A Woman's Journey Palm Beach 2017 Breakfast Keynote: Revolutionizing Breast Cancer Outcomes - YouTube
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00:00:05 00:00:08 Thank you Lisa, for that lovely introduction.
00:00:09 00:00:11 I'm truly excited to be here.
00:00:11 00:00:12 How about all of you?
00:00:12 00:00:18 >> [APPLAUSE] >> So today I'm going to talk to
00:00:18 00:00:22 you about some of the advancements in breast cancer research.
00:00:22 00:00:26 And we'll also touch upon other cancers as I go along.
00:00:27 00:00:32 So each year, breast cancer is diagnosed in 1.6 million
00:00:32 00:00:38 women throughout the world and 600,000 women die of the disease.
00:00:38 00:00:41 That means that every two minutes
00:00:41 00:00:45 a woman has died somewhere in the world of breast cancer.
00:00:45 00:00:50 Despite these grim statistics today more than
00:00:50 00:00:55 ever since 1970 when President Nixon launched
00:00:55 00:01:00 the war on cancer we're filled with hope that we're slowly but
00:01:00 00:01:05 surely overcoming this disease, one little step at a time.
00:01:07 00:01:13 We see and read success stories on TV, in print and
00:01:13 00:01:20 also news bites spread rapidly regarding the remarkable progress
00:01:20 00:01:24 that has been made in cancer research in the last 20 years.
00:01:24 00:01:27 Looking at the big picture, and
00:01:27 00:01:31 through my career span, I really do feel this is true.
00:01:33 00:01:36 Indeed, according to a study
00:01:36 00:01:40 published recently in the Journal of the American Medical Association,
00:01:41 00:01:46 American survive cancer today much better than they did 20 years ago.
00:01:48 00:01:54 In this study a million one million patience with common cancers study.
00:01:54 00:01:58 And the author is found that the risk of dying from a cancer
00:01:58 00:02:01 was considerably reduce.
00:02:01 00:02:05 So that a person with colon cancer, for instance,
00:02:05 00:02:11 has a 43% better chance of survival than they did 20 years ago.
00:02:13 00:02:18 So much of our success has come from getting a deeper understanding
00:02:18 00:02:24 of the workings of the missionary inside these cancer cells so that
00:02:24 00:02:29 we are able to develop drugs against tumors specific vulnerabilities.
00:02:30 00:02:33 Missionary inside the cells,
00:02:33 00:02:38 tumors specific vulnerabilities what do all these words mean?
00:02:39 00:02:43 Yes, we all understand it in these broad strokes
00:02:43 00:02:45 as to what those words mean.
00:02:45 00:02:50 But advances are made every single day and in so many different areas.
00:02:51 00:02:55 And making sense of all of this printed matter and
00:02:55 00:02:57 spoken materials is quite difficult.
00:02:58 00:03:05 So today, I'm here to try to convey the information in simple terms so
00:03:05 00:03:09 that what it means to us, to you and me.
00:03:11 00:03:15 And to provide a bird's eye view of the benefits and
00:03:15 00:03:19 the down sides of some of these findings.
00:03:20 00:03:22 These breakthrough drugs and
00:03:22 00:03:25 amazing technologies that have hit the news lately.
00:03:26 00:03:29 So I've divided my talk into four parts.
00:03:30 00:03:35 The first part is regarding drugs against breast cancer,
00:03:35 00:03:36 both old and young.
00:03:37 00:03:40 Each new drug is termed as a breakthrough by the press.
00:03:42 00:03:44 Which of this is a real game changer?
00:03:45 00:03:46 How do they act?
00:03:48 00:03:51 In the second part of my talk, I will deal with the knowledge
00:03:51 00:03:55 gained from sequencing the whole tumor genome.
00:03:55 00:03:58 And other types of deep tumor gene analysis.
00:03:59 00:04:03 Headlines say that gene testing of cancer tissue
00:04:03 00:04:06 provides information of specific mutations, or
00:04:06 00:04:10 gene abnormalities in our own particular tumor.
00:04:11 00:04:15 And this information will allow us to use magic bullets,
00:04:15 00:04:18 personalized medicine to eradicate the tumor.
00:04:20 00:04:22 How much of this lofty goal have to be achieved?
00:04:23 00:04:28 Also the same gene technologies have been used to develop
00:04:28 00:04:30 early detection methods.
00:04:31 00:04:36 We know that if detected early many patients will get cured and
00:04:36 00:04:40 effective treatment is able to achieve long term improvements and
00:04:40 00:04:44 survival, even up to 30 to 40 years.
00:04:44 00:04:47 What are these promising technologies?
00:04:47 00:04:48 How far have they come?
00:04:50 00:04:55 The third part of my talk will address the power of immunotherapy
00:04:55 00:04:57 for treatment of cancer.
00:04:57 00:05:00 Right now, there is a lot of excitement
00:05:00 00:05:04 about immunotherapy among patients and doctors alike.
00:05:04 00:05:09 The idea of harnessing body's own immune system
00:05:09 00:05:15 to fight against the cancer which is a foreign thing growing in the body
00:05:15 00:05:20 is so instinctive and so obvious.
00:05:20 00:05:23 So why did it take so long to reach the clinic?
00:05:23 00:05:25 And there are we there today with immunotherapy.
00:05:27 00:05:31 And in the last and forth part of my talk I will devote my attention, and
00:05:31 00:05:36 hopefully yours to the importance of prevention,
00:05:36 00:05:37 a topic that's dear to my heart.
00:05:38 00:05:44 However much we fight it, cancer comes back with new faces,
00:05:44 00:05:45 just like a hydra.
00:05:45 00:05:49 You cut off one head, and another head grows in its place.
00:05:50 00:05:54 We have successfully eradicated terrible human diseases
00:05:54 00:05:58 like smallpox, diphtheria, typhoid, cholera and
00:05:58 00:06:00 typhus from the face of the Earth.
