Genetics of Renal Cell Carcinoma: Paving the Way for the Next Generation of Therapies

Why don’t the various medications work better for RCC?  Why is it so hard to choose the right medicine?  This lecture explains why patients  and doctors must play the guessing game in treatment. It may be the most important lecture in this blog, and provides an explanation as to why RCC cancers behave so differently, even those variants  with similar pathologies. It is presented by Dr. James Brugolas, MD, PhD.: Kidney Cancer Program Leader Associate Professor of Internal Medicine & Developmental Biology; University of Texas Southwestern Medical Center

http://www.chemotherapyfoundationsymposium.org/mobile/player.php?id=476

I am going to talk to you today about the genetics of kidney cancer and how I believe the paving the way for the next generation therapies. There are no significant disclosures.Brug 1 What is the ProblemWhat is the problem? This is a problem that we are well aware of some nowadays. We’re using one drug for all patients with kidney cancer.   You may imagine that these are all patients with metastatic renal cell carcinoma. But it is a heterogeneous population. Some have the red tumor, some of them the green tumor, and the drug may work with a subset of patients, but it may not work for another subset of patients.(Left half of the slide with the meds not reaching the patients with GREEN tumors.)

The paradigm we should be evolving to is a paradigm where patients with different tumors should be treated with different drugs. (Right half of slide shows Drugs A and B going to different subsets of patients.)BRUG 2 Kidney Cancer subtypesIn the context of renal neoplasms , as you are well aware, we have kidney cancer with clear-cell carcinoma which accounts for the vast majority (75%) of that, and that’s going to be the focus of the first part of the talk.

BRUG 2 EDITSCaptureThe work from the Sanger Institute by Andy Futeral and Michael Stratton led to the identification of mutations in the polybromo1 gene. Polybromo1, like VHL, the most commonly mutated gene in clear cell renal cell carcinoma, is a two-hit tumor suppressor gene. That means both copies are mutated in tumors. They identified through truncating mutations in approximately 41% of clear-cell RCC. PolyBromo1 encodes BAF 180, which is a component of a nucleosome modeling complex which may regulate, among other processes, transcription.

BRUG 3BAP1 loss defiens new class of RCCCapture

Work from my laboratory led to the discovery of another gene mutated in RCC, the BAP1gene. Like the BPRM1 and VHL, BAP1 is a two-hit tumor suppressor gene, but it is mutated in only about 15% of sporadic clear-cell RCCs. This work was done focusing on tumors that were of high grade. Indeed, we found there was a correlation between BAP1 loss and high grade, and also activation of the mTOR1 pathway. BAP1 encodes a nuclear deubiquitinase. Of greatest interest, mutations in BAP1 and BPMR1, we found, are largely mutually exclusive. This is shown this more detailed the next slide.

BRUG 4Mutation in BAP1 ^ PBMR1 mut excluWhat you are seeing here are 176 tumors, each in a row. These are tumors that have a deletion in PBMR1, these are tumors with the insertion, this with a point mutation (referencing the various symbolsP. All the tumors in blue are tumors that have a mutation. As you can see most of the tumors, we see with PBRM1 mutations do not have mutations in BAP1. (in last column) Here you have some tumors with mutations in BAP1, and we only identified three tumors that had mutations in both genes. The probability of having mutations in both genes was statistically significant. Based on the individual mutation probability, we would have expected 13 tumors to have both genes. Only three were found, suggesting that BAP1 and BPRM1 mutations are largely mutually exclusive.

BRUG 5BAP1 & PBRM1 meta analWe went on to performing a meta-analysis. This is looking at data from that Beijing Genome Institute, at Memorial Sloan-Kettering and this from the TCGA (The Cancer Genome Atlas). As you can see, even though the numbers are small, the numbers of tumors with mutations in both BAP1 and PBRM1 was reduced, compared to the expected number of tumors based on the individual mutation frequency, and the p value was statistically significant.BRUG 6BAP1 & PBRM1 gene signatureI’m going to go through these and not spend much time, but suffice it to say that that we found that these tumors that have had mutations in BAP1 have a characteristic gene expression signature, and the tumors that have mutations in PBRM1 also have a characteristic gene expression signature. These gene expression signatures do not overlap. These are tumors that have different gene expression patterns and different biology.

BRUG 7 BAP1 & PBRM1 ex  diff SMALL

We think this establishes a foundation for the first molecular genetic classification clear-cell RCC. In our series, 55% have mutations in PBRM1, and 15% of the tumors have BAP1, and including 3% have mutations in both. BRUG 8Fdn Mole Gene sign ccRCC We also observed that there is a statistically significant correlation between mutations in BAP1 and high grade, and mutations in PBRM1 in low-grade.

So that let us to propose the following model. This is a model based on the fact that, very interestingly, VHL, BAP1, and PBRM1 are all located on chromosome 3. In fact, the short-arm of chromosome 3, and this is an area that is deleted in the majority of patients with von Hippel-Lindau-associated renal cell carcinoma, as well as in the majority of sporadic renal cell carcinoma, depicted here in blue.

BRUG 9  BAP1 & PBRM1 on chromo 3p VHLYou can imagine that with a single deletion, the kidney cell is losing, in fact, four copies or one copy of these four different tumor suppressor genes, the BAP1, PBRM1 and VHL.BRUG 10 VHL mutat high low grade diff

We have proposed the following model. We believe that renal cell carcinoma, and this is consistent with data from Gerlinger and colleagues, that it begins with an intergenic mutation in the VHL gene. And this is followed by loss of 3p, with a concomitant loss of one copy of all of these tumor suppressor genes. We then think that a mutation in PBRM1 leads to the loss of PBRM1 function, which is a two-hit tumor suppressor gene and low-grade tumors, whereas the mutation in BAP1 is associated with the development of high grade tumors.

REFER to ABOVE PIE CHART re High and Low Grades

This model also predicts that patients with BAP1 and PBRM1 deficient tumors may have different outcomes. So we simply took those patients whose tumors we had analyzed and asked what happens to their outcomes.BRUG 12 BAP1 & PBRM1 diff outcomesAs you can see here (LEFT), we found that patients with PBRM1 deficient tumors had a significant better Overall Survival than those who had BAP1 in their tumors, which had a Hazard Ratio for that of 2.7.

