With a particular focus on breast cancer, Dr. Sparano presents on progress in reducing mortality, advancing precision medicine for improved outcomes, and addressing disparities in care and outcomes.
Chapters (Click to go to chapter start) Progress/Declining Cancer Mortality Factors Contributing to Declining Breast Cancer Mortality Precision in Cancer Therapeutics Gene Expression Assays in Breast Cancer TAILORx Trial Precision—Discovery Through Secondary Analysis of TAILORx Tumor Microenvironment of Metastasis Equity—Racial and Ethnic Disparities History of Progress and Precision in Localized Breast Cancer
um yeah for some reason my zoom account on my laptop is not it's not working. So um I will be sitting in for dr thomas today. Who is probably sitting I hope on his balcony, looking at the ocean and not doing email good for him. So um Good morning Doctor Sparano, thank you for doing this today. So um what time is it? 8:31, maybe one more minute and then you take it away Emily. Mhm wow. Mhm. Mhm. I think we should go ahead. Okay thanks. Dr Rauscher. Good morning everyone. Welcome to grand rounds today we're joined by dr joseph Sparano who is the Ezra M. Greenspan Professor in clinical cancer therapeutics, chief of the Division of hematology oncology and deputy director of the Tisch Cancer Institute. He's a medical oncologist whose research is focused on clinical application of biomarkers and breast cancer and developmental therapeutic approaches for breast cancer lymphoma and HIV Associated Cancers. He also currently serves as deputy chair of the Cog A. C. R. I. N. And is the principal investigator and group chair of the AIDS militancy Consortium and is a recipient of funding from the U. S. National Cancer Institute and breast Cancer Research Foundation. Thank you very much for joining us. Doctor Sparano. Thank you. It's it's my pleasure to be here. Um I'll start with just a brief review of my financial disclosures including from industry and um the funders have supported some of the work I'll share with you. The educational objectives are summarized in this slide. I'll be reviewing three major themes that is progress, precision and equity and cancer care. And I'll start with progress um firstly, in terms of the cancer burden of mortality in the United States. As you know, cancer is the second leading cause of of death Behind heart disease and now above COVID-19, which has emerged as the third leading cause of death. Um The good news is that cancer incidents and mortality has been declining for the last 30 or 40 years. And this slide on the bottom right, depicts the number of cancer deaths that have been averted because of these. This progress that has been made much of this progress and decline in cancer mortality has been the result of more widespread use of screening, particularly for breast prostate. Um colorectal and cervical cancer um reduce smoking rates and use of tobacco, but also the more widespread application of adjuvant, systemic therapies and patients with localized disease treated with primary surgical therapy and the emergence of new, highly effective new therapeutic agents. This curve or this graph shows the annual number of new molecular entities and biological licensing applications um approved by the FDA over over the last 30 or so years. Um and you could see this um escalation recently with about 50 new agents approved annually. And as you can see about authorities agents In 2021 and over the last five years have been in oncology. I'm now going to hone in specifically on breast cancer in my area of interest and review the factors contributing to declining breast cancer mortality. There's been a 40% decline in mortality rates. And as I mentioned this has been due to more widespread demographic screening and early detection and the application of adjuvant systemic therapies. We also have better and less morbid local therapies. We've been able to deescalate surgery from mastectomy to now wide local excision. Um and from axillary dissection. Now just a central node biopsy we have better radiation techniques that result in better local control of disease and fewer long term complications. We also have access to better molecular testing such as fluorescent her to uh fluorescent inside to hybridization for protection of her to amplify tumors. We can identify germline pathogenic variants that predispose to an increased breast cancer risk for which we now actually have therapeutics. And we can also identify somatic activate activating mutations in patients with advanced disease um to target specific therapies. And this uh depicts on the right the number of systemic therapeutics we now have including the toxic agents anti estrogenic agents uh anti her two directed therapeutics antibody drug conjugate that can deliver a toxic payload specifically to tumor cells bearing specific um epic tops. Um we now can harness the effects of the immune system with immune checkpoint blockade with antibodies targeting PD ONE and PD 01. There are agents targeting poly ADP ribose that can be uh induced synthetic lethality in uh individuals harboring cancers associated with germline BRCA one or two mutations. We also have agents that can target activating somatic mutations such as Pick three CIA