00:06:02 00:06:06 Can we take equally strong steps to prevent breast cancer so
00:06:06 00:06:09 that our future generations will remain cancer free?
00:06:11 00:06:14 Also as we go on, I will touch upon some of the findings from my
00:06:14 00:06:19 own laboratory through the work of bright young people
00:06:19 00:06:23 who have trained with me and gone on to different parts of the world
00:06:23 00:06:25 to start up their own laboratories.
00:06:26 00:06:29 So let's start with the old and
00:06:29 00:06:31 new targeted drugs against breast cancer.
00:06:33 00:06:38 As it happens, to illustrate the concept of targeted therapy,
00:06:38 00:06:40 breast cancer is an excellent example.
00:06:42 00:06:45 Women with breast cancer were the first to benefit from
00:06:45 00:06:47 target-based therapy.
00:06:49 00:06:52 I have to explain to you that most of the research we do
00:06:52 00:06:55 is very much like solving a murder mystery.
00:06:56 00:07:00 We build evidence bit by bit, and then and
00:07:00 00:07:06 this evidence will be inside of the tumor cell and in its vicinity.
00:07:06 00:07:10 And then we put this story together to find out
00:07:10 00:07:13 what might have gone wrong to make this into a cancer cell.
00:07:14 00:07:18 Then other researchers take it one step further and
00:07:18 00:07:21 develop drugs to defuse the problem.
00:07:21 00:07:26 And the very problem that is allowing this cancer cell to grow
00:07:26 00:07:28 in an unabated manner.
00:07:29 00:07:33 Let me share an example, in the late 1960s Dr.
00:07:33 00:07:37 Charles Huggins who later got a Nobel prize for his work.
00:07:37 00:07:39 He was a physician chemistry in Chicago and
00:07:39 00:07:43 he was searching for which hormones breast cancers and
00:07:43 00:07:47 prostate cancers may depend on for their growth.
00:07:49 00:07:54 He found that if he removed the ovaries of rats that had breast
00:07:54 00:07:59 tumors, the tumors melted away And so also, if you remove
00:07:59 00:08:05 the testes of rats that had prostate cancers, those tumors melted away.
00:08:05 00:08:07 So what did this tell him?
00:08:07 00:08:11 It said that something was being produced by the ovaries
00:08:11 00:08:14 that was able to help the cancer cells to grow.
00:08:14 00:08:19 And so also, something very critical for the growth of prostate cancer
00:08:19 00:08:25 was being expressed, was being sent out into the body by the testes,
00:08:25 00:08:27 which was helping the prostate cancers to grow.
00:08:28 00:08:33 So he concluded that the breast tumor
00:08:33 00:08:38 really needed the ovarian hormones for growth and the prostate cancer,
00:08:38 00:08:42 similarly, was relying on the testosterone produced by the testes.
00:08:43 00:08:48 So Dr. Beatson, then, a breast surgeon from the United Kingdom
00:08:48 00:08:52 moved ahead with clinical trials to test this concept.
00:08:52 00:08:56 He removed ovaries of women with breast cancer, and voila.
00:08:56 00:09:00 The breast tumors of most of the women just disappeared.
00:09:02 00:09:04 What was happening here?
00:09:04 00:09:10 Well, it turns out that the ovaries produce a hormone call estrogen.
00:09:10 00:09:11 And let us now call it the key.
00:09:13 00:09:17 And removing the ovaries somehow cut off the gas
00:09:17 00:09:20 to the engine of the cancer cell, and the cancer cell died.
00:09:22 00:09:25 So if estrogen is the key, where is the lock?
00:09:25 00:09:30 And what is this lock that's present on the cancer cells?
00:09:30 00:09:34 More research on the bench, and by 1980s,
00:09:34 00:09:38 almost ten years later, we had identified the lock.
00:09:38 00:09:43 It was the estrogen receptor, and the receptor was expressed in and
00:09:43 00:09:48 out of the cancer cell, and when the key joined the lock, the cell got
00:09:48 00:09:53 the trigger to start growing and multiplying over and over again.
00:09:55 00:09:58 So how would you stop that cancer from growing?
00:09:58 00:09:59 You will block the lock.
00:09:59 00:10:03 You will put in a key that is somehow not shaped just
00:10:03 00:10:04 the right way.
00:10:04 00:10:07 And blocking this perfect joining of the lock and
00:10:07 00:10:13 key is the underlying principle of most targeted, anticancer therapy.
00:10:13 00:10:17 So when you hear the words anticancer, targeted anticancer
00:10:17 00:10:23 therapy, it means that, somehow, we have produced a misshapen key
00:10:23 00:10:27 that is able to really block the workings of this lock.
00:10:29 00:10:33 Well, in the case of breast cancer, this drug was tamoxifen.
00:10:34 00:10:36 And what does the drug do?
00:10:36 00:10:40 The drug tamoxifen binds to the Pushing away the estrogen,
00:10:40 00:10:43 and blocks its action on the breast.
00:10:43 00:10:47 And this leads to starvation of the cells and death of the cancer cells.
00:10:48 00:10:52 This drug has turned out to be a workhorse in the treatment
00:10:52 00:10:55 of ER-positive breast cancer.
00:10:55 00:11:00 As time went by, additional anti-ER therapy directed against
00:11:00 00:11:05 the enzyme that produces estrogen, the key, were developed.
00:11:05 00:11:08 These drugs, called aromatase inhibitors,
00:11:08 00:11:13 which many of you may have heard about such as anastrozole or
00:11:13 00:11:18 letrazole, have been very important additions to this anti-ER therapy,
00:11:18 00:11:22 particularly to treat post-menopausal women.
00:11:23 00:11:27 So within 20 years breast cancer became
00:11:27 00:11:31 from an untreatable disease to a treatable disease.
00:11:33 00:11:37 Another breakthrough for breast cancer came in the late 1980s when
00:11:37 00:11:44 Dr. Dennis Slamon from UCLA discovered the HER2/neu receptor,
00:11:44 00:11:46 again, in 30% of breast cancers.
