Gastroesophageal Cancers

November 30, 2020

Information

November 29, 2020

Yale Cancer Center

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00:00Support for Yale Cancer Answers comes
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00:12More information at astrazeneca-us.com.
00:16Welcome to Yale Cancer Answers with
00:18your host doctor Anees Chagpar.
00:20Yale Cancer Answers features the
00:22latest information on cancer care by
00:25welcoming oncologists and specialists
00:26who are on the forefront of the
00:29battle to fight cancer. This week
00:30it's a conversation about gastroesophageal
00:32cancer with Doctor Jill Lacy.
00:34Doctor Lacy is a professor of medicine
00:37and medical oncology at the Yale School
00:40of Medicine where Doctor Chagpar is
00:43a professor of surgical oncology.
00:45Jill, we don't often talk
00:48about gastroesophageal cancers much.
00:50Tell us a little bit more about them.
00:54How common are they?
00:56Who do they affect?
00:57What do they encompass?
00:59It is somewhat of a heterogeneous group of cancers
01:03and I will elaborate on that as we go along.
01:06And it is not a
01:09common group of cancers
01:11certainly, compared to, say,
01:13breast cancer or lung cancer.
01:15So if you combine esophagus and
01:18gastric cancer in the United States,
01:21there's about 46,000 cases a year,
01:24about 27,000 deaths.
01:25So it is quite a lethal cancer.
01:29And by contrast,
01:30lung cancer over 200,000 cases.
01:33Breast cancer,
01:34I believe over 270,000 cases.
01:36But interestingly,
01:37the death rate as I indicated,
01:40still is quite high.
01:41You compare this, say with breast cancer,
01:44where I believe we're down to in
01:48the range of 40,000 deaths per year.
01:50So even though it's not a common cancer,
01:54it is still a significant problem
01:56in terms of its lethality.
02:01What's interesting about these
02:02cancers is that there's quite
02:05a bit of geographic variation in incidence
02:07and gastric cancer actually
02:09is quite common worldwide and a
02:12significant public health problem.
02:14It's actually the third leading cause
02:16of cancer related deaths globally.
02:19Over 1,000,000 cases and over 800,000 deaths.
02:22So it does remain, I think,
02:25a huge issue globally and still
02:27problematic in the United States.
02:31And on top of that,
02:33gastroesophageal cancers not only are
02:35gastric cancers or cancers of the stomach,
02:38but also of the esophagus.
02:40But the esophagus is a long tube that
02:43goes all the way from essentially your
02:45mouth all the way down to your stomach.
02:49So talk a little bit about
02:51whether those cancers,
02:53the cancers of the esophagus
02:54and the cancers of the stomach
02:57are similar or different,
02:59and whether there are different
03:01types of cancers even within that.
03:03Sure, so we often divide these
03:06cancers into two anatomic groups.
03:09Esophagus cancer, as you alluded to,
03:12and gastric, or what we call stomach cancer.
03:17And esophageal cancer we now know really
03:20is comprised of two very distinct types,
03:23really essentially different diseases.
03:26One type is called squamous cell cancer
03:29an under the microscope and in terms of
03:33its molecular biology and risk factors,
03:36it's actually quite similar to cancers of
03:39the throat and the head and neck region.
03:42The risk factor there is tobacco
03:45and alcohol in poverty.
03:47And Interestingly,
03:47the incidence of squamous cell
03:49carcinoma of the esophagus has
03:52really dropped dramatically,
03:53particularly in the Western world,
03:55so that's the good news.
03:57The other type of esophagus
04:00cancer is called adenocarcinoma,
04:01and then actually arises at the
04:04bottom of the esophagus where it
04:06connects in with the stomach,
04:09often referred to as
04:10gastroesophageal junction cancer,
04:12and that looks much more like a typical
04:15gastric cancer under the microscope.
04:17And actually is much more similar to
04:20gastric cancer than it is to squamous
04:23cell cancers of the esophagus.
04:25And they are.
04:26They have different risk factors,
04:28so I,
04:28for I alluded to the risk factors for
04:31squamous cell of these saw fickas it's
04:34predominantly tobacco and alcohol
04:36as we see with head and neck cancer.
04:39For the adenocarcinomas of the esophagus
04:42that arise at the bottom of the esophagus.