We did a similar analysis with the TCGA cohort, and we found (RIGHT)essentially the same result in the same hazard ratio of 2.8, indicating that BAP1 mutant tumors are associated with worse outcomes in patients. This data has now been reproduced by Hakimi and James Ying ?at Memorial Sloan Kettering, as well as the TCGA with their own analysis and our colleagues in Japan and Tim Eisen.

BRUG 12 Limit of SequencingThere are some limitations of sequencing. We all like next generation sequencing, but it has some limitations. First, it focuses on DNA. Secondly. it uses pooled material. Thirdly, it has reduced sensitivity which is a consequence of contamination by normal cells. In addition, a negative result does not guarantee that there is normal function. There is poor discrimination of subclonal mutations in different cell populations. So as a consequence of using poor material, we cannot tell whether these mutations are found in the same cells or different cells. Typically, it involves fresh frozen samples which are reduced in numbers, and consequently has limited power for doing some analysis.

Interestingly enough, immunohistochemistry (IHC), which we’ve use for a long time is a lot more precise. This is because actually you get information at the cellular level, and you get information about the protein. I mentioned to you that BAP1 is a two-hit tumor suppressor gene, which basically means when it gets mutated, you lose both copies.BRUG 14 dev of BAP1 IHC testAs you can see here–this is the same series showed before. These are here in blue the tumors that had mutations, in the second column, you can see blue and brown, the results by immunohistochemistry. That is done by IHC. And BAP1 is a nuclear protein, as you can see in these beautiful nuclear staining.

The bottom line is the majority of tumors that had mutations (referencing blue column data points) had lost BAP1. There were two tumors with point mutations where we were able to detect the protein. But there were three additional tumors we could not detect protein, but where there was no protein. If there is no protein, there cannot be functioning.

The rest of the tumors, with one exception, were all positive. So compared to mutation analysis, in fact, there is positive predictive value is better and the negative predictive value is pretty similar.

BRUG 15BAP1 loss assc w red CSS ccRCC

We have used this immunohistochemisty test in conjunction with the Mayo Clinic, looking at their registry with over 1300 with localized ccRCC. As you can see, looking here with people with specific RCC survival, patients with RCC tumors that have BAP1 positive tumors have significantly better survival outcomes than those who have BAP1 negative tumors, again with a Hazard Ratio of approximately 3.

BRUG 16Evalu of PBRM1 by IHC cohortNow in the same cohort we looked at BPRM1, which like BAP1 in a two-hit tumor suppressor gene, and we find no significant differences.Brug 14Now in the same cohort we looked at BPRM1, which like BAP1 in a two-hit tumor suppressor gene, and we find no significant differences.

Importantly, this test allows us to identify tumors that are simultaneously mutated for BAP1 and PBRM1. This is important.BRUG 17a IHC ids tumors UpperSlide A                                                                                                 Slide B  

(This slide in presented in two parts to help understand lecture.)
Upper half of slide showing stained pathology images.)

I am going to show you look at this tumor over here (upper left path image A) you can see that the tumor cells, there are some that have brown nuclei, but these are the endothelial and the stromal cells (along the edge of the white). The tumor cells are negative for BAP1.

This is the immunohistochemistry (upper right path  image B) for PBRM1, where we find the same thing,where the tumor cells are negative for PBRM1.

BRUG 17b IHC PathSLIDESlide C                                                                                                                  Slide D

Now (left path image C) compare these tumors with these images below. You can see here that the tumor cells positive for BAP1 in this area (the upper right corner of the path image C) and they are negative (in the lower left corner of Slide C), where you can see specific nuclei which look blue over there.

Now if you look at the parallel section (Lower right path slide D) you can see the area that was BAP1 positive (left hand side???D) is actually also PBRM1 negative, and the area which was BAP1 negative is actually PBRM1 positive.

So what you have over here (in the upper slides A & B) is a tumor which has lost BAP1 and PBRM1 in the same tumor region, the same cells. The tumor has lost BAP1 and PBRM1 in independent regions. Obviously these tumors will be acting differently and the tumor we are most interested in is this tumor type (in the upper left image A).

BRUG 18 IHC BAP1 & PBRM1 ids 4 sutypes ccRCCSlide should include quote “BAP1 and PBRM1 do NOT predict outcomes independently of SSIGN”

You have seen in our immunohistochemistry test, and we believe we can separate clear cell renal cell carcinoma into four different molecular subtypes. This is looking at Mayo registries, where the patients with best outcomes are those whose tumors are well-typed for PBRM1 and BAP1. Then you have patients that have tumors which are deficient for PBRM1, patients that have tumors that are deficient for BAP1, and patients whose tumors are deficient for both. As you can see the Hazard Ratio is 1.3, 3.2 and 5.2, respectively.

As I mentioned to you at the outset, that these tumors were underrepresented and indeed in this very large cohort, we found a very large significant underrepresentation with 1.8% of the tumors being double mutant, compared to 5.3% (which would been expected) with a very highly significant p value, again indicating there is mutual exclusivity–for reasons we do not yet understand.

Importantly BAP1 and PBMR1do not predict outcomes independently of SSIGN, which is the nomogram created by the Mayo Clinic, which is based on Stage, SIze, Grade, and Necrosis. This is the SSIGN nomogram; this is the independent validation. You can see the curves separate beautifully, depending upon the score.

BRUG 19 Nomogr vs BiologyBRUG 20 Nomo vs Bio ANIMACapture

Now another question I submit to you. Should nomograms trump biology? In other words, if they live the same, “What do I care?” That has been the traditionally the thinking in the clinic. But look at these animals. A bullfrog and a grizzly bear also live about 30 years. However, they’re very different. The same is true for cottonmouth, a beaver or hummingbird or a newt. So even though they live the same, they are actually quite different!

We should be probing deeper and in fact, they should be dealt with differently!

BRUG 21ccRCC per genes

I believe that clear-cell renal cell carcinomas are in fact divided for at least four different subtypes. There are tumors that are wild type for both BAP1 and PBRM1, tumors that are PBRM1 deficient, tumors that are BAP1 deficient, and tumors that are deficient for both. In the future we are going to see different treatments for different tumor types.