00:11:48 00:11:52 And soon, with the introduction of monoclonal antibody therapy,
00:11:52 00:11:55 Herceptin or trastuzumab by Genentech,
00:11:57 00:12:02 to attack its action, the vicious HER2-positive disease was conquered.
00:12:04 00:12:07 A number of new drugs, pertuzumab, T-DM1,
00:12:07 00:12:13 etc., also acting on the HER2 receptor, are improving disease
00:12:13 00:12:17 outcome in women with previously untreatable breast cancers.
00:12:19 00:12:25 Now, a problem that comes hand in hand with a good drug is the ability
00:12:25 00:12:29 of the cancer cells to double up resistance to that therapy.
00:12:29 00:12:33 The drug acts for a few years and then suddenly tumor comes back.
00:12:34 00:12:38 And this drug resistance is a huge problem in every disease,
00:12:38 00:12:39 including breast cancer.
00:12:41 00:12:46 These tumors come back in areas of the body distant from the breast
00:12:46 00:12:49 as difficult to treat metastases.
00:12:49 00:12:53 Brain metastases are seen in as high as one-third of
00:12:53 00:12:57 the patients who have been treated with trastuzumab.
00:12:57 00:12:58 Why is that so?
00:12:58 00:13:02 Because these big molecules, the monoclonal antibodies,
00:13:02 00:13:05 are unable to cross the blood-brain barrier.
00:13:05 00:13:09 And, therefore, if the metastasis is sitting in the brain and
00:13:09 00:13:12 growing, this drug is completely useless for
00:13:12 00:13:16 that, to be able to treat those metastases.
00:13:16 00:13:21 So clinical trials are now testing a small molecule called lapatinib.
00:13:21 00:13:25 This drug also acts against the HER2.
00:13:25 00:13:29 But because it is small, it's able to cross through
00:13:29 00:13:34 the blood-brain barrier and is able to kill the brain metastasis.
00:13:35 00:13:39 Also new in the field of breast cancer research
00:13:39 00:13:41 are inhibitors of the cell division cycle.
00:13:43 00:13:45 Drugs such as palbociclib
00:13:45 00:13:49 appear to double the number of months that women live
00:13:49 00:13:52 after treatment with this drug rather than with conventional drugs.
00:13:54 00:13:58 So this drug has also received accelerated FDA approval, another
00:13:58 00:14:03 important hurdle for the drugs to go through before patients can use it.
00:14:04 00:14:08 So I've spoken to you about ER-positive and
00:14:08 00:14:10 HER2-positive cancers.
00:14:10 00:14:15 But what about those tumors that don't have the estrogen receptor or
00:14:15 00:14:18 the progesterone receptor or the HER2 receptors?
00:14:18 00:14:20 How do we treat these tumors?
00:14:20 00:14:23 These tumors are called triple negative breast cancer.
00:14:24 00:14:25 And they remain a sticky,
00:14:25 00:14:29 challenging problem, which are particularly difficult to treat,
00:14:29 00:14:34 because beyond chemotherapy, they have nothing in their armamentarium.
00:14:34 00:14:37 If chemotherapy fails, that's the end of the line.
00:14:37 00:14:41 So a lot of laboratories are spending a lot of time
00:14:41 00:14:45 trying to find new therapies for triple negative breast cancer,
00:14:45 00:14:47 which also seems to affect younger women, particularly.
00:14:49 00:14:52 Many laboratories are trying to study mutations
00:14:52 00:14:55 in the genes of triple negative breast cancers so
00:14:55 00:15:00 that they can develop new gene-targeted therapies.
00:15:00 00:15:04 Our laboratory decided to tackle TNBCs in a slightly different way.
00:15:04 00:15:09 We know the cells also try to shut down the expression
00:15:09 00:15:14 of genes by a mechanism called epigenetics.
00:15:14 00:15:17 Here, the sequence of the gene doesn't change.
00:15:17 00:15:22 But just by adding certain chemicals onto the nucleotide bases,
00:15:22 00:15:25 the gene can be completely silenced.
00:15:25 00:15:30 No change in gene mutations, no change in the gene sequence.
00:15:30 00:15:35 But putting these chemicals on and taking them off, the cell is able to
00:15:35 00:15:40 completely shut down some of the critical tumor suppressor genes,
00:15:40 00:15:44 and also is able to activate some of those genes that'll help it to grow.
00:15:46 00:15:51 So in our laboratory, we've taken full advantage of these
00:15:51 00:15:56 epigenetic changes to improve treatment for TNBC and, second,
00:15:56 00:15:59 in breast cancer for also early detection.
00:15:59 00:16:02 And this is a topic I'll touch upon a little later.
00:16:02 00:16:06 So our laboratory, working with these triple negative breast cancer
00:16:06 00:16:10 cells, recently published a paper in cancer research.
00:16:10 00:16:12 And here we were taking a novel approach.
00:16:12 00:16:17 We decided that instead of hitting one target at a time and
00:16:17 00:16:22 in sequence, why not hit three targets in the triple negative
00:16:22 00:16:27 breast cancer cells, three areas that it's depending on for growth?
00:16:27 00:16:32 So here we combined an epigenetic therapy called entinostat.
00:16:32 00:16:36 We put in a retinoic acid, which is a differentiation agent.
00:16:36 00:16:40 And then we put doxorubicin, the workhorse of TNBC,
00:16:40 00:16:43 which is a DNA damaging agent, and this kills cells.
00:16:43 00:16:48 We found this combination worked beautifully to cure mice
00:16:48 00:16:50 of their tumors.
00:16:50 00:16:53 These mice have human tumors growing in them.
00:16:53 00:16:58 And then, even further, we took metastatic cells from patients
00:16:58 00:17:03 in Johns Hopkins and added this triple treatment to them.
00:17:03 00:17:06 And we found that these cells responded extremely well to
00:17:06 00:17:11 the triple treatment compared to any one of them by themselves or
00:17:11 00:17:13 even other combinations.