inhibitors with alterations of victory. See a being the most common um alteration in in breast cancer. A critical concept in the evolution of cancer therapy was proposed by the league. Bernard Fisher, a surgeon who posited that breast cancer is a systemic disease from inception and this was a radical and paradigm shifting concept when it was initially proposed because up until that time in the seventies um there was a whole steady in approach to cancer therapy was follow. Whereas more and more local therapy, surgical therapy and debilitating therapy was used to try and get better systemic control of disease. Dr fisher proposed that tumor cells can um see the circulation into the circulating blood and also the lymphatic which can then um see the circulating blood. But evidence from the clinical trials that he led with 20 years of follow up indicated that there was this inexorable annual recurrence risk after local therapy for breast cancer. Whether that local therapy included total mastectomy lumpectomy um with with an axillary dissection or a lumpectomy with radiation providing proof of principle of his concept and that concept or or the principles have evolved since that time and we now know that that there is evidence suggesting that there may be minimal seating from axillary lymph nodes and much much of this seating may actually be directly from the into the systemic circulation. In addition there's now evidence that tourists can self seed that is that you can see the circulation um and then see the primary tumor which can induce epigenetic and other changes that promote further seating. And then you can also have secondary seating from distant metastatic sites. And I'll get back to this concept later building upon this concept and progress was the concept espoused by um the late jonny Bandana medical oncologist that adjuvant systemic therapy and early breast cancer um could help reduce the risk of recurrence if indeed patients had systemic occult metastatic disease that could not be identified and perhaps administering side of toxic therapy in this early Pre clinical stage could help reduce the risk of recurrence. And in fact this was initially proven back in 1976. In addition, Dr Donna Donna was promoted the notion of combination chemotherapy and use this to to affect in treating um and curing Hodgkin's lymphoma. And this same principle was used to was applied to the treatment of early stage breast cancer Fast forward um approximately 30 years or were actually at about that time that Dr. Bandana promulgated this and made this initial discovery regarding the role of adjuvant chemotherapy. Dr Susan Harwood to the Albert Einstein College of Medicine identified um that a natural product derived from the bark of a tree Taxol can promoted microbial assembly um and could actually have an idea plastic effects. and fast forward. 30 years later took about 30 years to prove that this. Um The use of this drug in the adjuvant setting for early stage breast cancer could help reduce the risk of recurrence specifically. Um And especially in patients who had triple negative breast cancer that is tumors that lack the expression of er PR and her two Which accounts for about 15% of all breast cancers more common in younger women and black and Hispanic women. And characterized by earlier time to relapse and for whom we have no specific targeted therapies. Up until recently and in this particular case we demonstrated that the administration of paclitaxel on a weekly basis was associated with better outcomes than other taxing schedules of taxing administration. So this progress within 25 years of Dr. Bandanas. Original report led to the demonstration that adjuvant chemotherapy uh was recommended for most women with localized breast cancer. Based on a US NIH consensus panel Convened about 2020 years ago. And it was based in part on the totality of evidence that was that was present time but also on evidence from clinical trials. Even in patients with low risk lymph node negative axillary lymph node negative breast cancer indicating a beneficial effect of chemotherapy. Well the price of progress was uh both the short and long term complications of chemotherapy used in a potentially curative setting. These included the typical well known complications of chemotherapy including nausea, vomiting, alopecia immune suppression and rarely patients can die from the side side of toxic therapy. There are also long term adverse consequences such as neuropathy infertility um and leukemia, Mds and cardiomyopathy with certain agents. Um There's also this issue of over treatment and that we are some patients would be cured with just local therapy alone. And so for those patients we are unnecessarily administering this chemotherapy and there are issues related to cost financial toxicity, the cost of treatment, the disruptions and unlike the ability to work uh and and the resulting loss of income. So we clearly needed better precision in cancer therapeutics. And up until I would say the last 15 years, the print. The major principle in treating a patient with adjuvant therapy with early breast cancer was prognosis. In other words, we we recommended chemo based on on those individuals who had a higher risk of recurrence, based