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KU Cancer Center Researcher Identifies Four Hallmarks of Metastasis

May 03, 2019

Danny Welch
Danny Welch, PhD

It is estimated that cancer metastasis, which means that cancer has spread to a different part of the body from where it started, is responsible for about 90 percent of cancer deaths. Virtually any cancer type can form metastatic tumors. Once a cancer metastasizes, it is very difficult to treat.

Since the term “metastasis” was coined nearly 200 years ago, thousands of scientific papers have been published on the subject. A comprehensive literature review authored by Danny Welch, PhD, associate director of Education at The University of Kansas Cancer Center, and published in Cancer Research seeks to summarize the metastatic research landscape and identify the distinguishing features of metastasis.

A literature review is a valuable tool for researchers as it surveys and concisely recaps previously published studies. Reviews also identify needs for additional research or research inconsistences. Metastasis has been the subject of many comprehensive reviews, but this is the first paper that attempts to define the process in terms of core hallmarks.

In the review, Dr. Welch identifies four hallmarks of metastasis:

  • Motility and invasion
  • Ability to migrate to secondary site or local microenvironments
  • Adaptability
  • Ability to colonize other tissues

“My research colleague and co-author, Douglas Hurst at The University of Alabama at Birmingham, and I scrutinized well over 10,000 studies and publications to draw these conclusions,” Dr. Welch said. “By defining these first hallmarks of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.”

Dr. Welch has dedicated his 40-year research career to better understanding the regulation of cancer metastasis. His laboratory discovered eight of the 30 known genes that suppress metastasis. Over Welch’s research career, metastatic cancer survival rates have improved as understanding of the metastatic process has increased.


“With some of the new data comes the need to refine, consolidate and reflect upon what the next steps are so that the pace of research and delivery of research findings to cancer patients accelerates,” Dr. Welch said.

Doctors Welch and Hurst hope that refining definitions and bringing together diverse data will identify vulnerabilities that metastasis researchers can exploit in the quest to treat cancer metastasis. Controlling or preventing the metastasis of cancer is necessary to improve cancer survival and quality of life.

“There is nothing more important – it is metastases that kill cancer patients. I have known too many patients who have succumbed to metastatic cancer,” Dr. Welch said. “Too many others who currently have metastatic cancer deserve our uncompromised attention to that which most risks their ability to live longer and well.”


Metastatic Breast Cancer and Research

Priyanka Sharma, MD, and Danny Welch, PhD, discuss latest available treatments and ongoing research aimed at improving patient quality of life related to metastatic breast cancer.

Narrator: Welcome to Bench to Bedside. A weekly series about advances in cancer from the research bench to treatment at the patient's bedside and now your host and the Director of the University of Kansas Cancer Center Dr. Roy Jensen.

Dr. Roy Jensen: Welcome to Bench to Bedside. Today we're talking about metastatic breast cancer as well as the latest available treatments and ongoing research aimed at improving patient quality of life. With me to day is Dr. Priyanka Sharma a breast oncologist and clinical researcher and Dr. Danny Welch a researcher specializing in cancer metastasis. First of all thank you for joining us today on Bench to Bedside. Can you explain to us Dr. Sharma what it means when breast cancer metastasizes?

Dr. Sharma: For any cancer when we say it has metastasize it means that the cancer has landed in an organ outside of its primary origin. If breast cancer cells settle in bone it's called metastasis of breast cancer to the bone. It's still not bone cancer. It's breast cancer because that's the primary source. Various cancers can metastasize to different parts of the body.

Dr. Roy Jensen: Dr. Sharma are there factors like breast cancer sub type that put you at greater risk for metastasis?

Dr. Sharma: Certainly. Different breast cancers subtypes have different propensity of metastasizing. For example triple negative breast cancer has a highest risk of metastasizing especially the ones that don't respond to pre operative chemotherapy. Among hormone positive breast cancers the ones that categorize into higher general make [inaudible 00:01:51] also have a higher risk of metastasizing. Of course our conventional staging factors like lymph node and walnut in size also play a role in risk of metastasizing. Cancers that have multiple lymph nodes that are involved at the outset have much higher risk of metastasizing.