BRUG 22 Conclusions

In conclusion, the discovery of BAP1 and PBRM1 mutations in clear cell renal cell carcinoma, how they relate to each other, and how they affect outcomes establishes the foundation for the first molecular and functional classification of sporadic ccRCC.

These two genes define for distinct subtypes, which I just went over and you have the Hazard Ratios and p-values written down there. These two tumors are not only associated with different outcomes, but they are also associated with different activations on the mTOR1 pathway and gene expression. Finally we identify mutations in BAP1 which define a novel clear-cell renal cell carcinoma syndrome. I have forty seconds left!BRUG 23 nnRCC graphic

I will go through these very quickly. Suffice it to say, we have also done molecular genetic analysis in non-clear-cell renal cell carcinoma, papillary, chromophobe, oncocytomas, This is now in press in Nature Genetics.

We found that papillary clear-cell carcinoma have more mutations than clear cell carcinoma, whereas chromophobe and oncocytomas have significantly lower mutation burdens, which is depicted there.

BRUG 24 Intr gen analy subtype RCC

These are some genes we found overrepresented– five seconds! You can see the copy number alterations, gene expressions. Anyway, these papers will be coming out next week.

BRUG 25 Associates

Finally, to acknowledge people who did the work in my laboratory, Pena-Llopis. We have had a close collaboration with the people at Mayo Clinic, and also the group at Genentech. We also work very closely with our surgeon and Payal Kapur, our pathologist.

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Filed under genetic testing, genomic testing, Pathology, Rare Cancers

HD IL2: Cures, Partial Response or Stable Disease=Clinical Benefits to Patients

Is it a cure or nothing for cancer patients? 

Is there another way to measure the benefit from any medication?

We all want the cure, the Complete Response (CR) that can lasts many months or years.  Often we have to settle for some reduction in our tumors or mets, a Partial Response (PR). But even “Stable Disease” is welcome news.  To get that cancer back in its cage, even for a time, is  better than “Progressive Disease”.  When the cancer is progressing, your life may be regressing, and that isn’t what you want to hear.  That Progression Free Survival (PFS) has to start with stopping the cancer.

As complete and durable (ten years) responder to high dose interleukin 2 (HD IL-2), I welcome any discussions of “Clinical Benefit (CB)”.  CB includes all the good responses with any cancer treatment, CRs, PRs, and SDs.  We and our doctors need this information to make informed decisions about treatment, for IL2 or other meds. The value of Stable Disease has been ignored in many studies.  Maybe there are lessons here for you and your doctors, especially about the under-utilized HD IL2.

Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).

Source URL: http://meetinglibrary.asco.org/content/123909-142

(Abstract is below)

There are few new studies about the use of HD IL2 following the approval of the targeted therapies. The ease of use of these agents, along with the desire not to send patients to specialty centers for IL2, limited its use. It was difficult to select patients, and the CR and PRs were relatively small in number. Doctors often did not discuss the possibility of a cure with their patients.  Did patients also miss the chance for Stable Disease, and with it, a  “Clinical Benefit”?

Patients in this study who did not have a CR, but whose cancer stopped growing benefited.  That CB was not counted in terms of the approval of the drug, nor do doctors consider it in their recommendations. Should this possibility be discussed with patients?  Most patients would surely answer, “Yes!” to that question.

The researchers recognize of the value of Stable Disease (SD) as an outcome, versus only Complete Response (CR) or Partial Response (PR). The usual outcome measures, Progressive Free Survival (PFS), or Overall Survival (OS), are noted, as isTime to Next Treatment (TNT). TNT implicitly recognizes that a failed or limited response will likely be followed by another treatment.  Early on, there were no subsequent treatments, sad to say.

The original clinical trial which led to FDA approval of HD IL2 recognized only CR, which was 5%, with the median not reached during the trial, and PR, which was 14%. Study footnotes indicate that three of the PRs had surgery which rendered them disease free at the time of the publication. This would now be called a “salvage therapy”, and put them in the No Evidence of Disease (NED) class. A different analysis of this data would have upped the CRs some small percentage, and some SD would also have been found.

Also the definition of PR was 50% or greater reduction in measurable tumor size, the sum of the perpendicular diameters of all lesions, with no new increase of size of any other mets. Far less strict measurements of PR were used in the targeted therapy trials, with a 30% tumor reduction defined as a Partial Response.

 With those definitions in mind, note that there are CRs in 11% of patients, with a PR in an additional 6% of patients. Most important is the SD category, which was achieved for 31% of all patients.   This total of 47% is described for the group as being of Clinical Benefit (CB). Certainly patients value the responses of SD, which seems to have provided slightly over one year versus 3-4 months benefit to those who did not have SD.

 When comparing the value of Objective Response (OR) with its median of 1616 days to that of Stable Disease (SD) measured as 1476 days, one can clearly see the value of achieving Stable Disease. Unfortunately, those patients with Progressive Disease, or with responses Not Evaluable (NE), showed OS of 365 days.

Patients should be aware of these definitions and the impact the lack of parallel comparisons in making these critical decisions.  Ten years ago, the patients reminded one another to stay alive until the next treatment.  Having Stable Disease made that possible.  Let’s apply the same tests to all the available treatments when making these life-changing choices of treatment.

ABSTRACT FOLLOWS Citation: J Clin Oncol 32, 2014 (suppl 4; abstr 461)

Author(s): Neeraj Agarwal, David D. Stenehjem et al University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, UT

Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB (OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2.

Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer.

Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table.

Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC patients. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling patients for treatment with HD IL-2.

  PFS, days TNT, days OS, days
Overall 152 264 817
SD vs PD and NE 337 vs 78 (p<.0001) 373 vs 110 (p=.0001) 1,476 vs 365 (p=.0003)
CB vs PD and NE 791 vs 78 (p<.0001) 735 vs 110 (p<.0001) 1,616 vs 365 (p<.0001)
OR vs SD, PD and NE NA vs 99 (p=.0003) 953 vs 166 (p<.0001) 1,616 vs 603 (p=.0021)
OR vs SD NA vs 337 (p=.0234) 953 vs 373 (p=.0015) 1,616 vs 1,476 (p=.2094)
Abbreviation:PFS, Progression Free Survival; TNT, Time to Next Treatment, OS, Overall Survival; NA, not achieved;SD, Stable Disease; PD, Progressive Disease; NE, Not Evaluable; CB, Clinical Benefit;CR, Complete Response; PR, Partial Response;OR, Objective Response
 

Abbreviation: NA, not achieved.