on clinical pathologic features such as nodal status, tumor size and grade. And in this case, If one applies an adjuvant therapy, one will see an improvement in therapy um at all risk levels, but one can't really distinguish which patients are deriving benefit so that the higher the underlying risk of recurrence for those patients on the rights and decided part of this curve drive greater absolute benefits than those who are who have a lower risk of occurrence within the last 20 years. Now we've used biomarkers such as the expression of the estrogen progesterone receptor protein expression and her too protein expression and gene amplification to identify patients who can benefit from specific therapy. So we can now identify who is benefiting from specific therapies. And these biomarkers have an essential role in the management of early breast cancer and a variety of cancer uh types. But in order to rely on these breasts on these markers, one needs to assure that they need certain criteria. Firstly there needs to be analytic validity that is, the acid needs to be reliable and reproducible. Second, there needs to be clinical validity. That is the association with a biomarker result and a clinical outcome. But thirdly and most importantly, and this applies to some of the gene expression profiles that I will describe to you in a minute. There needs to be a value in the management of patients in guiding treatment which is associated with an improvement in clinical outcomes. And these criteria are derived from the gap um guidelines which were specifically derived to provide a guidance or framework for the use of gene expression profiling in early breast cancer and other cancer types. Um and just to point out that there are specific guidelines for the for the use of her two testing um and estrogen and progesterone receptor testing. So here's one example of precision that is that hormone receptor expression is predictive of benefit from adjuvant anti estrogen endocrine therapy, namely tamoxifen. So moving from the left to the right, you see greater benefit from tamoxifen and those patients who have estrogen receptor positive disease and less than those who have positive progesterone receptor negative, very little benefit and poor disease and no benefit in patients who have er and PR negative disease. The second example of precision is her two over expression which is predictive of benefit from anti her two therapy when using the advanced setting. The figure on the right shows the time to recurrence. For those treated Who had heard two specifically had her two over expressing diseases is a meta analysis of nearly 14,000 patients demonstrating that the addition of trust to chemotherapy could reduce the risk of recurrence by about 1/3, resulting in a 10 year gain of about 9%. The figure on the right shows the that the same therapy transit in a prospective randomized trial had no beneficial effect in patients who had heard two non amplified disease but low levels of protein expression. The third example of precision is the activity of inhibitors part inhibitors and patients who have um breast cancer associated with pathogenic germline variants and braca one or two that are associated with a market increase in breast cancer and ovarian cancer. Risk the use of part inhibitors in this population in these patients in these patients can induce synthetic lethality specifically in the tumor by blocking a second um mechanism of DNA repair. With one mechanism DNA repair already being knocked out by the absence of a functional protein. And here you can see when used in metastatic breast cancer in patients who had germline mutations. The this particular drug elaborate had only a very modest effect in improving progression free survival. And this was based on a blind and independent central review of imaging studies. And this study here on the left led to FDA approval even though the drug did not improve overall survival, it improved the clinical endpoint uh progression free survival. The figure on the right shows that the use of the same agent which was only marginally effective in metastatic disease, actually had an improvement in invasive disease free survival Um when used in early stage breast cancer in patients who harbored Braca one or two mutations. And in fact the FDA just approved Elaborate in the adjuvant setting in patients with Bracha one or 2 mutations last Friday I'd now like to move on two. The use of gene expression assets which I would consider the third generation of biomarkers um to guide the use of adjuvant chemotherapy recall that I previously pointed out that up until recently recent being the last 15 or so years, we've we've um recommended chemotherapy solely on the basis of the patient's underlying risk. And we've dialed down that risk level so that even patients who had relatively low risk of recurrence, we were recommending adjuvant chemotherapy such that The absolute benefits were in the range of only about 3-4%. So we had to treat, we're over treating many patients. Um What made this possible. One of the first reports was of gene expression in breast cancer was an unsupervised analysis demonstrating that breast cancer is a heterogeneous disease with distinct subtypes whose