Dr. Roy Jensen: Dr. Welch did you want to weigh in there?

Dr. Danny Welch: I was just going to add the different types of breast cancer can go to different organs. Hormone receptor positive breast cancers most commonly go to bone. They can go anywhere but triple negative goes everywhere a lot more frequently. So different types of cancer have different patterns of where they spread.

Dr. Sharma: Different hormone organs that they like to attach to.

Dr. Roy Jensen: Dr. Sharma what kind of treatments are available for women who are diagnosed or discovered to have metastatic breast cancer?

Dr. Sharma: We provide a wide variety of treatment options available for women with metastatic breast cancer. Often the treatment choices are based on the subtype of breast cancer and the extent of spread. For hormone positive breast cancer there are multiple types of anti estrogen or anti hormone therapies. Targeted drugs like CVK46 inhibitors or MT inhibitors that can be combined with endocrine therapy. There are different types of chemotherapy agents. There's several HER2 targeted drugs that are available of women with BRCA. One or two mutations associated breast cancers now we have part inhibitors that are available to use and also there's emerging data on the activity of immune therapy. Especially for a sub group of patients with triple negative breast cancer. In addition to this there are clinical trials that are available that are often offering newer treatment options for women.

Dr. Roy Jensen: If you're just joining us we're with Dr. Priyanka Sharma and Dr. Danny Welch and we are talking about metastatic breast cancer. Remember to share this link with people you think might benefit from our discussion. Use the hashtag #benchtobedside. Dr Sharma what questions for a patient who's diagnosed with metastatic breast cancer what should they be asking? What are the key things they need to know?

Dr. Sharma: They should ask their providers about the subtype of breast cancer that they have because that definitely determines treatment options and the spread of disease. Beyond that discuss the available treatment options and the side effects because that's an important decision to determine what fits the best for an individual patient. The recommendations that we make for a patient should fit their goals for the treatment. I always encourage my patients with metastatic breast cancer to ask for availability of clinical trials because that's how you get access to newer and sometimes better treatment options.

Dr. Roy Jensen: What is the importance of when a patient is in that situation of getting a second opinion you feel?

Dr. Sharma: I think it's very important. Number one to be certain of your diagnosis and the type of breast cancer you have and to come up with the right treatment plan that best fits that individual's need. Different individuals have different expertise, different institutions have different things that they can offer to the patients. It's just a matter of finding the right fit for an individual. Also different institutions and places might have access to different types of trials and based on the need of that individual patient one place might be a better fit. I personally am never hesitant if my patients want to get a second opinion. If anything I think it helps us improve care.

Dr. Roy Jensen: I totally agree with that. I think physicians that are afraid of getting a second opinion are probably afraid of their first opinion is the way I like to put it. So Dr. Welch we've certainly seen a lot of advances over the course of our career. More and more patients are surviving and living with metastatic breast cancer. What do you attribute that phenomenon to?

Dr. Danny Welch: Well it's tough to assign a particular reason that people are surviving longer but I think earlier diagnosis is helping a lot. Improved surgical techniques. A bigger repertoire of chemotherapy agents. Even though the immune therapies are not working as well in breast cancer right now they're looking like they might. There are a lot more options for breast cancer physicians to treat patients. I'd like to think that the research that's going on in the laboratory even though people like myself are treating rats or mice that have breast cancer, a lot of the things that we've learned in the laboratory are translating in practical ways for physicians to modify how they're attacking the breast cancer. There are a lot of things that go into it. I think a nice way to illustrate the progress that's been made when I was studying as a graduate student the statistics were that no woman with stage four or metastatic breast cancer lived five years. I personally now know probably 30 or 40 women who are 20 years out with metastatic disease. It's still a struggle. They are not cured, but they're alive and they're having a reasonably good quality of life. That's a big, big advance.

