Predictive/Therapeutic Markers

by Richard Mitchell, MD, PhD

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    00:01 We can also, based on the tricks that we have in our pathology bag, be able to say, what is likely to be a way to treat a particular tumor.

    00:11 So shown on the left upper corner, is an H&E of a breast cancer.

    00:15 That's fine, it's very straightforward, there's a significant amount of desmoplasia, it's a breast cancer, not too much inflammatory cells.

    00:23 Will this tumor respond to anti-estrogenic therapy? Or anti-progesterone therapy? Or do I have to give a monoclonal antibody against a cell surface, activating molecule receptor HER2/neu? Well, I do my immune histochemistry and in some of the tumors, you get a very prominent estrogen receptor signal, that's the brown dots, estrogen receptor is within the nucleus, this tumor with a positive estrogen receptor appearance, will respond very well to estrogen antagonists.

    00:56 Similarly, I can do a progesterone receptor study and see that, wow that tumor, is going to respond to progesterone receptor antagonist or progesterone antagonist.

    01:07 And then finally, this last tumor from a different patient, will respond to monoclonal antibodies against HER2/neu, a cell surface activating molecule.

    01:20 And so, even though all three of those would have looked the same, on H&E, I can specifically tell the surgeon now or the oncologist, treat this patient with X or Y or Z.

    01:35 Important predictive therapeutic markers as well, increasingly because we have immune checkpoint therapies, that we can apply to tumors.

    01:44 Being able to predict whether a tumor will respond to those is is very important.

    01:48 So, what do I mean by that? So, in this particular case, we are looking for a PD-L1, that stands for, “Program Death Ligand 1” and some tumors will express it, some tumors will not.

    02:02 If tumors express PD-L1, that acts on lymphocytes through the PD1 receptor, as shown there in that green circle on the left-hand side and will tell the lymphocyte, “Stand down, do not respond,” so, it's a very clever way that tumor cells have, of turning off the immune response to them.

    02:22 Well, if I know that a tumor is making a lot of PD-L1, such as we see here, I can add a blocking antibody, I can add an antibody against PD-1 or PD-L1, that will block that interaction and now the T-cell won't stand down, it will continue to recognize and aggressively pursue that cancer cell.

    02:42 So, anti-PD-1, monoclonal antibodies include, pembrolizumab, nivolumab, there's actually a lot of, “Mabs.” Mabs just stands for monoclonal antibodies.

    02:52 But by doing this immunostaining, I can tell the oncologist, this patient is very likely to respond to, immune checkpoint inhibitor monoclonal antibody therapy and may even save them, having to go through chemotherapy.

    03:10 So, we have a variety of ways that we can do the classification of tumors and these involve the cytogenetics, the fluorescence in situ hybridization or FISH or PCR-based technologies.

    03:24 These are particularly helpful in classifying leukaemia’s and lymphomas, that may look very, very, very similar.

    03:31 Sarcomas, which sometimes are very poorly differentiated and we don't know where they came from and renal tumors.

    03:39 These technologies as well, cytogenetics FISH, PCR-based technologies are also helpful in terms of quantitating tumor burden, how much tumor is there left, how much tumor was there to begin with and then once we remove it or treat it, is there any tumor left or is it coming back.

    03:59 We can also use all of these technologies, cytogenetics FISH, PCR-based etc., to help us with prognosis and prediction in a variety of tumors, not just the ones listed, but those leukaemia, gastrointestinal stromal tumors, long colon melanoma, rely very heavily on these ancillary technologies, to provide good prognostic prediction.

    04:25 And this is just showing you one of the ways, that we can monitor residual disease, so, this is a patient who has chronic myelogenous leukaemia, this is driven, by a single driver mutation, which is a fusion, a translocation of the BCR-gene with the ABL gene.

    04:41 The BCR provides dimerization, the ABL gene provides kinase activity, so it's one of the major drivers for CML.

    04:50 You can see this patient comes in, with 7% positivity of the of the total DNA, that we're looking at, containing this BCR able fusion transcript.

    05:02 So, we have a moderate amount of disease, starting about April, on the timeline, that patient gets treated and we see the amount of the BCR-able fusion transcript, that we're measuring by polymerase chain reaction, the PCR.

    05:16 We see that curve trending down and there is very minimal residual disease and actually, getting the levels where it's barely detectable.

    05:26 And that patient can be maintained like that, we can follow the BCR able in the blood because this is a leukaemia, we can find that fusion transcript and provided it stays low, we won't do anything new, if it starts trending back up, we may amplify therapy.

    05:45 So, finally as we come around to the very end just a cautionary note, there are tumors that look malignant, but they are not.

    05:52 So, the title is not all that glitters is cancer.

    05:57 So, here uterus cross-section, is it benign or malignant? Well, on this one, I can look at and say that tumor, which is primarily in the upper left-hand corner, that white kind of lobular tumor, but it's is kind of solid, but then there's areas of hemorrhage adjacent to it, and big areas of necrosis.

    06:19 So, grossly it's got all the features that we expect to see in a malignant tumor and that is clearly malignant. But take a look at this one, as a final test of all your pathology knowledge.

    06:33 Benign are malignant? It's again it's a uterus cross-section, the tissue that's off on the right, is actually the uterine wall and we've basically cut open the uterus, bivalved it and just inlaid it open.

    06:47 You can see that white tumor, that is present on the left-hand side, turns out that's a benign leiomyoma.

    06:55 But it also turns out that when we took out this uterus for a benign leiomyoma, there's one other thing and I don't know whether you notice that, it's a benign tumor, uniform, not necrotic not hemorrhagic.

    07:08 But in the middle of that there was also, this new growth and the woman who had had this uterus resected was unaware of the pregnancy, but would not have wanted to retain that.

    07:22 So, not all that looks malignant is so and that's why we do all the special studies.

    07:30 Take home points from this very last talk, when we about cancer, is that, you understand the role of a surgical pathologist in patient care.

    07:38 We are not just the guys behind the curtain, we actually have a very important role in telling pathologists or telling oncologists, telling surgeons, what needs to be done.

    07:54 There are many, many techniques that are used to establish a diagnosis and inform prognosis and therapeutic choices and we have a huge bag of tricks, that are only getting better and better.

    08:06 And with that we'll close.

    About the Lecture

    The lecture Predictive/Therapeutic Markers by Richard Mitchell, MD, PhD is from the course Surgical Pathology of Tumors.

    Included Quiz Questions

    1. Cancer that expresses estrogen receptors
    2. Cancer that expresses progesterone receptors
    3. Cancer that expresses HER2/neu receptors
    4. Cancer that produces estrogen
    5. Cancer that expresses PD-1 receptors
    1. This interaction decreases the host immune response against the cancer.
    2. The tumor undergoes programmed death through apoptosis.
    3. The T lymphocytes are able to recognize the tumor cells as non-foreign.
    4. There is no interaction between PD-1/ PD-L1.
    5. The tumor differentiates into a less aggressive tumor.
    1. They are monoclonal antibodies.
    2. They are estrogen receptor antagonists.
    3. They are progesterone receptor antagonists.
    4. They decrease the immune response against cancer.
    5. They interact with HER2/neu receptors.
    1. To classify cancer, detect minimal residual disease, and determine prognosis
    2. Mostly to classify a tumor
    3. Usually to detect minimal residual disease
    4. To determine the prognosis
    5. To determine the stage of a tumor
    1. Tumor relapse
    2. Tumor regression
    3. Good response to treatment
    4. Healing of the scar
    5. No prognostic value

    Author of lecture Predictive/Therapeutic Markers

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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