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My Radiologist or New Best Friend

In our kidney cancer world, it is unusual even to know the name of the radiologist, and most patients rely on his report, as given to the doctor. Many kidney cancers are “incidental findings” on CTs given with another diagnosis anticipated, broken rib, for example. Thus, it is the radiologist who recognizes the cancer long before either the doctor or patient. It may be a metastases that is found, with the primary tumor not yet imaged, or vice versa. If the tumor is relatively small, and no mets are seen in that initial scan, most patients are assumed to have localized disease. Often there are sudden plans for surgery, but not necessarily to search for other distant mets. The patient may be told, “I got it all.”

Of course, that is the best news, and the only news we want to hear.  But we are wrong, as what we NEED to know, even before the surgery, is whether or not there has been a spread of the cancer.  Treating kidney cancer is already a guessing game, and without knowing the whole game and all its rules, the patient is too often the loser. (Look for a longer, somewhat geeky post on small primary tumors and their potential to metastasize, both quickly and years later.  Ain’t a pretty picture.)

Any good radiologist will know that even small primary tumors can have already produced distant mets. That radiologist likely knows  that additional imaging should be done in such cases. The GP or even the urologist without RCC experience may NOT know that.

Too often small, overlooked mets in the lungs or on a bone can go unnoticed for months or years. Only the radiologist can provide a complete understanding of the extent of the cancer, and only with imaging outside the area of the “incidental finding”. He is the first line of defense, and often the first real expert in determining the extent of the disease. Thanks to those unsung heroes!

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Durable Response to a Med: Long-lasting or a Hard Time? More Translation Required!

When you are suddenly thrust into the medical world, unwillingly and without any kind of road map, you are surrounded by poorly marked turns, meaningless abbreviations and the sudden shift in the dialect.  The Wellness Center is usually about having lost one’s “wellness”, a word used only in the medical world, and not by real people.

Pressed to make decisions that may change your life, for the better or worse, you can be confused by those clever new words, some  from the marketing people (see above) and others from the clinical side. It is critical to understand how familiar words get reworked to explain new concepts.  Such explanations rarely reach patients, who are numbed and deafened after a shocking diagnosis.  And in the medical “new-speak”, those same patients may be told that this is the time in which they must take charge of their health, and make wise decisions quickly and correctly.  I find this a cynical and self-serving approach, as rarely is any real education offered in the language of the patient.

In kidney cancer, we have been blessed with new drugs these past eight years, but have no clear way to determine which of these agents might be of benefit to any of us.  On top of the shock of diagnosis, the patient is thrust into a guessing game.  Even the doctor is forced to play along, and often neither party knows the rules or the chances to win.  The doctor may recognize the vocabulary used in this new guessing game, but the patient does not.  Words which have meaning in day to day life don’t work the same.  Even some of the goals of the game are unclear to the patient. Wait! You probably think that being cured is the goal.  you

For example, we patients think that “progress” is good, but that is not true in cancer.  Progression is the goal of the cancer, so Progression Free Survival (PFS) measures the time between treatment and when the cancer is on the visible move again.  The word “visible” is important here, as that is a reminder that cancer does not just start at a size or style to match the sensitivity of imaging.  X Rays cannot see things as small as a CT scan can.  Bone scans see bone mets better than other scans and so on.

In reading clinical trials, you will encounter “durable” to explain how long a median PFS can be.  It may be described as remarkably durable, but in the pre-patient world, we would think that is pushing into years and years.  In reality is may be 15- 18 months.  We happily grasp at any more months than the non-treatment reality may be, but be aware of your and your doctor’s expectations in durability.

“Durable response” is surely what we want, but that is not translated to a cure, which might be the patient’s interpretation.  When you hear that, do ask for clarification, “How long does that response last?  What do you mean by ‘durable’?  What do we do after the duration of response comes to a stop?”

Having a firm grasp of this term and all others is an absolute necessity, and even if that is hard–in the real sense–it will be worth it to you.  You will have greater understanding of the treatments, the disease process, and a bit more sense of where you are.

More on these topics later, but do track the language, and remember than you still speak the old language.  At the very least, be ready to question anything that has that new dialect sound to it!

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“We Are All Patients.” True or the Latest Cliche?

  1. The lovely cliche, “We are all patients” is just that. At every medical conference, or in the new lobby of the hospital, that phrase is offered.  While it is true in a statistical sense, it has a snarky sound to the new patient, reeling from his induction into the medical world, foreign and threatening.  It can really seem snarky to those who know how poorly patients can be treated, how overwhelming the language of illness is, and how chaotic a hospital setting is for most.

    The patient experience for someone who speaks the language, whose  friend is a specialist, or can understands the imaging reports and lab values, is in stark contrast for those lacking such resources.  Not much we-ness in those two patient groups!

    Certainly the medical people who suddenly become patients, or are thrust into being a caregiver, can offer their own colleagues insight into those new roles. But rarely is the newly diagnosed patient, one who has never “known” how the system works ready to take on this role. He is often the patient at the greatest risk–especially when told, “Be your own best advocate.”  Most of the time, that “Be your best” does not give the patient anything, but a reminder of how lost he is.

    The recent convert to patienthood who can navigate the system may be a wonderful translator of the dialect and the cultural mores of that system, but with limited impact.  If that medical pro turned patient is not also willing to change that culture, to be more open, to provide ready access to information, and to teach to the wider world, most patients will not be well-served by this new awareness.  As a society, we will continue to be inefficient in our care of the sick, have poorer individual and community health, and waste incredible sums of money.

    Patients could be given readable information about what the standard of treatment is for their disease. They can learn that the oncoloigst should recommend more frequent imaging, or that there are other treatments than the scalpel and chemotherapy. They can learn how to enhance their daily health, how to monitor side effects, to clarify their own health concerns.  Patients can be guided to credible online resources or patient groups so they can ask the new question, compare notes, learn the changing vocabulary.