00:17:13 00:17:15 Two double combinations of each of them.
00:17:15 00:17:18 So we believe that there's a lot of potential here for
00:17:18 00:17:23 being able to try to see whether this will work in clinical trials.
00:17:25 00:17:27 Next, we come to the second topic of the day.
00:17:27 00:17:32 And that is, how gene testing is helping us make advances in
00:17:32 00:17:36 both personalizing medicine and development of tests for
00:17:36 00:17:38 early detection of cancer.
00:17:39 00:17:44 The promise of personalized medicine is that each person could be given
00:17:44 00:17:50 drugs that hit the gene abnormality present in your own tumor.
00:17:50 00:17:54 So we'll sequence the tumor, find out what is the gene abnormality in
00:17:54 00:17:58 your tumor, and we'll be able to give targeted drugs
00:17:58 00:18:00 hitting that particular Achilles heel.
00:18:02 00:18:06 And so this tailoring of the therapy
00:18:06 00:18:10 according to your abnormalities is really very exciting.
00:18:10 00:18:15 And so this has led to a flurry of gene testing of all cancers.
00:18:15 00:18:17 And why are we doing it?
00:18:17 00:18:19 We are doing it to achieve two things.
00:18:19 00:18:24 We are cataloging changes in different types of cancer
00:18:24 00:18:29 to see if some common abnormalities, mutations, are observed.
00:18:29 00:18:33 And, second, to see if these mutations in the primary tumor
00:18:33 00:18:38 change over time when the tumor metastasizes to different places.
00:18:38 00:18:40 So based upon the primary tumor,
00:18:40 00:18:43 you may be giving the patient a particular treatment.
00:18:43 00:18:47 But actually the metastasis may have changed completely.
00:18:47 00:18:49 What was ER-positive may have become ER-negative.
00:18:49 00:18:53 What was HER2-positive may have become negative, and so
00:18:53 00:18:54 also the reverse.
00:18:54 00:18:57 I'm just giving you two common examples, but
00:18:57 00:19:00 there are hundreds of genes that are mutated.
00:19:00 00:19:04 And these mutations, some of them, have targeted therapy.
00:19:04 00:19:07 So if the metastasis has a different gene mutation, and
00:19:07 00:19:10 there is a target, there is a drug
00:19:10 00:19:14 that can treat this particular mutation, usually used for leukemia.
00:19:14 00:19:15 But, good heavens,
00:19:15 00:19:19 can we try it against this tumor because it has the same mutation?
00:19:20 00:19:22 This was our dream, but
00:19:22 00:19:27 this dream has not been realized in the short-term.
00:19:27 00:19:33 Very rarely do we have drugs needed to treat these unusual mutations.
00:19:33 00:19:36 The pharmaceutical industry just cannot keep pace
00:19:36 00:19:40 with our new discoveries of new mutations.
00:19:40 00:19:44 In certain cases, even if the drug is available, just suppose you have
00:19:44 00:19:48 an eGFR mutation, and we do have drugs to treat it, sometimes
00:19:48 00:19:53 our tumor just does not behave the way we wanted it to behave.
00:19:53 00:19:57 Those tumors may not respond to the therapy at all.
00:19:57 00:20:01 This is contrary to our expectation, but it does happen.
00:20:01 00:20:05 So I think it'll be a while before we do precision medicine.
00:20:05 00:20:08 With precision and confidence.
00:20:08 00:20:13 But, in the meantime, we have to keep gathering data,
00:20:13 00:20:17 so that we are able to hone our tools, and do a better job.
00:20:19 00:20:23 Now, researchers have known for some time that tumors have a different
00:20:23 00:20:26 gene expression profile, compared to the normal.
00:20:26 00:20:28 So, I talked about mutations, now,
00:20:28 00:20:32 I'm talking about what does the cell express in terms of its mRNA of
00:20:32 00:20:35 proteins that is different from normals.
00:20:36 00:20:39 So, this gene expression profiling of this tumor
00:20:39 00:20:44 can help the oncologist to make important treatment decisions.
00:20:44 00:20:47 For example, to determine whether a patient's cancer
00:20:47 00:20:50 will respond to chemotherapy or not.
00:20:50 00:20:54 In the olden days, we just looked at several parameters and
00:20:54 00:20:57 decided, yes, I think you should go on chemotherapy,
00:20:57 00:21:02 because you will do well later on, even though you had early cancer.
00:21:02 00:21:06 So, it was quite dependent on some parameters and
00:21:06 00:21:08 our oncologist's decision.
00:21:08 00:21:14 But now, using a test called the Oncotype DX test
00:21:14 00:21:18 which analyzes 21 genes in the tumor to determine whether or
00:21:18 00:21:23 not your cancer will respond to chemotherapy.
00:21:23 00:21:26 So, a new study described in the New England Journal of Medicine.
00:21:26 00:21:31 Confirmed that the Oncotype DX test was able to predict
00:21:31 00:21:35 which treatments would be most effective in early stage.
00:21:35 00:21:36 Just surgery alone?
00:21:36 00:21:39 Or does this person need chemotherapy?
00:21:39 00:21:44 It's saving these people who are given unnecessary chemotherapy
00:21:44 00:21:47 from all the toxic effects of chemotherapy.
00:21:47 00:21:49 If chemotherapy was not going to help,
00:21:49 00:21:52 why give that patient chemotherapy at all?
00:21:53 00:21:57 Clifford Hudis, the author of this study noted, that this protocol of
00:21:57 00:22:03 using Oncotype DX to make decisions spared 1,626 women
00:22:03 00:22:09 in his own study from receiving unnecessary chemotherapy.
00:22:11 00:22:15 So, these very same mutations and
00:22:15 00:22:18 changes in gene expression in the tumor as you can imagine,
00:22:20 00:22:25 could also serve as red flags for early detection of tumor cells.
00:22:25 00:22:29 So, I'm going to know talk to you, about how we can use these mutations
00:22:29 00:22:33 and these abnormalities to detect tumor cells, not only
00:22:33 00:22:37 in your breast tissue but also floating around in the circulation.