04:46What's interesting about that
04:48is that there actually has been
04:51quite a dramatic increase in the
04:54incidence of this particular entity.
04:57Gastroesophageal junction adenocarcinoma,
04:58particularly in Caucasian males,
05:00a great male predominant we don't
05:04fully understand that increase some
05:07of the risk factors that are linked.
05:10Two adenocarcinoma of the esophagus
05:13are high BMI or obesity.
05:16Possibly Dyett gastro oesophageal
05:19reflux disease is certainly risk
05:22factor in some cases,
05:24but smoking and alcohol do not seem
05:27to play a predominant role in risk
05:32factor the gastroesophageal adenocarcinomas.
05:36Then you get into the stomach an we're
05:40talking about classic gastric cancer.
05:43And there what's very interesting is
05:46that there's been a progressive decline.
05:50Across the globe and in the United States.
05:53In the incidence of gastric cancer
05:55as it was the number one cause
05:58of cancer related deaths globally
06:00until about the 1980s,
06:01when it was surpassed by lung cancer
06:04and there are a lot of interesting
06:06theories about why that is.
06:08And we do know that there are some risk
06:12factors for stomach or gastric cancer,
06:15and these include some environmental
06:17and lifestyle risk factors.
06:19One of the most prominent is a
06:22bacteria called Helicobacter pylori,
06:23which is quite prevalent and some
06:26strains of that bacteria are cancer
06:29causing and do increase the risk of
06:32gastric cancer through been a lot of
06:35studies over the decades about diet.
06:38So it does seem that.
06:40Salt preserved and smoked foods increase
06:42the risk as well as dietze that are
06:46low in fresh fruits and vegetables.
06:48Modest risks risk factors would be
06:51smoking and obesity and probably
06:53lower social economic status.
06:55So there are a lot of differences,
06:58not only anatomically and in terms
07:00of the pathology under the microscope
07:02but also risk factors, and it's
07:05interesting deals that you mentioned
07:07that the oesophageal cancer rate
07:10and the gastric cancer rate.
07:11Both seems to have dropped,
07:15but gastroesophageal cancers,
07:16those cancers that occur at that junction,
07:21the add node cancers.
07:23Have increased Ann.
07:25You mentioned that we we don't know
07:28why exactly those have increased,
07:31but do we have any insight into
07:34what played a role in decreasing the
07:38incidence of oesophageal cancers and
07:41of gastric cancers?
07:43So for squamous cell carcinoma
07:45of the esophagus it is related
07:48to a decrease in smoking.
07:51And improvements in social
07:53economic status and nutrition.
07:55Those seem to be quite linked to squamous
07:58of the esophagus and for gastric cancer,
08:03we do think that it does relate
08:06to decreasing incidence of
08:09H. Pylori colonization or infection related,
08:11likely due to refrigeration
08:13over the last century or so.
08:16So in areas of the world that are
08:20underdeveloped we see
08:22a drop in the incidence of gastric cancer,
08:25so that's the prevailing theory.
08:27But you know, it's interesting
08:29that despite these advances,
08:31and certainly there's a long way to go,
08:34this is still, as you mentioned,
08:37a fairly lethal cancer
08:38when we think about gastroesophageal
08:41cancers as a whole,
08:42is that because they tend to
08:44present at late stages in general?
08:47I think it's a combination of factors.
08:51Yes they are lethal cancers,
08:54and that's why even though they're
08:56not so common in the United States,
08:59they're still very problematic.
09:00So the five year cure rate for
09:03esophaeal cancer was only about 20%.
09:06It's a little bit higher for gastric cancer,
09:09about 30%, and I think the reasons for
09:13this are multi factorial if you will.
09:16In some cases, due to a delay in diagnosis,
09:20but I don't think that's the major reason.
09:23I think it has much to do with the
09:27inherent biology of these tumors.
09:29A propensity to disseminate
09:31or spread early on,
09:33and then the need for better
09:35and more effective therapies to
09:37deal with disseminated disease.
09:39I would add that in contrast to
09:43the common cancers such as breast,
09:46colorectal, lung, and cervical
09:47there is no widespread screening
09:49for these cancers,
09:51at least in the Western world.