prognosis varied by subtype and subsequently unsupervised analyses where gene expression patterns were compared in patients who relapse versus had no relax. There were several prognostic essays that were developed and it was shown that there was a lack of concordance in the prognostic classification by these essays. one of these essays Was the 21 gene expression of recurrence score type and shown here is um the genes that are involved In in this essay including five genes that reflect proliferation for that reflect reflect sector signaling to that reflect her two signaling to invasion and three other individual genes. The expression of these genes is normalized relative to a reference range. And then plugged into a coefficient. So you can see that those genes reflecting proliferation drive the score up there associated with the positive coefficient ah And the proliferation coefficient has the highest number associated with this. This really drives the score up the her two group you can see also drives a score up whereas the er score drives the score down and this is in the presence of anti estrogen therapy which is helping drive this more favorable prognosis. You can see these other individual genes also had some prognostic effect either in a positive or negative direction but the coefficients are less having a less less dominant effect on driving the score. And in the original cut points that we used, patients were classified as low intermediate or high risk based on recurrent scores and these ranges. And then we embark on a large randomized clinical trial that where we adjusted these ranges to try and refine the prognostic and predictive ability of of this essay. The first evidence That provided level one be evidence and extra positive no negative disease was a prospective validation of the 21 gene recurrence score for prognosis. And this showed that overall Um if you look at the proportion of patients who had a low intermediate or high recurrence score by the original definitions, about 50, and 25% of patients fell into these three groups and the ten-year risk of distant recurrence. For those who had a low intermediate and high recurrence score was 7, 14 and 31%. Well that's important. But the game changer and this was remain significant in a multi varied model and it was independent of age and size. But the game Changer came when it was demonstrated that high recurrence score greater than 25 was predictive of chemotherapy benefit In a her two negative population. So here the 10% of patients who had heard two over expressing disease were excluded. And that was because at about this time her to direct therapies became a um standard part of a german addition to adjuvant chemotherapy. And so you can see these patients have a hazard ratio of .27. So rather than having about a 25% reduction in the risk of recurrence from The addition of chemotherapy, they have a 75% reduction in the risk of recurrence and this translates into about a 25% absolute improvement and um disease free survival which was statistically significant. In addition, the local recurrence score was predictive of benefit from tamoxifen again, because high er signaling is driving the prognosis here in independence when this as they became commonly used in clinical practice in situations where there was where there was therapeutic equipoise and Esther receptor positive, her two negative no negative breast cancer, which accounts for about half of all breast cancers in the in the US and About 8% of all cancers in the us. It was found that the majority of patients, About 2/3 had a recurrence score. That was in the mid range between 11 and 25 and there was still therapeutic echo points about the value of chemotherapy. So back in around 2005 we designed a trial that was designed to address this conundrum. Um The population included patients with no negative or positive, her two negative disease Basically stage one cancer. Um and there were about 10,000 patients enrolled in this trial of uh and for those patients in whom they were, we had evidence level one be evidence where we were confident in the in the recommendation, we guided these patients to endocrine therapy alone if the recurrent score was low or chemo plus endocrine therapy. If the recurrent score was high based on the data that I just showed you. And for the remaining two thirds of patients where the recurrent score was in the mid range. We randomized those patients to the standard arm which was endocrine therapy plus chemotherapy or to the experimental arm which was endocrine therapy alone. And we used a non inferiority design with a hazard racial margin of 1.3 3 2. And we expected full information after 835 invasive disease free survival events. We had the first results for the low risk registry back in 2015 when we showed that in the 16 or 17% of patients who had our current score of 0 to 10 who are prospectively assigned to endocrine therapy alone, they had a Only about a 1% risk of less than 1% risk of distant recurrence at five years. Another key point here is you'll notice that The invasive disease free survival rates about 94%. So in other words for everyone, This recurrence, there was about four or five non recurrence events. Either I should say either a local