00:22:39 00:22:43 So, the use of the circulating tumor DNA may prove quite
00:22:45 00:22:47 beneficial for breast cancer patients
00:22:47 00:22:51 in the monitoring of treatment in the metastatic setting.
00:22:51 00:22:55 For detection of cancer, for early detection of cancer using these
00:22:55 00:22:59 mutations or abnormalities we have not come very far.
00:22:59 00:23:03 We have yet work to do, we are trying to get there.
00:23:03 00:23:07 But, for monitoring of disease using these mutations,
00:23:07 00:23:10 I think we are getting almost ready to use these tests.
00:23:12 00:23:15 So, the current methods what are the current methods and
00:23:15 00:23:18 why should we be looking for a new test?
00:23:18 00:23:22 So, the current methods use CT-PET imaging.
00:23:22 00:23:27 But, it's relatively ineffective tool for early disease evaluation.
00:23:27 00:23:31 You have to wait eight to 12 weeks after you start the treatment
00:23:31 00:23:34 before the CT-PET will give you any reliable results,
00:23:34 00:23:38 whether the tumor is shrinking or increasing in size.
00:23:38 00:23:42 But, it looks like the available data suggests
00:23:42 00:23:46 that the circulating tumor DNA does reflect
00:23:46 00:23:50 the tumor burden better compared to the available tests.
00:23:50 00:23:55 And really promising data are emerging from both the CTC,
00:23:55 00:23:58 which is the circulating tumor cells themselves, And
00:23:58 00:24:01 the circulating tumor DNA camps.
00:24:01 00:24:05 Circulating tumor DNA, is the DNA that the tumor sheds
00:24:05 00:24:09 when the cells die or the cells get into the circulation and then die.
00:24:10 00:24:15 So, if Dr Ben Park from our program uses the gene mutations present in
00:24:15 00:24:20 the patient's tumor ASs a flag or indicator of the tumor.
00:24:20 00:24:25 And we in our lab look for similar altered gene makers floating
00:24:25 00:24:30 in the plasma, and these markers are called methylated gene DNA.
00:24:33 00:24:37 Methylated DNA is also, very specific
00:24:37 00:24:41 to the tumor cells in certain genes and not to the normal cells.
00:24:41 00:24:41 So, if you look for
00:24:41 00:24:45 these methylated genes when they are floating in the blood, it means
00:24:45 00:24:50 there's tumor somewhere, either the primary tumor or metastasis.
00:24:50 00:24:54 So, using very sensitive techniques, we then look for and detect
00:24:54 00:25:00 these unique red flags In just a teaspoon of blood from the patient.
00:25:00 00:25:02 How does this assay work?
00:25:03 00:25:06 This marker disappears from the blood,
00:25:06 00:25:08 if the tumor is surgically removed.
00:25:08 00:25:11 There's no source of DNA.
00:25:11 00:25:13 The blood DNA is gone.
00:25:13 00:25:17 But, in some cases, these markers linger in the blood.
00:25:17 00:25:19 This raises questions,
00:25:19 00:25:24 is there a tumor mass hiding out of site and is still feeding DNA?
00:25:25 00:25:30 Does this patient need further treatment to get rid of that
00:25:30 00:25:31 hiding tumor?
00:25:31 00:25:35 Again, when the patient comes back with the recurrence of metastatic
00:25:35 00:25:37 breast cancer.
00:25:37 00:25:40 The same floating DNA markers in their blood goes up.
00:25:41 00:25:46 And we can detect it in the blood more than 90% of the time.
00:25:48 00:25:52 So, such tests are really exciting to hear about, but they still need
00:25:52 00:25:56 to go through rigorous examination to determine their accuracy.
00:25:58 00:26:01 After working on this test for more than ten years and
00:26:01 00:26:03 publishing several papers on it.
00:26:03 00:26:08 This year, in late 2016, we published a paper in Journal of
00:26:08 00:26:13 Clinical Oncology, that shows that in a blinded study the people
00:26:13 00:26:18 in the laboratory did not know whose serum or plasma they were testing.
00:26:18 00:26:23 That our test called the c-MET DNA successfully separated,
00:26:23 00:26:26 those who were responding to therapy from those who were not responding
00:26:26 00:26:27 to therapy.
00:26:28 00:26:32 And this test could also predict whether they would do well
00:26:32 00:26:35 long term, will they live many years or
00:26:35 00:26:37 are they not going to live many years after this treatment.
00:26:39 00:26:42 Is this test now ready to go to the market, this is the question
00:26:42 00:26:45 that many people ask me when I make this presentation.
00:26:45 00:26:51 I'm happy to say that in a few years yes, the answer will be yes.
00:26:51 00:26:55 A company from California has now automated the test and
00:26:55 00:27:00 we are in the process of converting a lab test that took us two
00:27:00 00:27:03 weeks to complete, to a little cartridge,
00:27:03 00:27:09 an automated cartridge test that can fit into the palm of your hand.
00:27:09 00:27:13 And more exciting, this test completes the essay in three hours
00:27:13 00:27:17 instead of two weeks it took us in the laboratory.
00:27:17 00:27:19 Also working with expert personnel.
00:27:20 00:27:23 We are truly excited about this innovation.
00:27:24 00:27:27 Before I leave the area of tumor markers,
00:27:27 00:27:32 I wanted to share with you how these markers and the tests may prove to
00:27:32 00:27:37 be of use to millions of women with breast cancer throughout the world.
00:27:38 00:27:42 This is the statistics on the incidents of breast cancer
00:27:42 00:27:44 is highest in the western world.
00:27:44 00:27:49 However, the good news is that women who undergo mammography screening
00:27:49 00:27:52 for breast health, the tumor is detected early and
00:27:52 00:27:56 modern methods of treatment are instituted.
00:27:56 00:28:01 And most women live out their lifetime, in fact, living for
00:28:01 00:28:06 20 to 40 years after the first diagnosis is not uncommon.