    Doctors can tell patients that diagnosis is tricky and requires testing and feedback along the way. They can remind patients of the uncertainty and complexity of cancer, or a chronic disease. They can welcome questions about side effects, new studies, and treatment options.   The dynamic will shift as the patient becomes more knowledgeable, or has greater medical needs, and the doctor must shift as well.

    Patients and their providers need to partner with one another, with the patient at the center of all those relationships.  The patient needs ready access to his records, information relevant to his needs, and an atmosphere of collaboration, appropriate to the moment.  Anything less is damaging and wasteful, and we ain’t got time and money for business as usual.

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Pathology and Why It is So Damn Important!

INTRO SLIDE

How Does the Pathology Report Help Direct my Treatment Options?

Lecture by Dr. Daniel Luthringer of Cedars Sinai Medical Center of Los Angeles at Kidney Cancer Association meeting December 2013. https://www.youtube.com/watch?v=-6emPs-mc1E   (Follow via YouTube)

I have transcribed the lecture edited for readability, included the slides, to make it easier to follow.  If you have not seen your own pathology, GET THAT REPORT now. Important to read!

A terrific introduction by Dr. Robert Figlin reminds us of the work of those people we never meet, but who care for us. “One of the people behind the scenes is the pathologist at this and other institutions. Often times the pathologist is in a different part of the hospital evaluating tissue, and helping the clinician figure out what the tissue looks like. It’s become, as Hyung (Dr. Kim) mentioned, time to start to think about personalized approaches to kidney cancer, and the relationship between the pathologist, the surgeon, and the clinician becomes ever more important. Dr. Daniel Luthringer is Professor of Pathology and Section Chief of the Genitourinary Pathology. He will talk to us about how the pathology report and how what he does– is important to then what we decide how to go forward with treatment.”

Dr. Luthringer begins:

“Thank you, Bob, for this introduction and the ability to speak at this conference. I am the guy behind the scenes, at least at this institution responsible for doing the histologic/microscopic analysis of genitourinary malignancies, primarily renal cell carcinomas. (RCC)

1 PATH 1 PathReportTypesThere are really two main categories of specimens we receive, samples from the real tumor itself, which can either be biopsies or resections, as Dr. Kim alluded to, or samples from a metastatic site, a recurrence or a metastatic site. The most common specimens that we see are nephrectomies, resections of the tumor, andeither partial nephrectomy or complete nephrectomy.

2Path 2 Types of Spec These are examples. A partial nephrectomy, as per Dr. Kim, are smaller resections or partial resections of the entire tumor.They include a bit of nephric fat and a little bit of the perinephretic fat as well. The goal is to get the entire tumor out, with a negative margin of resection. With tumors that are bigger generally, or infiltrative, we tend to get the entire kidney. This is an example of a nephrectomy with perinephric fat, the sinus fat, drainage area down here, maybe an adrenal gland up top and this would be an example of tumor that is completely resected.

Occasionally we will get tumors from metastatic sites or—unusually from the primary tumor—and will get a core biopsy, which is really a small smaller sample of the tumor mass. Usually it is about a millimeter or two in diameter; it’s a core, maybe up to several millimeters up to a centimeter in length. Generally, it is just a small sample of a much larger tumor .

Path 3 Speci Handling3  A bit about the specimen handling: within a few minutes of having the tissue removed, it comes to the pathology lab. We do some initial assessment on it.  We have work stations where they will come and the pathology team will assess it. Assume it is a nephrology specimen.  We look at it and measure it, cut it open, procure some of the tissue.  If there is some tissue that needs to be taken fresh, potentially for a biobank to be stored away, or if some tissue needs to be taken for immediate diagnosis or margins or something like that, we will do that.

If you’re enrolled in a study where there some fresh tissue is needed, sent to a particular institution or a reference laboratory for an analysis, we will procure that as well and make arrangements to send it off on an immediate basis. At that point we do photography, tissue fixation and over the next few hours we will dissect the specimen, will analyze it, do a lot important evaluation with our eyes and ears, whatever it takes. Then we will take what are called representative sections of that tumor or specimen, put them. We put them into these little capsules called cassettes and then we process them overnight in these tissue processors. These are pretty standard from institution to institution.

Path 3a Specimen Handling3a The next morning the tissue is taken out of the processors and is manually placed in these other tissue cassettes which are filled with paraffin wax essentially. They are embedded into these wax molds, and then the blocks. Then very thin sections of 4 to 5 microns are cut with these special microtomes and they are picked up on the glass slides. They are again processed, stained, and cover slipped. Ultimately we get a sample of glass slides from that tumor that has been removed.  On an average partial or complete nephrectomy, we will go anywhere from 5-10 paraffin blocks, equating to 5 -10 glass slides.

Path 4 Speci Handling2This takes about a day or two to complete this. Then the initial slides are delivered to the pathologist, who will begin the process of microscopic analysis. He uses obviously his microscope and whatever tools he needs.

He’ll be looking at those sections from the slides, and it will usually be the sections from the kidney, maybe some lymph nodes, margins, adrenal glands, things that were provided by the surgical resection. The whole process usually takes 2-3 days to complete. There is a bit of a time lag, due to the technical processing involved.

Path 4a Import element of report4a The Elements of the Report. Once we generate the report, and it becomes available, there are really three categories of information that are really relevant– not just the diagnosis, but the future care of the patient. The first is the diagnosis. What is the diagnosis? Is it really renal cell carcinoma or is it some other unusual type of renal cell cancer? I will talk more about that. Then: aspects related to cancer stage–tumor size, local infiltration. Has it metastasized or spread? Last, the other features that Dr. Kim alluded to in his talk—resection margins, grade, vascular invasions. We will talk to about these just briefly.

Path 4b Not all masses4bThe first aspect is diagnosis. The important thing to remember, and \I think everyone in the room is a little bit beyond this, but remember that at the initial phase, tumors are resected and often times it is not know if it is a RCC. Often times it isn’t even know if it is a neoplasm at all. Not all tumor masses are neoplastic or malignancies.