regional recurrence or a contra lateral breast cancer or a second primary breast cancer or death from other causes. And this information It was published and it was integrated into the 8th edition of the A. J. c. into a prognostic staging for the first time in early breast cancer. We then had the results from the from the primary Trial results in the randomized group after 836 invasive disease free survival events. These events included distant or local regional recurrence, second primary cancer or deaths from other causes after a meeting of 7.5 years. And of these about 40% of these patients have recurrence as the first event of which about 25% was a distant recurrence. And we demonstrated for the primary endpoint non inferiority for invasive disease free survival um And non inferiority for distant relapse free interval. So the primary trial endpoint was met and we changed the standard of care. My demonstrating that chemotherapy was unnecessary for about 70% of all patients with early breast cancer. We also followed patients assigned to chemo plus endocrine therapy who had a high recurrence score. And we found that these patients had a worse outcome compared to those who had a low recurrence score irrespective of therapy despite the use of adjuvant chemotherapy. Um So the question is how would these patients have done had they not received um chemotherapy? Well this is not a substitute for a randomized trial but we simulated what the outcomes would have been in this population based on the treatment effect for chemotherapy. We saw in the earlier b 20 cohort and what we see here for, for patients who had a recurrence score of 26 to 30 Which accounts for about 40-50% of patients who have a high recurrence score, there's about an 8% absolute improvement in invasive disease free survival. And for those who have the remaining half who have a higher recurrence score, there's about a 30% absolute improvement. So very substantial improvements. Some of the other key findings from this trial Are shown here. 1st, clinical pathologic factors added to the prognostic information, but we're not predictive of benefit for chemo. Second, there was no chemo benefit in both the low or the high clinical risk groups as defined here. And thirdly, we saw statistically significant chemo treatment interaction. There was a two way interaction between age and chemo benefit and a three way interaction between age or menopausal status recurrent score and chemotherapy benefit. So that for patients who are under the age who are 50 or under who had a recurrence score of 16-20, they had about a 1.5 to 2 Um, absolute improvement in in distant relapse free survival in nine years. And for those who are recurrent score of 21-25, Defly substantial benefit of about 7%. When we look at this as a continuous variable adjusting for tumor size and grade. Again, we see no benefit at all for for women over 50. But we do see these curves diverge the endocrine therapy alone curve versus the chemo endocrine therapy curve, indicating indicating there's some chemo benefit within this range. And in fact, if we look at population based data, Um we see a similar phenomenon where there is a chemotherapy benefit emerges at a different recurrent score. Cut point for a woman over the age of 50 compared with women 50 or under. And if we compare the outcomes in the taylor X, so called taylor X trial, We see again, benefits for a woman who are 50 or under and premenopausal have a high clinical risk, but no benefit in older women. The same was true in another trial using a different gene expression profile called Our Mind at trial and also Similar effect. Was seen in another trial called the responder trial, where we use the same 21 gene recurrence score, but now tested this in patients with 123 positive nodes. And here you can see there's a chemo benefit in the range of about 5-6%. What's driving this chemo benefit. Well, it may be the chemotherapy induced early menopause. There is data from previous studies demonstrating a benefit for those patients who developed a Maria compared with those who do not develop chemotherapy induced gonorrhea. Um in both overall survival and left and disease free survival on the right and on the bottom, you can see this benefit is seen only in patients who have hormone receptor positive disease and not in patients who have hormone receptor negative disease. So we really need a trial to address this remaining knowledge gap and premenopausal woman who have a high clinical risk and a low genomic score comparing ovarian function suppression, essentially complete estrogen blockade with ovarian function suppression and an aromatase inhibitor versus chemotherapy plus the same adequate therapy. This Trial was attempted approximately 20 years ago before we had gene expression profiling but we and it closed due to poor cruel. But we may see this trial uh in in order to address this remaining knowledge gap. Well I told you that the um clinical pathologic features still provide very useful information above and beyond The 21 gene recurrence score. How do we integrate that and combine those two pieces of information to make better informed decisions. In order to address this, our group embarked on a project two to develop