00:28:06 00:28:08 But, the story is not the same for
00:28:08 00:28:11 all the women in the undeveloped parts of the world.
00:28:11 00:28:14 Of our own country and the rest of the world.
00:28:14 00:28:16 These women have no screening programs, and
00:28:16 00:28:20 they have very poor access to care.
00:28:20 00:28:24 They present with large tumors because they can not ignore it any
00:28:24 00:28:28 longer, and most often even if they come to the clinic they can not for
00:28:28 00:28:31 stay for the full course of surgery and radiation,
00:28:31 00:28:35 etc., because their families need them back in their villages.
00:28:36 00:28:41 When they get biopsies, publications that focus on the global health say,
00:28:41 00:28:47 that the overworked Pathologist, a full two to ten months
00:28:47 00:28:51 can go by to get their slides examined, and provide a diagnosis.
00:28:52 00:28:56 So, a group of ASAT Hopkins, with the help of our global health
00:28:56 00:29:00 affiliate Jhpiego, are trying to change this picture,
00:29:00 00:29:05 taking advantage of teams already on the ground that provide AIDs and
00:29:05 00:29:10 HPV and cervical cancer screening and care.
00:29:10 00:29:13 We are trying to drum up support for efforts and
00:29:13 00:29:19 breast health in the same countries in Africa, Asia and South America.
00:29:19 00:29:24 We believe that this can be done, Susan Harvey,
00:29:24 00:29:28 an interventional radiographer at Johns Hopkins, is teaching nurses
00:29:28 00:29:33 and healthcare providers to screen for breast cancer using ultra sound,
00:29:34 00:29:38 but once a suspicious legion is discovered, then what?
00:29:38 00:29:41 Leave it to the pathologist to tell them, two months,
00:29:41 00:29:44 ten months later, what is happening, they'll never come back.
00:29:44 00:29:47 The women will just go home.
00:29:47 00:29:51 I decided that we can double up the same automated cartridge based
00:29:51 00:29:57 methylated marker tests for tumor biopsy tissue, that can be used one,
00:29:57 00:30:01 to distinguish between benign, which are harmless lesions.
00:30:01 00:30:08 Most of them will be benign, maybe two out of 100 will be malignant.
00:30:08 00:30:12 And it can distinguish these harmless lesions from the really,
00:30:12 00:30:14 truly worrisome malignant lesions.
00:30:14 00:30:19 And to also, a second cartridge, to provide us information
00:30:19 00:30:24 of the estrogen receptor, progesterone receptor,
00:30:24 00:30:28 HER2 receptor, and KI-67 status of the tumor,
00:30:28 00:30:32 all within three to four hours of doing the biopsy.
00:30:32 00:30:38 The woman can literally go home with a supply of tamoxifen, pills to
00:30:38 00:30:44 fight the tumor if she has no time to stay for surgery or radiation.
00:30:44 00:30:49 This step alone, I believe, could save up to 70% of the women
00:30:49 00:30:54 with breast cancer and extend their lives until their kids grow up.
00:30:55 00:30:59 This, even if they have palpable lesions.
00:30:59 00:31:04 Needless to say, we are very excited at the potential
00:31:04 00:31:08 impact this could have on women throughout the world.
00:31:08 00:31:12 We are working really hard to get this ready, and
00:31:12 00:31:14 the progress has been phenomenal.
00:31:14 00:31:17 The people in my lab have been working day and
00:31:17 00:31:19 night to get this test through.
00:31:19 00:31:23 I will not be surprised if these two tests get ready for
00:31:23 00:31:26 use within the next two or three years.
00:31:26 00:31:28 Amen.
00:31:28 00:31:32 Part three is about immunotherapy, the new frontier.
00:31:34 00:31:38 I arrived at National Cancer Institute in Bethesda,
00:31:38 00:31:40 Maryland, in 1978.
00:31:40 00:31:42 Fresh off the boat, as a bright-eyed,
00:31:42 00:31:45 bushy-tailed post-doctoral fellow,
00:31:45 00:31:49 just as the concept of immunotherapy was gaining popularity.
00:31:50 00:31:53 The idea of immunotherapy was simple.
00:31:53 00:31:56 Tumor cells are so different from normal cells.
00:31:56 00:32:01 Their DNA is different, their proteins are different.
00:32:01 00:32:05 And we had previously successfully fought many disease-causing bacteria
00:32:05 00:32:10 and viruses, such as smallpox and measles, with vaccines.
00:32:10 00:32:14 So vaccines against tumor cells which are also foreign to our body
00:32:14 00:32:15 ought to work.
00:32:17 00:32:23 So in the early days, we mixed dead tumor cells as a source of antigen,
00:32:23 00:32:27 and dead BCG bacilli to boost the immune system,
00:32:27 00:32:33 put it into an oil emulsion, and injected them into skin melanomas.
00:32:33 00:32:35 And then we waited.
00:32:35 00:32:41 Hm, this did work, but in just a few people.
00:32:41 00:32:44 And for just a short time.
00:32:44 00:32:46 Why did this approach fail?
00:32:47 00:32:52 Are the tumor cells not foreign enough to mount an immune reaction?
00:32:52 00:32:55 Yes, we knew from our lab work that they are.
00:32:56 00:33:02 How, then, does the tumor cell escape immune surveillance
00:33:02 00:33:06 that is normally so active in keeping bacteria at bay?
00:33:06 00:33:11 And other times quite troublesome, such as the allergic reactions we
00:33:11 00:33:14 have to peanuts or mushrooms or whatever.
00:33:16 00:33:21 So extensive research was needed through the last 30 years
00:33:21 00:33:24 to understand the workings of the immune system
00:33:24 00:33:25 as it related to the tumor.
00:33:26 00:33:28 To identify the targets and
00:33:28 00:33:33 to develop drugs that would hit the same target each time so
00:33:33 00:33:37 that that would give us consistent results.
