n=189) and were treated until disease progression or unacceptable toxicity. 

Tumor tissue samples were examined with a next-generation sequencing assay to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA). This test was also used to determine the percentage of genomic loss of heterozygosity (LOH). Positive homologous recombination deficiency (HRD) status was defined as tBRCA-positive and/or LOH high. Three patient outcomes analyses were performed on the following groups: all patients, HRD subgroup, and tBRCA subgroup.

NGS ASSAY WAS REQUIRED TO IDENTIFY BRCA MUTATIONS

 

ARIEL3 demonstrated a statistically significant improvement in estimated median progression-free survival (PFS) assessed by investigator for patients randomized to rucaparib compared with placebo in all patients (median PFS 10.8 vs. 5.4 months, HR 0.36; 95% CI:0.30, 0.45; p<0.0001), in the HRD subgroup (median PFS 13.6 vs. 5.4 months, HR 0.32; 95% CI: 0.24, 0.42; p<0.0001), and in the tBRCA subgroup (median PFS 16.6 vs. 5.4 months, HR 0.23; 95% CI: 0.16, 0.34; p <0.0001).

 

The FDA also concurrently approved the complementary diagnostic test, FoundationFocusTM CDx BRCA LOH, for tumor samples to determine HRD status. 

In ARIEL3, the most common adverse reactions in at least 20% of patients treated with rucaparib included nausea, fatigue (including asthenia), abdominal pain/distension, rash, dysgeusia, anemia, ALT/AST elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/URI, stomatitis, decreased appetite, and neutropenia. Myelodysplastic syndrome and/or acute myeloid leukemia occurred in 7 of 372 (1.9%) patients treated with rucaparib and in 1 of 189 (0.5%) patients assigned to placebo. Discontinuation due to adverse reactions occurred in 15% of patients receiving rucaparib and 2% of those assigned to placebo. 

The recommended rucaparib dose is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

 

This approval is another example of the exploding need to broad access to next generation sequencing in routine clinical care of cancer patients forming the foundational basis of personalized oncology

” This most recent approval of yet another therapeutic advance that is reliant on NGS for patient selection further increases the urgency for access to routine NGS for all cancer patients”  – Anthony M Magliocco MD

The Moffitt Morsani Laboratories have developed and launched a new NGS assay ‘Moffitt STAR(TM)” that covers the key actionable target genes including BRCA1 and BRCA2

Moffitt STAR NGS panel covers the key mutations

PierianDx Customer, Moffitt Cancer Center, Launches Clinical NGS Assay, STAR

VISIT MOFFITT CANCER CENTER WEBSITE

http://www.moffitt.org

 

New Mechanism Involving NFkappaB Drives Metastasis in Cancer with Chromosomal Instability

By Anthony M Magliocco MD

An interesting and important new study recently published in Nature gives new insights into possible targetable molecular mechanism linking chromosomal instability observed in some cancers and progession and metastasis.

https://www.nature.com/articles/nature25432

A subset of cancers develop chromosomal instability via disjunction errors during mitosis. This can lead to highly aneuploid and abnormal karyotypes more prevalent in certain cancers than other. For example, ovarian cancer is notorious for developing a  disrupted and unstable karyotype.

Metastatic Cancer

It appears that chromosomal instability in itself does not promote metastasis, however, in an intriguing observation it was noted that tumors with chromosomal instability also developed micronuclei when under mechanical stress.

These micronuclei are more prone to cytoplasmic rupture. Free DNA in the cytoplasm triggers a non-canonical NFkappaB cascade which may lead to mesenchymal transformation and a propensity to metastasis.

Interestingly cancers with high aneuploidy do not generally develop a high mutational burden such as cancers like melanoma. Nor do they tend to have targetable driver mutations.

“Cytosolic DNA from micronuclear rupture appears to trigger non-cannonical NFKappaB signaling which could lead to tumor metastasis”

 

DNA in the cytoplasm triggers NFKappaB as part of a host response to viral infection, but cancer may subvert this mechanism. In addition,  NFkappaB non-cannonical activation by cytosolic DNA from ruptured micronuclei may lead to a variety of effects immune activation which could assist with tumor metastasis.

These new insights into the consequences of chromosomal instability create opportunities for developing new therapeutic strategies for these types of cancer that lack specific driver mutations and significant neoantigen loads