Path 5 Exp of non cancer tumors 5 Examples of non-tumor masses would be like cysts, a lot of cysts. A lot like this or areas where the collecting system is dilated called hydronephrosis or multiple cysts can present or look just like a RCC. They are resected as if they were RCCs. But in fact they are not—they are benign

There are other types of tumors besides kRCCs. Angiomylipomas are a very common tumor. They could be very big like this one. Here’s a kidney. Here’s a big one. They could be multiple. Here’d two. They could be small one or 2 cm like this, but they all look like fatty tumors, but not all RCCs. Different types of tumor like fibroma or oncocytoma can be very big and aggressive-looking, but in fact, they’re not malignant at all.

Path 6 ex of cancer not RCC6 There are other types of malignancies, true malignancies of the kidney which are not real carcinomas. Urothelial tumors, those that are derived from the lining of the kidney that can extend into the kidney, be derived of the kidney. These are examples of some of these here. They were resected, thinking that these are probably RCCs, but in fact they turned to be urothelial, not RCCs.

Different types of tumors like sarcoma can be derived of the kidney or around the kidney. Other types of tumors can metastasize to the kidney or near the kidney. Adrenal tumors, lymphomas—there is a whole host of malignancies which can mimic RCC.

Path 7 RCC7 What were really talking about today here obviously is renal cell carcinomas which represent probably 90% of more of all true malignancies of the kidney. These are the tumors which are derived from the renal tubular epithelian cells, those little ducts that line the epithelium of the kidney. The diagnosis of RCC really is contingent upon microscopic analysis. You can’t make the diagnosis any other way.

The pathologist needs to look at the gross, take a section, look under the microscopic, and then there’s a spectrum, a range of features that will ensure the diagnosis or put it into a diagnostic category of RCC. Sometimes is not so simple. We need special testing–the use of antibodies, immunohistochemical studies or even as Dr. Young Kim alluded to, sometimes we need to refer to some molecular analysis to put it into a diagnostic category of RCC.

Path 7a RCC Subtypes7a Once we’ve done that, the next phrase is to determine the subtype. There are many different subtypes of RCCs really based primarily on the appearance of the tumor cells and their architectural growth patterns. Sometimes they can rely on immunohistochemical, some of the molecular properties or genetic profiles that put it in the proper subtype category.

Now the subclassification of RCCs and probably this is familiar. You’re familiar with RCCs and it is not so simple. It’s an evolving, sort of complex and ever-changing categorization. In fact, the overall categorization of subtypes just changed a few months ago. We like to think about RCC and subtypes in a sort of developmental pathway.

There is a sporadic type– that which just happened to occur–which is probably the type of cancer that most people in this room happen to have. Those are our typical clear cell, chromophobe, papillary renal cell carcinomas or maybe a few of the other rare variants.

There are those which tend to be familiar; these represent 90+ percent of all RCCs. The familial patterns–again what is associated—they are pretty rare. They are associated with and in families, multiple tumors. Different family members can have these, and we will talk a little bit more about these. There is actually going to be a talk about later in the afternoon or the morning about genetic-based or familial-based RCCs.

There are those rare—really associated with treatment of other types of cancers, and there is unusual category when you have scarred or damaged kidneys. Those kidneys are at risk for developing RCC.

Let’s move through this little bit. Once we have made the diagnosis of RCC, we’ve sub categorized it. I know it seems complex, but there are really only three or four main subtypes that we really need to talk about, especially in the context of a setting like this.

Path 8 RCC Most types8 The most common subtype is the clear cell type. This represents about the vast majority of all sporadic types of renal cell carcinoma. Then there are the papillary and chromophobe renal cell carcinomas. Since these are really the usual types. The much less common type is collecting duct carcinoma which is really more like a urothelial cancer, it behaves like a urothelial cancer, it’s a more aggressive type of RCC.

These are really the main four that we need to be concerned about. They are each unique based on their gross appearance and these are all partial nephrectomies (this is complete down here). Look at their gross appearance. They are very unique under the microscope. Look at their microscopic appearance.

The clear cell is clear, the papillary, very architectural pattern of a papillary tumor. These are chromophobe. This unusual eosinophilic cytoplasm are the tumor cells. Probably doesn’t mean a lot to you, but it means a lot to us, also to some other clinicians. So they have very characteristic gross, microscopic and they are very unique biochemical—and as Dr. Kim alluded to—very specific molecular and genetic profiles as well. This is all really evolving as we speak.

And we all know—this is small graph—that these also behave differently, Some behave better than others, so it is really important that we subclassify these RCCs based on their appearance—all the appearances that we talked about.

Path 9 Potential Therap Implic9 The other thing that Dr. Kim alluded to, and I think we are going to talk about this a little later, and I won’t get into detail on this, but just to point out that the sub-classifications, the sub-categories, they respond differently to the different armamentaria that we have in terms of treatment modalities. So it’s very important for the pathologist to sub classify the type of RCC.

Path 10 typ report10 So on any standard pathology report, you are going to see the diagnosis, RCC, then the subtype, buried somewhere in the report; It will say, clear cell type, papillary type, chromophobe. That’s a very important part of the report.

 

 

 

Path 11 Imp Elements of path11 After diagnosis, the next important aspect is the cancer stage; The cancer stage is really defined by the size of the tumor and its local growth. Is it extending, is it staying confined to the kidney, outside the kidney to the local fat, is it going into any regional lymph nodes that might have been removed during surgery, or was it extending into the adrenal gland, which might have been removed as well? So we analyze each case on what we have and what we see.

This is a typical example of a partial nephrectomy specimen of clear cell carcinoma with a margin that’s out here. Here it measures about 2.1 centimeters the margin is negative. This is a very small tumor of clear cell RCC. This would stage out at T1a, pretty low stage tumor. This would have a pretty good prognosis based on that staging profile.

Path 12 Imp elements of Path 212 Now compare that with this tumor which is a complete nephrectomy specimen, shown the kidney, a lot of nephritic fat. Here’s the sinus of the kidney and here’s the tumor out here. Much bigger, about 9 centimeters and it is growing into the fat. It’s growing into the sinus fat; it is demonstrating more aggressive local growth. This would stage out—this is a microscopic showing it extending into fat. We would stage this out at T3a tumor, as it is obviously larger and more infiltrative.