00:33:37 00:33:41 To understand how we finally got immunotherapy working,
00:33:41 00:33:44 we need to understand an important concept.
00:33:45 00:33:51 In the normal person, an overactive immune system can lead to excessive
00:33:51 00:33:56 inflammation and development of autoimmune diseases like lupus.
00:33:56 00:34:01 What the body does in counter-response is to mobilize
00:34:01 00:34:04 molecules called immune checkpoints,
00:34:04 00:34:09 which then control the strength and the duration of this response.
00:34:10 00:34:15 So this is a protective mechanism that minimizes damage to
00:34:15 00:34:18 normal cells and the healthy tissue.
00:34:18 00:34:25 Tumors have learned to hijack this mechanism, the same molecules and
00:34:25 00:34:30 use it to put a break on the body's immune system.
00:34:30 00:34:32 The body's immune response to the tumor.
00:34:33 00:34:39 We have now developed drugs called immune checkpoint inhibitors,
00:34:39 00:34:42 which work in the body by releasing these breaks
00:34:43 00:34:47 that the tumor cell has imposed on the immune system.
00:34:47 00:34:52 Allowing the body to unleash the full strength of the immune system
00:34:52 00:34:56 to attack the malignant tumors and stop their growth.
00:34:56 00:35:01 Five years ago, the results of a landmark clinical trial of an immune
00:35:01 00:35:07 checkpoint inhibitor was reported by a team of researchers lead by Dr.
00:35:07 00:35:10 Suzanne Topalian at Hopkins, who is with us and
00:35:10 00:35:12 who'll be speaking today.
00:35:14 00:35:19 This drug was found successful against a deadly skin cancer,
00:35:19 00:35:25 melanoma, which until then had no cures, as well as lung cancers and
00:35:25 00:35:31 kidney cancers that had not responded to conventional therapies.
00:35:31 00:35:36 These antibody therapies with tongue-twisting names such as
00:35:36 00:35:42 Nivolumab, Pembrolizumab, etc., are mainly against three molecules.
00:35:42 00:35:49 PD-1, PDL-1 and CTLA-4 on the tumor cells and immune cells.
00:35:49 00:35:53 These therapies are breaking new ground every single day.
00:35:55 00:36:00 New immune therapies have e extended survival time of cancer patients for
00:36:00 00:36:02 months to years.
00:36:02 00:36:05 For many different types of cancer.
00:36:06 00:36:11 Additional clinical trials showed that the approach holds promise for
00:36:11 00:36:16 patients with other hard to treat cancers including advanced blood
00:36:16 00:36:20 cancer, head and neck cancers, Hodgkin's lymphoma,
00:36:20 00:36:23 leading to FDA approvals for all of these diseases.
00:36:23 00:36:27 In a small study in Johns Hopkins led by Dr.
00:36:27 00:36:32 Leisha Emens has shown significant effects of immunotherapy in
00:36:32 00:36:35 patients with triple negative breast cancer.
00:36:37 00:36:41 This therapy, like all others, is not without side effects.
00:36:42 00:36:46 The activated immune system can go awry and
00:36:46 00:36:48 start attacking normal cells as well.
00:36:48 00:36:54 Flu-like symptoms, fatigue, rashes, fever, GI problems,
00:36:54 00:36:59 and inflammation in other normal tissues have been reported.
00:36:59 00:37:03 As more studies go on, oncologists are learning how to manage these
00:37:03 00:37:07 side effects, and to keep the patient safe.
00:37:07 00:37:10 With each clinical trial, they learn new things, and
00:37:10 00:37:11 they learn how to manage the disease.
00:37:13 00:37:17 Thus, immunotherapy medication that activates
00:37:17 00:37:22 a person's own immune system against the tumor could one
00:37:22 00:37:26 day be a promising therapy for all types of cancer.
00:37:26 00:37:32 A story that began 30 years ago as an inexact science is gaining
00:37:32 00:37:38 ground every day because of our deeper understanding of the tumor's
00:37:38 00:37:44 ability to manipulate the immune system to its advantage.
00:37:44 00:37:49 Immunotherapy is now viewed as the fourth pillar to cancer treatment,
00:37:49 00:37:54 alongside surgery, chemotherapy, and radiation therapy.
00:37:56 00:38:03 Now turning to the fourth and last topic of my talk today, prevention.
00:38:03 00:38:09 Global cancer, breast cancer incidents is increasing every year.
00:38:09 00:38:13 In the 30 years between 1980 at 2010,
00:38:13 00:38:18 it increased from 640,000 cases to 1.6
00:38:18 00:38:22 million cases throughout the world.
00:38:22 00:38:26 And mortality has continued to increase at the rate of 2% per year.
00:38:26 00:38:33 And this amounts to 600,000 deaths every single year.
00:38:33 00:38:36 What is driving these numbers up?
00:38:36 00:38:37 Many factors.
00:38:38 00:38:42 The first is that there is a rising population of older women,
00:38:42 00:38:44 we are living longer, and
00:38:44 00:38:48 we know that cancer is mainly a disease of old age.
00:38:50 00:38:54 Changes in our lifestyle, changes in the way we eat,
00:38:54 00:38:59 the changes in the way we live are also responsible.
00:38:59 00:39:04 So for a disease like breast cancer, which is predicted to take
00:39:04 00:39:08 on epidemic-like proportions in the near future,
00:39:08 00:39:12 I believe prevention modalities are sorely needed.
00:39:13 00:39:16 So why are we moving so slowly in this arena?
00:39:17 00:39:21 As we all know, what convinces the FDA and
00:39:21 00:39:25 our doctors to use any treatment is clinical trials.
00:39:26 00:39:30 Testing preventive agents in clinical trials is not practical
00:39:30 00:39:35 because we need thousands of women to be recruited into the trial and
00:39:35 00:39:38 we need to follow them up for decades.
00:39:38 00:39:42 Because it takes decades for people to develop cancer.
00:39:42 00:39:46 So if you took 1,000 women, maybe you will get 100 cancers and
00:39:46 00:39:49 that's too few to come to any conclusion.