this model that we call RS Clin. Where we performed a patient specific meta analysis using data from some of the trials that I showed you for individualized prognosis and individualized prediction of chemO benefit. The factors the co variance we used included the 21 gene current score, tumor grade size and age. And we perform this meta analysis using cox regression of previous trials for the um law accumulative hazard estimate for prognosis For 10 year distant recurrence rate. And we combine this with cops regressions for chemotherapy benefit to estimate chemo benefit. We then performed once the model was developed, we performed external validation to compare the R. S. Clean risk to the observed distant recurrence risk in a real world experience in a a registry in Israel. And what we show here is that the Rs Klain provides more prognostic information than clinical pathologic features alone. Or the recurrent score alone shown here are the likelihood ratio chi square, which captures the amount of information provided by a model. And the likelihood ratio test, Which compares the amount of information provided by the two models. When the Rs clint is compared to clinical pathologic features alone. The likelihood ratio test favors Rs Clin and likewise when Rs clinton is compared to a recurrent score alone, it also favors Rs Clint. Therefore, the likelihood ratio tests confirm that the Rs clean model provides more prognostic information than either the clinical pathological variables alone or the recurrent score alone. This graph shows the external validation and it shows the average R. S clinton distant recurrence risk for the cohort in blue compared with the actual Kaplan Meier risk estimate observed in the cohort shown in quintiles and as you can see the risk estimate provided by the R. S. Clean tool was significantly associated with this recurrence rate with the standard standardized hazard ratio of 1.73 and furthermore the calibration plot on the right demonstrates a link concordance correlation of 0.962 between the distant recurrence risk estimate provided by Rs Clyne and the actual outcomes in this population. And then finally, in order to distinguish prediction versus prognosis, we calculated the RS plan tenure, distant recurrence risk in a what we call a clinical low risk and a clinical high risk scenario described here on the top of each curve. Um The two figures show the RS Klain estimated absolute chemo benefit in a typical clinical low and high risk scenarios from 55 year old woman. And as shown in the black solid line representing the RS clint estimate compared with the red dotted line indicating no prognostic or predictive effective or current score. And this is this is a counterfactual. The RS Clinton estimated absolute chemotherapy benefit varies widely, with a recurrence score ranging from 11 to 15, both scenarios from both 0 to 15% in the low risk group and 1 to 33% in the high risk scenario, as shown in the table below the figures. And this is and this This is much a narrow estimated absolute chemo benefit in a hypothetical scenario, a contra factual scenario where the chemotherapy benefit, hazard ratio is held constant with a varying 21 gene recurrence score. So this I think model or modeling um provides and distinguishes the predictive versus prognostic information provided by the 21 gene recurrence score, and how does this apply to a real world patient? Well, if you had a typical 55 year old patient with a two centimeter tumor and intermediate grade histology, um without the recurrent score, You would estimate this patient mate might have about 7% or so recurrent score. Excuse me, Risk of distant recurrence without the recurrence score information. But here you can see With a recurrence score of 10, 20 or 30 the tenure these these patients would have this patient have very different outcomes. The tenure, distant recurrence rate with endocrine therapy alone would be 47 and 11 and the estimated absolute chemotherapy benefit would be 1% or less for the Lower scenarios but 6% for the higher a scenario. I'd like to move on now to show other examples of precision through and discovery through secondary analysis of clinical trials And in this secondary analysis of this trial, we looked at patients who are cancer free. Five years after diagnosis and did a simple blood test looking for the presence of circulating tumor cells which we found in about 5% of the patients and these patients had about a 13-fold higher risk of recurrence. We also looked at the presence of circulating cytokines in the blood at the time of diagnosis using a discovery based platform and found that Serum Aisle six was prognostic for early recurrence of breast cancer. The take home message here is that we may be able to further refine prognostic utility and biomarkers through the application of other biomarkers added to the ones that I've already shown you. Well I've shown you before that distant metastasis is the primary cause of death despite local presentation of local therapy. I've also shown you that more aggressive therapies such as mastectomy does not reduce recurrence and there is this continued risk of recurrence beyond 5-10 years, especially in er positive disease. I've also shown you that adjuvant