Dr. Sharma: I think it's to team sciences Dr Welch noted that the information that we gather about the biological heterogeneity of the disease from the lab is now translating into better drug development and better treatment options for patients. Prime example is HER2 positive breast cancer where the natural history of disease is really changed over the last 15 years. Once we understood that targeting the over expression of HER2 leads to better treatment and now we have several drugs that are available in clinic and several more that are in clinical studies.

Dr. Roy Jensen: You mentioned the word heterogeneity and I would say one of the most important reasons why we've made so much progress against breast cancer. When I started my career five year survival for all comers in breast cancer was probably 75%. Now it's well over 90%. Dr. Welch talked about a number of reasons. Earlier diagnosis and that thing, but I think a big reason is the recognition of heterogeneity and the development of tailored and targeted therapy for HER2 neu, for endocrine positive disease and it's just been absolutely critical to get over the idea that you treat all breast cancers the same. They're not the same. They're biologically different and recognizing that and then specifying your therapy based on those differences is absolutely critical.

Dr. Danny Welch: I don't want to make this sound like a negative thing, but heterogeneity is probably one of the most challenging aspects of any cancer be it breast or any other cancer. What most people don't know is that the smallest tumor we routinely diagnose is a billion cells. In of that billion it's thousands of different sub populations. Some are sensitive some are resistant to therapy. It just makes the task of eliminating all cells all the more challenging. Some will metastasize and some won't. While we have different kinds of breast cancer we also have different kinds of cells within each tumor. There will never be a cure for cancer, because we're not treating one thing. Even with one tumor. We're not treating one thing.

Dr. Roy Jensen: You're known really all over the world for research into metastasis and breast cancer is certainly one of your major areas, so the biology of breast cancers has been an evolving field over the last few years. What kind of research is taking place that really focuses on improving the quality of life for our patients and not just an investigation into the biology?

Dr. Danny Welch: There's a new funding mechanism that came with the approval of the Affordable Care Act. The acronym is PCORI, Patient Centered Outcomes Research Institute. There's an entire arm of research that's going on to address what patients see as their particular needs. 15, 20 years ago Dr. Sharma wouldn't have said there's no such thing as chemo brain. The aspect of after chemotherapy. There are issues with remembering things, finding words, all sorts of things. In the last six, eight months there are actually a few papers that have come out that are seeing a chemical reason for what is euphemistically called chemo brain. There are a number of other things that I've seen come up in the last few years looking at the genetics. The underlying genetics even though that's the biology that you talk about, help address why for example African American women develop what's known as triple negative breast cancer at a very high frequency percentage wise than Caucasian or Asian women. There's evidence that there are genetic reasons underlying that. That affects what they get but also how they're being treated. I think Dr. Sharma's the world's expert on triple negative and can address that better.

Dr. Sharma: Quality of life what also we're seeing now is a lot are now faced with studies for registration trials and new drugs improve quality of life as one of their key end points. It's not just important to show dot A plus B is better than B. One has to keep in mind the toxicities the addition of B brings upon. Is that something that's palatable to our patients? In addition to that a lot of our big trials are now including patient reported outcomes as one of their key secondary measures. Engagement of patient advocates in our trial design is a key element now for all big trials. With all of this we're understanding that just showing efficacy is one part of the coin, but we've got to maintain the quality of life as we do that. As we just said these patients are living longer and longer so maintaining quality of life and allowing them to because able to do and enjoy things they like to do is very important.

Dr. Danny Welch: As you mentioned advocates the involvement of advocates both in the clinical but also in the laboratory has been really critical to educating people. Metastatic patients who have metastatic disease now have support groups and teams of people who are not just their care givers but their entire families. Their quality of life improves because everybody's better educated and the options again get greater because of that.