00:39:50 00:39:53 So what did we have to do in this arena?
00:39:53 00:39:58 We have to identify people who had a high risk of developing cancer so
00:39:58 00:40:03 they might develop cancer in ten years or 20 years, and
00:40:03 00:40:05 test out some safe agents in them.
00:40:05 00:40:06 Two things.
00:40:06 00:40:09 We need markers to say which one of
00:40:09 00:40:13 us Is at risk of developing breast cancer.
00:40:13 00:40:16 And number two we need safe agents to give to them so
00:40:16 00:40:20 that even given throughout life they will not have any side effects.
00:40:22 00:40:26 So we at Hopkins are attacking this problem from both ends.
00:40:26 00:40:30 We are trying to identify women In the population at
00:40:30 00:40:33 high risk of people developing breast cancer again
00:40:33 00:40:38 using those methylated gene markers that maybe floating in the blood or
00:40:38 00:40:40 maybe present in the breast tissue itself.
00:40:41 00:40:45 The second challenge has been to identify the best agents
00:40:45 00:40:48 that can reverse precancerous conditions in the breast.
00:40:48 00:40:51 And protects us from future breast cancer.
00:40:52 00:40:55 Both Tomaxifen and aromatase inhibitors
00:40:55 00:40:58 have been proposed as preventive agents in women.
00:40:58 00:41:05 However, we all know that there are side effects of using these drugs.
00:41:05 00:41:09 The side effects are weak bones, also,
00:41:09 00:41:12 a small risk of developing endometrial cancer.
00:41:12 00:41:15 So why would one want to take something that
00:41:15 00:41:16 will give you some other cancer?
00:41:18 00:41:20 So we need agents that are safe.
00:41:20 00:41:24 And importantly, ones that can be used throughout life,
00:41:24 00:41:28 childhood onwards, without any side effects.
00:41:28 00:41:31 So, planned products have been used in the Indian and
00:41:31 00:41:36 Chinese pharmacopeia for a variety of ailments and are backed
00:41:36 00:41:40 by hundreds of years of experience regarding their indications.
00:41:40 00:41:45 An agent that we know a lot about is the yellow spice turmeric.
00:41:45 00:41:49 Turmeric has been used in there Chinese and Indian pharmacopeia for
00:41:49 00:41:52 thousands of years for many many different ailments.
00:41:52 00:41:57 And I remember that when the kids came to school they would have
00:41:57 00:42:01 yellow elbows and yellow kneecaps because the mother has just slashed
00:42:01 00:42:04 on some of the turmeric powder then they felled on and
00:42:04 00:42:07 that was it, they let them go.
00:42:07 00:42:11 So curcumin is the active component of turmeric and there are hundreds
00:42:11 00:42:15 of papers in the literature talking about its good effects.
00:42:15 00:42:19 It blocks the inflammatory molecule called NF kappa b, and
00:42:19 00:42:24 in recent clinical trials it has also shown to be very beneficial for
00:42:24 00:42:26 patients undergoing radiation.
00:42:26 00:42:29 The radiation burns, the tightening of the skin,
00:42:29 00:42:33 the thickening of the skin is all improved by consuming curcumin.
00:42:34 00:42:39 But I have to tell you that raw curcumin is not soluble in water.
00:42:41 00:42:43 So that when you take it orally as pills,
00:42:43 00:42:46 only a tiny bit of it gets into your circulation.
00:42:47 00:42:51 This can be corrected very easily by adding it to hot oil,
00:42:52 00:42:55 to vegetable stir fry, to the pasta sauce, and
00:42:55 00:42:59 even to the oil that you use for your vingirete.
00:42:59 00:43:01 So you can just add turmeric to oil and
00:43:01 00:43:05 you'll have all the goodness of curcumin come to you.
00:43:05 00:43:08 So what do we need to get it into general use?
00:43:08 00:43:13 Maybe the trials we need to perform, to convince our own colleges and
00:43:13 00:43:16 doctors, and to first test whether curcumin can help and
00:43:16 00:43:20 improve the therapeutic effects of chemotherapy, and
00:43:20 00:43:22 improve tamoxifen therapy.
00:43:22 00:43:26 So can we take curcumin while we are undergoing these therapies and
00:43:26 00:43:30 would it help us to achieve better cures.
00:43:31 00:43:34 So we have now generated data in the laboratory
00:43:34 00:43:39 using many models of breast cancer, that mice given chemotherapy,
00:43:39 00:43:44 curcumin substantially improved tumor aggression.
00:43:44 00:43:46 The same was true for tamoxifen therapy.
00:43:46 00:43:51 But clinical trials need to be done to test this concept.
00:43:51 00:43:54 Mind you, drawing upon the plant kingdom for drugs for
00:43:54 00:43:57 treatment of cancer is not new.
00:43:57 00:44:00 Taxol, from yew trees, vinca from vinca plants,
00:44:00 00:44:05 vincristine from vinca plants, are plant products that have been
00:44:05 00:44:08 extremely useful for treating cancer.
00:44:08 00:44:11 Similarly, plant products such as turmeric,
00:44:11 00:44:16 the golden spice, could provide a successful approach towards managing
00:44:16 00:44:18 this devastating health problem.
00:44:18 00:44:25 In conclusion, today we have covered a lot of ground in cancer research.
00:44:25 00:44:30 From novel drugs, to novel tests, to immunotherapy, to prevention.
00:44:31 00:44:34 All through the day you will hear many talks
00:44:34 00:44:38 that provide a wealth of new information about women's health.
00:44:39 00:44:46 Cancer still remains a formidable foe, but continued research support
00:44:46 00:44:51 from the government and through grassroot efforts from all of you.
00:44:52 00:44:57 This is going to be critical for us to make new discoveries.
00:44:57 00:45:02 I wish all of you a great day and a great year ahead of you.
00:45:02 00:45:06 Thank you.
00:45:06 00:45:12 [APPLAUSE]
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