09:55But it is a little bit different in Asia
09:57and therefore early detection
09:59is less likely to happen with
10:02these cancers as opposed to
10:05breast cancer,
10:06so that certainly would be a contributing
10:09factor.
10:12Talk a little bit about the differences in screening in Asia.
10:16How do people in Asia get screened for
10:18esophageal cancers and why
10:20hasn't that been adopted in the US?
10:24Usually we find screening to be more
10:27prevalent in the Western world than
10:29we do in less developed countries.
10:32In terms of
10:35screening in Asia for gastric cancer
10:37they do pretty sophisticated
10:39radiographic studies to look at
10:42the surface of the stomach to
10:44see if there are irregularities,
10:46and then for esophagus cancer
10:49screening modalities is to have
10:51patients swallow a balloon and sort
10:54of pull it up through the esophagus
10:56and you pull off abnormal cells
10:59in the lining of the esophagus.
11:01And those are two screening modalities.
11:04That can be applied widely in the United
11:08States because it is an uncommon cancer.
11:12I think there's just not been a lot
11:15of focus on widespread screening
11:19for these cancers.
11:20So you mentioned that these cancers
11:23tend to, because of their biology,
11:26be more advanced
11:28at the time of presentation
11:30and more rapidly get to a more
11:34advanced or metastatic stage,
11:36what proportion of
11:38these patients present with
11:39advanced or metastatic disease,
11:41out of all
11:44the gastroesophageal cancers that you see?
11:47Still the majority of the
11:50patients are presenting with non
11:53disseminated or nonmetastatic disease,
11:57so that's the good news.
12:00But despite that, again
12:03oftentimes particularly
12:05with the more advanced but
12:07still nonmetastatic cases,
12:08there is what we call a cult dissemination,
12:11and that is where we look to additional
12:14therapies such as chemotherapy
12:16to try to increase security.
12:18You know, it's something that
12:20we've been doing for several
12:23decades in the breast cancer world,
12:25and certainly has a role
12:27in these cancers as well.
12:29Even in those patients who
12:31appear to have localized and
12:33potentially curable disease.
12:35And I want to kind of get
12:38into how exactly we treat patients,
12:42and so with those patients with
12:44localized disease, can we treat
12:46these patients for curative intent?
12:48And how do we do that?
12:51Absolutely, patients who
12:53present with nonmetastatic disease,
12:55so no evidence of dissemination
12:58to other sites in the body,
13:01and that we determined
13:03simply by getting imaging,
13:05usually a CAT scan or in
13:08some cases a PET scan.
13:10And for those patients there is a path
13:14to cure for many of those patients,
13:18and that often involves
13:20surgery as the centerpiece
13:22of the cure and then in many cases where
13:25the disease is more locally advanced,
13:28we will need adjunctive therapies
13:30in addition to surgery to
13:32further increase the cure rate.
13:35And that's true both for
13:37esophagus cancer and for gastric
13:39cancer.
13:42When the disease has spread or is more advanced,
13:46I would imagine that therapies can be a
13:50little bit more challenging or problematic
13:54but I do understand that
13:56there are some new advances that
13:58may help patients who have more
14:00advanced or metastatic disease.
14:02So I want to get into all of that,
14:05but first we need to take a short
14:08break for a medical minute,
14:10so please stay tuned to learn more
14:13about gastroesophageal cancer
14:14with my guest Doctor Jill Lacy.
14:17Support or Yale Cancer Answers comes from AstraZeneca,
14:20a science LED biopharmaceutical company
14:22dedicated to partnering across the
14:24oncology community to improve outcomes
14:26across various stages of cancer.
14:28More at astrazeneca-us.com. This is a
14:34medical minute about breast cancer,
14:36the most common cancer in
14:38women. In Connecticut alone,
14:40approximately 3000 women will be
14:42diagnosed with breast cancer this year,
14:44but thanks to earlier detection,
14:46non invasive treatments,
14:48and novel therapies,
14:49there are more options for patients to
14:52fight breast cancer then ever before.
14:54Women should schedule a baseline
14:56mammogram beginning at age 40 or
14:59earlier if they have risk factors
15:01associated with breast cancer.
15:03Digital breast tomosynthesis or
15:053D mammography is transforming
15:06breast screening by significantly
15:08reducing unnecessary procedures
15:10while picking up more cancers and
15:13eliminating some of the fear
15:15and anxiety many women experience.