Dr. Roy Jensen: I'm really glad you mentioned that the advocates because when I began my career basically every woman with breast cancer had a radical mastectomy and was given the same type of chemotherapy. It didn't matter what type of breast cancer you had. It didn't matter what stage it was or anything else. It was like we have one treatment. You're going to get that treatment and you're going to like it. I think it was really because of the advocates who pushed back on that and said, "This is not acceptable." You guys and at that time, it was mostly guys who were driving these treatment decisions, need to do better. You need to listen to us. This is not an acceptable situation. It forever changed the landscape. I can think back in no doubt a critical event in all of this was when Betty Ford was diagnosed with breast cancer. That was an absolute game changer because she decided to not hide her diagnosis. It wasn't that long before when she was diagnosed when basically many women felt like this was something they had to hide. They didn't want to talk about their treatment. They didn't want to talk anything about it and she brought it out into the open and encouraged us to make an issue out of it and say this is not right and we have to do better. I give her a huge amount of credit. It took a lot of bravery. At this point everybody's kind of, "Why wouldn't you do that?" Believe me that wasn't how it was.

Dr. Danny Welch: Cancer was the C word. Talked about only with a few people. In many ways having metastatic cancer in 2019 is the M word. Many patients are marginalized by their employers, insurance companies, and even friends fear talking to them because they don't want to say the wrong thing. Metastatic often means dying. Now that people are living longer it's becoming a little less hidden. It's more mainstream like Betty Ford's breast cancer diagnosis.

Dr. Roy Jensen: I think certainly back in the 1970s when if a woman was diagnosed with metastatic cancer it was kind of close the book. We're done. We have nothing else to offer you. Go home and make the most of whatever months or less left in your life. We're a long, long way from that now. Dr. Sharma what would be your advice if a woman is suddenly diagnosed with metastatic breast cancer? What should they do?

Dr. Sharma: I think I would tell the women that we now have numerous new options to treat that cancer than we did 20 years ago. The outlook is so much better with several new drugs that are on the horizon and in clinical trials. She should learn about her cancer. Understand the type of cancer she has and understand the treatment options available. As I said now we're in this era where we're not just saying you will take this treatment. We will say, "Well we have these three options. We'll go over the pros and cons and the side effects and the impact on quality of life. Let's go over the goals of therapy for you as an individual sitting in front of me and make the right choice. Knowing that once this stops working we will have other treatments to discuss and talk about." I personally have several patients with metastatic disease that saw their kids complete college, get married, have grandkids, while still living with metastatic disease and moving from one treatment to another treatment. Of course the story is not the same for everybody. That's what our hope is for future. But it is much better than it was 20 years ago.

Dr. Danny Welch: You said something and I know it was inadvertent but you said she and it's important for people to know men also get breast cancer and that's one of the issues that was emphasized to me at this PCORI conference that I participated in. There were five or six men there who have metastatic breast cancer. It's important that we recognize it's everyone involved.

Dr. Sharma: Right. And the treatment options are as wide for men with breast cancer as there are for women with breast cancer. There's special efforts to study the biology of male breast cancer.

Dr. Danny Welch: My raising that point was to show that I'm being educated by the patients and the advocates as well. Sometimes it's the little things not to be ignored as a patient. The males felt like they were ignored. They were never treated in Kansas that's the important part.

Dr. Roy Jensen: Could you tell us a little bit about the Women's Cancer Center that we just opened and maybe use that as a platform to discuss what are all the components that you think a woman ought to have at her disposal in terms of the comprehensive services that go into making up a really premiere breast cancer program?

Dr. Sharma: I think it's very vital to have a multi disciplinary team because it's a team approach that provides expertise from a medical oncologist. Provides expertise from a surgeon and a radiation oncologist. Provides expertise in terms of cancer psychology, cancer genetics. These all are important aspects of delivering the best and the personalized care to our patients. Also as patients advance through their metastatic course and run through the first few lines of treatment I think it's also important to be able to have access to a phase one unit where you can get information on newer phase one trials if you wish to go in that direction. What we've done here is we've always had this multi disciplinary focus where based on the patient's need. The patient is seen by every discipline that needs to play a role in their care. For patients with early stage disease, surgeons, the radiation oncologist, oncologist, cancer genetics, if that is needed. Financial counselor, social services if we need to arrange for their travel or overnight stay for treatments for patients with metastatic disease the team is slightly different but the important concept is to have a team approach. There are all the individuals that are part of the team communicate with each other and do so with the sole focus of providing the person the best care.