Path 13 Imp Elements313 A different example would be the same thing. A RCC clear cell type; this is a full nephrectomy specimen. Here’s the kidney. Notice that the tumor is extending into the renal vein. This is another feature that we analyze and look for. We look for it grossly and microscopically and look for tumor extension into that vein, because that will upstage the tumor, overall tumor stage, and this is associated with generally adverse outcome. It is telling us this tumor is behaving more aggressively with local growth. We might see a lymph node, with metastatic clear cell RCC. Again, another aspect we would examine grossly and microscopically.

Path 15 Import elemts 515 So we take all these features, once we have analyzed the tumor and we apply the grading system created by the Joint Council on Cancer Staging, the AJCC and we apply the pathologic stage. Why? Because as Dr. Kim alluded to, we all know, that cancer staging, and it is true for any type of cancer, the higher the stage, the more aggressive that tumor will likely behave therefore the therapy needs to be tailored to their particular stage. And the report should indicate clearly dictate the tumor stage. And that’s part of the standard reporting. Any good cancer report.

Path 14 Impor Elements 414 The final cancer features I’m going to talk about we’re talking about are; resection margin, the grade, vascular invasion, tumor necrosis and this this unusual rhabdoid or sarcomatoid differentiation. These are elements which go beyond cancer staging and the diagnosis. Here’s two examples.

Path 16 impor eleme616 Let us talk about resection margins. These are indirectly related to or they indicate the local aggressiveness of a tumor, if they are growing to a margin. It’s ideal when a partial nephrectomy or a complete nephrectomy is performed, as we have here, the surgeons always try to get the whole thing out so we achieve negative margins . That is optimal. Sometimes it’s not possible, especially if we have a high stage RCC like this one which is extending into fat. Sometimes it’s impossible to get a clear margin. This might get portend some additional therapy when it comes to therapeutic– time for a therapy . With a smaller resection sometimes it’s impossible to get a negative margin or the surgeon needs to go back and take cleaner margins. That interpreted for frozen section analysis, and clear out that margin, again because optimally, we want to achieve a negative resection margin.

Path 17 Imp elements 717 The next factor is vascular invasion. When the tumor invades into those lymphatics that Dr. Kim talked about in surgery. They have a propensity for them to go to the lymph node or they can go into veins or even sometimes arteries and then they have unfortunately, the capacity to go to the lungs or bones or other sites. Those confer an adverse prognostic indicator. Those are an indicator that this tumor might behave in a more aggressive manner. So if we see it microscopically, we include it in the report. Also if there’s tumor cell degeneration and necrosis, that is usually associated aggressive growth in the tumor and we will report that, too. Sometimes that will dictate how the next round of therapy will be undertaken.

Path 18 Imp elem 818 Dr. Kim already talked about tumor grade. We apply–the pathologist applies the tumor grade. The Fuhrman grade is the one that is used for RCC, and it a grading system for 1 to 4. Really, it delineates the degree of differentiation. Grade 1s are well-differentiated tumor, grade 4 are poorly differentiated and in any type of tumor–doesn’t matter if it’s breast, color, renal cell carcinoma–generally well-differentiated tumors behave better than poorly-differentiated tumors.And we assign a grade based on our observations.

Path 19 Imp Ele of report19  Finally, sarcomatoid or rhabdoid differentiation. Most tumors will have just one type of differentiation. This is an example of RCC. The vast majority are RCCclear cell, the conventional type. But in it, there were some pockets where the tumor cells had this unusual morphology under the microscope, called sarcomatoid differentiation, or over here, with we had this rhabdoid differentiation. You can see it that it’s very different than clear cell. These, for whatever reason, are associated with tumor aggressiveness. So when we see this, we need to report it. We need to quantitate it, and we put it in the report because these mandate some additional therapy, independent of stage, because they are really associated with aggressive tumors

All these last category features that I talked about, once we have observed them, we include them in the report. Again, usually any standard RCC report will have these features included in them because they will really impact upon therapy. *See slide10

Path 20 Hereditary20 Two quick categories and I will be done here.I was say a couple of words about hereditary genetic syndromes associated with RCC. This is taken out there that long list that \I presented a few slides back. We all know that there are well-known, well-defined syndromes–genetic syndromes or familial syndromes that put you at increased risk from dying from other neoplasms, including RCC, notably Von Hippel Lindau, tuberous sclerosis, Birt-Hogg Dube, these sorts of things. The bottom line: as a pathologist, I can’t look at most of these tumors and say, “this is a clear cell carcinoma. It’s clearly Von Hippel-Lindau, tubersclerosis, or whatever.” All I can say is that it is clear cell carcinoma.

Path 21 Hereditary Genetic21 There are a few types of tumors that I can look at and say, if they have unusual morphology, like this tumor up here, or this tumor up here (references images) , they don’t comfortably fit into the typical types of RCC. Maybe it is a syndromic-type of carcinoma. Very, very rare, less than one percent that we would ever suggest to a clinician that maybe this is syndromic. What we can do is when we get samples like a renal resection like these three different cases, where there are multiple tumors. Here we have multiple tumors or multiple cysts—here we have maybe 20 or 30 different tumors in the particular kidney—or here’s a younger patient with one, two, three separate tumors. Then we can suggest that there is something odd about this, as we usually don’t see this in sporadic type tumors. Maybe it is associated with a genetic syndrome. So; multiple tumors, cysts, a young age, presentation of a renal cell carcinoma of unusual histology, we will suggest to your treatment team that maybe this is a genetic or syndromic pattern of RCC. There’s going to be more on this topic later this morning.

Path 22 Secondary Reviews22 The final topic I was asked to talk about the performance of secondary slide reviews. It’s kind of important. It’s really important when you come to an institution for definitive therapy, it’s always good to have that team—and we do this all the time—review the outside slides to be sure that you have an expert team who works with your treating physicians. We work as a team through tumor board reviews and discussions, and almost every discussions–.                                                                                                                                                       Almost every single individual case, to ensure that we have the correct diagnosis. We have the critical elements included in that report. The specific special testings have been performed, and we have accurate diagnosis and staging and things like that. What you need to do is provide, when you come here, is a copy of the reports, a set of the glass slides, sometimes we call them the recuts. That is all we need to provide an incoming secondary review.