15:17More information is available
15:19at yalecancercenter.org.
15:20You're listening to Connecticut Public Radio.
15:24Welcome
15:24back to Yale Cancer Answers.
15:27This is doctor Anees Chagpar
15:29and I'm joined tonight by
15:32my guest doctor Jill Lacy.
15:34We're talking about gastroesophageal
15:36cancer and right before the break
15:39Jill was telling us about
15:41how this is a rare cancer,
15:43but one that really is fatal
15:45for some patients and
15:48especially difficult or perhaps
15:50more challenging to treat in the
15:53advanced and metastatic setting.
15:55So Jill tell us a little bit more
15:58about historically the options that
16:00we've had for advanced metastatic
16:04gastroesophageal cancers and
16:05some of the new developments that
16:08maybe can give patients more hope.
16:11For most of my career,
16:15when patients develop
16:18metastatic or disseminated
16:19esophageal or gastric cancers,
16:22we were able to offer some treatments,
16:26but the prognosis was poor and the
16:30survival was relatively short and those
16:34treatments up until relatively recently
16:37were basically the use of chemotherapy,
16:40or cytotoxic drugs.
16:42Traditional chemotherapy drugs.
16:44And those drugs,
16:46often provided some palliation
16:48and mostly prolong survival,
16:51but it was unusual to
16:54see long-term survivors,
16:56and we were not curing patients
17:00with those treatments.
17:03What changed more recently?
17:07There have been some very exciting advances in
17:11the treatment of metastatic, or disseminated,
17:15both esophageal and gastric cancers.
17:18The first advance came about a decade
17:21ago and this was in the area of gastric
17:27and gastroesophageal adenocarcinomas.
17:29And what we had learned was that these are
17:34heterogeneous from a molecular perspective.
17:38And about 20 to 30% of these tumors carried
17:42high levels of a protein called Her 2,
17:46and we knew that this protein
17:49also was present in breast cancer.
17:55And a drug had been developed
17:58called an antibody that
18:00targeted her 2 in breast cancer and
18:03it was extraordinarily effective.
18:06That drug is trastuzumab, or Herceptin.
18:08And so it was
18:10theorized that perhaps
18:12Herceptin would have
18:14activity in the her 2 positive
18:17gastric and esophageal adenocarcinomas.
18:20So there was a large global effort
18:23to answer that question.
18:26Patients with advanced disease, metastatic
18:29or stage four were assigned to get
18:33the standard of care at that time,
18:35chemotherapy with two drugs
18:38or chemotherapy plus
18:39Herceptin and the results
18:41of that study were really quite stunning
18:45in that survival was significantly
18:47improved for those patients who
18:50received Herceptin.
18:53So I would say that was the first
18:56big advance and changed the paradigm
18:59about how we think about these
19:02cancers in terms of looking at the
19:05molecular profile and thinking
19:07about using targeted therapies.
19:09So that was very exciting.
19:13And then what happened?
19:14It sounds like there's
19:16another shoe that's about to drop.
19:19There is, so in the breast cancer world
19:22what followed on after the discovery
19:24of Herceptin was the development of
19:27other drugs that targeted this protein
19:30Her 2 and there were additional
19:32drugs that were developed and
19:34approved and that were effective.
19:36But unfortunately when those drugs
19:38were tested in gastroesophageal
19:41cancers that were positive for her 2,
19:43They were not effective and that was
19:46disappointing and so we were learning
19:49that her 2 positive gastroesophageal
19:53cancer is not the same thing as
19:55her 2 positive breast cancer.
19:57That's interesting. So wait a second,
20:00what you're saying is that
20:03trust Herceptin worked in her
20:062 positive gastric cancer,
20:08but Pertuzumab, I'm assuming
20:10that you meant pertuzumab,
20:12which also targets her 2, did not work.
20:19It did not in the studies that were conducted as well as the antibody
20:21drug conjugate TDM one and lapatinib.
20:26Any why was that?
20:28I mean do they think that
20:31there was something particular about
20:33her 2 or was it or about Herceptin
20:37versus the other drugs in terms
20:39of what particular subunit of her 2
20:42that we're targeting?
20:43Or what was the
20:46hypothesis behind why
20:48one drug would work, but the
20:51others didn't?