Dr. Roy Jensen: I'm going to add one thing to your list. Pathology.

Dr. Sharma: Yes. Because that's where you get the right diagnosis.

Dr. Roy Jensen: That's right.

Dr. Sharma: If you have an error in the pathology read that will impact every decision down from there.

Dr. Danny Welch: You might want to address the issue of specialization even in pathology. Pathology is not the same as G high pathology had that type of ...

Dr. Roy Jensen: Right. Yeah. Most of my early career was spent doing breast pathology and I had the luxury and the privilege of really training with what I considered to be the best pathologist of all time and that is David Page. He really helped define the field and it's just so important to making sure you get that diagnosis right because all of the heterogeneity issues that have arisen with breast cancer over the last 20 years you have to make that call correctly or else you're going down the wrong path.

Dr. Danny Welch: The difference between seeing tens of slides versus thousands of slides.

Dr. Roy Jensen: We in my time with David we literally saw almost 70,000 cases. There's no substitute for that amount of experience. The other thing that I would add to that is a comprehensive program of prosthesis and an appearance center. Many therapeutic options that are available to breast cancer patients. They're going to lose their hair. That is critically important. In fact when you talk to patients that's one of the things that they complain about most.

Dr. Sharma: Breast reconstruction. To have options available for women that want to avail those options. Regardless of the type of surgery they would need or radiation or not. To have options available to have reconstruction. I think that's also increasingly important because that's part of the whole care. It's not just taking the tumor out. It's healing the patient from one end to another end so they can continue on with their life.

Dr. Roy Jensen: For the last several years by far and away we've treated more patients with more breast cancer at the KU Cancer Center than any other type. We treat well over 1,000 patients a year. One of the things that that does it affords us the luxury of being able to specialize in this area. In fact while you treat a variety of different type of breast cancer, your specialty is really triple negative breast cancer and you're a world renowned expert in that regard and you've built one of the largest registries in the world for that disease. We've really done some wonderful things in term of designing clinical trials. Really understanding triple negative breast cancer at a molecular level. Understanding the response to therapy and you know you just can't do that when you're treating 15, 20 cases a year.

Dr. Sharma: Then I would add to that that out of those 1,000 patients at our center a quarter of them have opted to go on clinical trials. Which means that we have the menu trials available for women if they do want to explore different treatment options. I think that's an opportunity I feel like no cancer patient with a new diagnosis of cancer should miss.

Dr. Roy Jensen: Absolutely.

Dr. Danny Welch: Since you've mentioned clinical trials. In talking with several patients. Not as many as either of you, but one of the fears that a lot of people have is that clinical trial means we're experimenting on people and trying to do things to them that are not the best care possible. I think it's just important to emphasize every patient gets standard of care and clinical trial is to try something new. To offer new options. I think making a definition is absolutely critical especially of the metastatic patient.

Dr. Sharma: In this era where it used to be where you would opt for clinical trial once you've exhausted every available option in clinic. In this era now we're and better drugs are moving on earlier in this pace in this space in the metastatic disease. If one would wait till the end of clinically available options sometimes there's no trial available. Just a prime example. For as you said immune therapy is new to the world of breast cancer and it is now showing efficacy in women who have triple negative breast cancer. The randomized phase three restriction trial for immune therapy in triple negative breast cancer was done in newly diagnosed patients with metastatic disease. Where patients received standard of care chemotherapy with or without immuno therapy drug. That's newly diagnosed women not later down the line. The women who got immune therapy in combination with chemotherapy they had a particular marker expressed on the tumor cells their overall survival was doubled. That's a prime example of where there now are trials are moving earlier in the course of disease and for good reasons.

Dr. Roy Jensen: Well thank you so much. Both you Dr. Sharma and you Dr. Welch. That's it for today. Tune in next Wednesday at 10:00 am for our next episode of Bench to Bedside.

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