The other scenario when you go off, you might need to off somewhere else for some additional testing for some additional therapy. In that situation, you might need to take, or you should take a set of slides with you to that institution because they will probably want to the same thing and review to ensure that we are all talking about the same disease process.

Remember that your slides or blocks, when you are treated here, or whatever institution, generally those tissue blocks are stored in an incredible huge file, either in the basement of the hospital right below us here or in a warehouse as we have done down in Torrance. T. They are basically saved forever. So when you need to go somewhere in five or ten or fifteen or twenty years, God forbid that there is a recurrence, and you need to get some additional testing, we can pull those blocks out from Torrance (CA) and create a second set of recuts, or a third or fourth set. We can send it off wherever it needs to go for some additional testing or evaluation.

Path 23 Authorizat23 What you need to do is fill out this authorization form here at Cedars if you are being treated here at Cedars. All you need to do is check off “Get a copy of the pathology report” and please provide a set or recut. It’ll take a few days, three days. We’ll get that for you, send it where it needs to go, or we can give it to you directly and you can just carry it with you to that next institution or wherever you need to go.”

With that Dr. Luthringer thanks the KCA, the audience and Dr. Figlin for the chance to speak.  And with that, I agree remind you to get a copy of your own pathology report, and know where your slides are stored. If there is any questions as to your own pathology, if the tumor seems to be unusual, or of an especially high grade, do yourself and your family a big favor, and discuss whether a review of your slides is in order!

With this rare disease, and the complexity of doing the kind of analysis you see here, do not be afraid to get that second opinion.  Go back and see so that pathology may affect the treatment options given–very important!

 

 

 

 

 

 

 

 

 

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Genetic Sequencing for Dummies and Me–not necessarily in that order.

The following is the transcription of the above YouTube video, explaining how DNA sequencing of tumor cells can guide treatment. Thanks to the University of North Carolina for posting this. A terrific explanation. (And it’s OK to view it a few times!)

“You were composed of cells–lots and lots of cells. Each of your cells contains DNA which is its instruction manual. If you are exposed to lots of things that cause cancer, so are your cells. If you lay in the sun, your skin cells get burned. If you smoke cigarettes, your lung cells get their nicotine fix. Exposure of cells to carcinogens can damage their DNA. Sometimes when cells divide, DNA can be damaged–just by bad luck.

Damage to DNA is usually repaired, but sometimes it is not. When damaged DNA goes unrepaired, the cells receive bad instructions, and can turn fromhealthy cell to cancer cells. Cancer cells divide too fast and crowd out other cells and grow with they are not supposed to grow. When cancer cells cling together, they form a tumor that might be found by a doctor or a patient.

Today most patients are treated based on what a piece of tumor looks like when viewed under the microscope. This is how oncologists have done it for 50 years. While this approach is better than nothing, it doesn’t work that well. Even if doctors agree what type of cancer a patient has, it does not always mean it is clear what is the best therapy to treat that patient’s cancer.

Recently, it has become clear that the cells instruction manual the DNA determines how s the cancer will to behave and in particular, it determines if it will grow quickly or slowly, if it will respond to one kind of therapy or another, and if it will be cured or come back.

Given that the cancer’s DNA is so important in determining how it will behave, doctors and scientists at the UNC Lineberger Comprehensive Cancer Center have determined to treat patients based on their and their tumor’s DNA. This approach relies upon new DNA sequencing technology, called massively parallel sequencing or next generation sequencing. So we call the Lineberger effort “UNseq”.

Here’s how it works. When a patient with cancer comes to UNC and agrees to participate in our study. Some normal DNA is taken from the patient, usually their blood and some DNA is collected from the tumor. From the tumor DNA and normal DNA are broken into smaller pieces and the importance pieces of the DNA are captured. This capturing is important so we don’t have to sequence all the DNA of a patient, just the DNA which is important in cancer. It is like going into a gigantic library and choosing the one book on cancer ignoring all the other books on eye color or heart size or height.

The captured DNA from the tumor and the normal tissue are then processed using next generation sequencing. After sequencing, we have two gigantic books of DNA sequence. One is the tumor’s DNA and the other is the patient’s normal DNA. Although the captured DNA is much smaller than the patient’s entire genetic sequence, each book is still several million letters long.

The tumor DNA book and the normal DNA book are then compared letter by letter. In most places the books are the same, but in a few places the letters are different. These differences represent mutations in the DNA, that resulted from DNA damage. Finding all the mutations involves a lot of math, but eventually, UNseq identifies all the mutations that are present in the cancer cell and not in the normal DNA .

Just having a list of the mutations is not the end, however. Only a small number of the mutations change what the cancer cells do. Most mutations are harmless. Whether a mutation is good or bad, largely depends on what gene it affects and what part of the gene it affects.

Once the list of mutations has been identified, a team of doctors sits down together and review the mutations at the molecular pathology tumor board or the MTB. Each mutation is reviewed. Some mutations are clearly innocent. Some mutations are clearly bad. For some mutations, it is unclear of their importance and the MPB not always certain what to do with these.

This is all done by doctors were not directly involved in the patient’s care, s so that similar decisions are made about the same cancer.

Once the bad mutations are found, they are confirmed by another clinically approved test. Information about the mutations that are confirmed is given to the patient and their treating doctors.

With this knowledge, the patient’s care can be more tailored or focused. The doctor may decide the patient to try a different therapy. The doctor may decide that the patient has a better or worse chance of recovery. Sometimes the DNA looks makes the cancer look like a different cancer than was found under the microscope. New treatment plans based on DNA sequencing are called targeted therapy.

Importantly, UNseq does not put patients at risk. If there is a good therapy for their cancer, they get that therapy. UNseq only changes care for patients who do not have any good options left. Unfortunately, that is a common problem for cancer patients.

Some day soon, we believe all cancer treatment will be targeted, that is based on what the tumor DNA, rather than what the tumor looks like under the microscope.

Doctors at UNC recognize that technology moves at a rapid pace, but applying new technology to patients can be slow for patients with advanced cancer. Having successfully implemented UNseq, UNC physicians are building upon the approach to develop a range of advanced tests for patient care. We believe that these new approaches will help patients with cancer live longer and better lives.”

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