20:52That is a great question and I don't
20:55know that we have all the answers.
20:58We do know that gastroesophageal cancers
21:00are much more heterogeneous in terms
21:03of their levels of expression are
21:04more likely to lose expression overtime,
21:07so that's one issue.
21:08Some of it may have been related to how
21:11the studies were designed and conducted,
21:14but I don't think we fully understand
21:17why we don't see the exact same activity
21:20of some of these agents in gastric
21:22and esophageal adenocarcinomas that we're
21:24seeing in breast cancer.
21:27Sorry to interrupt, but it still
21:29sounds like there was another shoe that
21:32was going to drop.
21:34Well, I think we're very excited in
21:37that it does appear that there is
21:40going to be newer generations of her
21:432 targeting agents that are going
21:45to be effective in gastric cancer.
21:48So one of them is a very
21:51interesting drug that is
21:52also used in breast cancer now very recently
21:56where you take Herceptin and you
21:59link it up biochemically to a
22:01chemotherapeutic drug.
22:09And that has been approved in breast cancer.
22:13That's her 2 positive and has been
22:16tested now and her 2 positive gastroesophageal
22:19adenocarcinomas in patients
22:21who have already been on trastuzumab
22:24and have failed treatment and the
22:26results really were stunning.
22:27With major shrinkage in more
22:29than half of the patients,
22:31which is not something that we
22:33typically see in this disease.
22:35Really with any line of therapy
22:37and very impressive survival.
22:39So this is very exciting.
22:40There was a New England Journal
22:42of Medicine paper regarding this
22:44data earlier this year,
22:46and I do believe this
22:47new drug will be approved not
22:50only in breast cancer but also in her
22:532 positive gastroesophageal cancer.
22:55So we're very excited about that.
22:58And again,
22:59this is for our patients who
23:02have her two positive tumors.
23:05So it's not for all comers.
23:08So that's one development.
23:10And then I think we will also see
23:13some newer generation antibodies
23:15that are similar to trastuzumab but
23:19more potent in recruiting the immune
23:22system into action to kill the cancer.
23:25And so one of those is called margetuximab,
23:29so quite similar to trastuzumab,
23:32but it enhances the immune response
23:35and we've already seen really positive
23:38and exciting preliminary data when
23:40it is combined with immunotherapy.
23:44And there's a very exciting on
23:47going clinical trial
23:48looking at this combination of
23:51margetuximab in immunotherapy with
23:53chemotherapy in newly diagnosed patients.
23:56So we're very excited
23:57about the second and third generation
24:00iterations
24:03and then there are other novel antibodies
24:06targeting her 2 that are being developed,
24:09so I do think that the field is
24:11really going to open up in terms of
24:14treatment of her 2 positive stage
24:17for gastroesophageal adenocarcinoma.
24:20I'm very hopeful that the prognosis
24:22for these patients will improve
24:24significantly with these therapies.
24:26But there's still a large fraction of
24:29patients who are her 2 negative,
24:32So what about them?
24:34Does standard immunotherapy,
24:36for example with checkpoint inhibitors,
24:38help them?
24:41This is where there's some excitement really
24:44just in the past few months.
24:47So we hear a lot about
24:50immune checkpoint inhibitors.
24:51Drugs like KEYTRUDA
24:55or Opdivo in colon cancer,
24:57lung cancer, Melanoma,
24:59and many other cancers where
25:01these immunotherapeutic agents
25:03have really been game changers.
25:05These agents in the way the studies
25:08have been done to date have not
25:11appeared to have a significant
25:14impact in gastroesophageal cancer.
25:18But there is some activity and we're
25:21learning more about who should
25:23get these agents who will benefit
25:26most when and how to use them.
25:29And I think that's where the field is
25:33moving forward in a very positive way.
25:36So there are already FDA approvals
25:41for classical immune checkpoint inhibitors,
25:43and gastroesophageal cancer,
25:45so we can use KEYTRUDA
25:47in patients who failed standard
25:50several lines of standard therapy
25:53if their tumor expresses the target PDL1
25:57that's for gastric and gastroesophageal
25:59adenocarcinomas and it
26:02is also approved in esophageal
26:04squamous cell carcinoma after
26:06standard initial chemotherapy works.
26:09And the results are very
26:12impressive there and it's also active
26:15in a very small subset of patients
26:18whose tumors are characterized by what
26:21we call microsatellite instability.
26:24Or loss of a DNA repair mechanism.
26:27These tumors are characterized by lots
26:29of mutations in abnormal proteins.
26:32And respond very well to
26:34checkpoint inhibitors,
26:36but that's a small percentage in the
26:39range of three to 5%.
26:42So what's most exciting is data that
26:45we heard really just a few months ago
26:48regarding the incorporation of
26:50immune checkpoint inhibitors into
26:53the initial treatment of stage four,
26:56gastric and esophageal cancers.
26:58And so there were a couple of
27:01studies that were presented at
27:04the major meeting in Europe.
27:07Both had similar designs.
27:09One was focused on gastroesophageal
27:12adenocarcinoma and in this study
27:14patients were given either the
27:16standard two drug chemotherapy,
27:19standard of care, or those same
27:21two chemotherapy drugs with no
27:24OPDIVO and again
27:26really exciting results with the
27:28significant improvement in survival.
27:31A higher response rate and
27:33excellent tolerability.
27:35So lots of excitement about that.
27:38And then a second study with a very
27:42similar design of chemo or chemo,
27:44with in this case KEYTRUDA
27:48and here the focus was an again on esophageal cancer,
27:52both squamous and adenocarcinoma,
27:54and again a similar exciting result showing
27:57a significant improvement in survival.
28:00Actually a doubling of survival at two years.
28:04So this is really great news
28:08for patients with these diseases,
28:11and I do think that these studies
28:14will ultimately lead to new
28:16indications and FDA approvals.
28:18We're not there yet,
28:20but I think we're
28:22getting close.
28:25What about in terms of other targeted therapies?
28:27You know we have talked on this
28:30show with other people from other
28:33disease groups and other cancer
28:35types about looking at cancers
28:38and seeing what genes are turned on
28:41and turned off to try to target these?
28:44How much of that goes on in
28:47gastroesophageal cancers?
28:48Are we getting there in terms of
28:50genomic analysis of these cancers
28:53and being able to target them
28:55aside from her 2?
28:58Yes, absolutely, so we routinely
29:00recommend that all patients with advanced
29:04gastroesophageal adenocarcinomas
29:06and squamous cell carcinomas
29:09undergo what is referred to as tumor
29:13profiling or molecular profiling to look
29:16at the genetic makeup of the tumor
29:20to see what makes it tick.
29:23Now we haven't identified a high
29:27frequency of recurring targets.
29:29To date, other than her 2,
29:32but there are targets that are
29:35expressed with reasonable frequency
29:37that are what we call actionable or
29:40druggable where we can develop a
29:42drug or have a drug that potentially
29:44could target that abnormality.
29:46So we've talked at length today
29:49already about her 2,
29:50and that's a critically important
29:53target in those 25 to 30% patients
29:56and again another exciting development
30:01that I think we are on the cusp of is another targeted therapy.
30:03This again is an antibody
30:08that is targeting another
30:10protein called fibroblast growth
30:13factor receptor and
30:16like her 2,
30:17is expressed on the surface and
30:20again in about probably 20 to 30% of
30:25patients is expressed at very high
30:28levels or overexpressed and this has been
30:31a target for the development of an antibody,
30:35and we heard really just this
30:38week from a press release,
30:40so we haven't seen the data,
30:43so we have to stay tuned, that a
30:46study looking at patients who have
30:49this target looking at
30:52these patients and combining the
30:54antibody that targets FG FR2 with
30:57chemotherapy and comparing that to
30:59standard of care chemotherapy alone.
31:02And at least based on the press release,
31:05this looks like it will be a positive study.
31:09So again,
31:09quite a bit of excitement and
31:12buzz in the field.
31:22So there's one example,
31:23there are several others and drugs in
31:26the pipeline looking at other targets.
31:28Doctor Jill Lacy
31:29is a professor of
31:31medicine and medical oncology
31:33at the Yale School of Medicine.
31:35If you have questions,
31:36the address is canceranswers@yale.edu
31:38and past editions of the program
31:40are available in audio and written
31:42form at yalecancercenter.org.
31:44We hope you'll join us next week to
31:46learn more about the fight against
31:49cancer here on Connecticut Public Radio.