that biomarker directed adjuvant systemic therapy reduces recurrence risk and breast cancer mortality, including endocrine therapy for the 70% of patients with you're positive disease. Anti her two therapy for the 20% with her two positive disease and chemotherapy and and high risk disease. But some are cured with no therapy and others are not cured despite of therapy. And so uh one fundamental problem here is that there are no biomarkers that reflect the underlying metastatic process or and there's no treatment that can block metastases. So 11 strategy would be to advance precision through science by better understanding the mechanisms of metastases and I present to you. One mechanism here and this is the discovery of a of the micro environment has the so called team in which my colleagues at Einstein believe is the doorway from a task this and this was demonstrated initially with intra vital imaging using fluorescent labeled cells in a model here. You see dexter and red within the blood vessel. Um And you see green tumor cells in the institution. And you see these blue um macrophages that are adjacent to the um to the blood vessel and right next to um a tumor cell. And this tripartite structure is we've dubbed the team M. And we believe is the point of entry into our cells into the circulation. And in this P. Y. M. T. Model you can see this green tumor. So when it when it is now superimposed on this blue macrophage uh it now appears yellow. And you now see these green tumor cells in the circulation. And conversely as these cells are entering into the circulation. You see dexter and red exiting into the extra vascular space. And so you see this bursting phenomenon at these TMM sites in this P. Y. M. T. Model. Um And in this model it was demonstrated that the our cells enter the circulation at the same at around the same time that this bursting phenomenon occurs. Well it turns out that one can identify These team and structures by using a triple immune in Spain that I for CD 68 to identify macrophages CD 31 of blood vessels and a pan minna antibody that can identify this sub population of invasive um tumor cells. And where these three cells are in direct contact is called the team structure. And this has been shown to be prognostic and er positive breast cancer and three in independent cohorts involving about 1100 patients and it's significantly higher in er pr negative disease which we know has a higher risk of recurrence than er positive disease. It's also been shown that the TMM are present in lymph nodes and distant metastases in human breast cancer and in this and then yet of the patients that I treated um quite some time ago who had early stage breast cancer in a low recurrence score treated on the taylor X. Study who developed lung metastases. Seven years later we showed that the team was were identified in the lung and that the primary had a high TMM score explaining the conundrum of why this patient with a low recurrence score relapse. We also showed in a Prospective validation study involving nearly 300 patients who had a positive her two negative breast cancer, 103 nodes who were treated with adjuvant chemotherapy and for whom we had recurrence. For information that that the team m score provided independent prognostic information for those who had a mid range of the current score, especially if you compared high versus low Team in density. There was a 4-fold higher risk of recurrence. We also demonstrated that in patients treated with neo adjuvant chemotherapy. If you look at team and density in the primary before therapy compared with after chemotherapy in residual disease at the time of surgery with the red line indicating a high team in density associated with a higher risk of recurrence. You could see that in the majority of patients there was actually an increase in team in density in the residual graph on the right shows that this difference was statistically significant. We then went from the bedside to the bench and try to recapitulate this in animal models. Um And we demonstrated that the that chemotherapy in this model increased the team M. Score and circulating tumor cells despite decreases in tumor size in both the P. Y. M. T. And P. D. X. Models. So four different models um demonstrating an increase in TMM score in the primary and an increase in circulating tumor cells despite the fact that the we're actually decreasing in size. So the take home message here. And our interpretation was that as the tumors shrink, they may become more efficient in disseminating tumor cells which we believe is a previously unrecognized mechanism of resistance to side of toxic therapy. So how do we overcome this? Um The uh my collaborators pursued a strategy of targeting tie to um the tie to and using a tie to Canada's inhibitor called which um we believe can block T. Mm function. And Travis ation and tacis. This blocks the tie two receptor on these tie to hive edge of high sub population of macrophages that are part of the team structure pants Release of. Andrew code in two by the Niels Elvis triggers, Binds the type two receptor triggering Lisa Jeff which then causes in the field cells to contract them when they contract around the rigid TMM structure. This opens the door to allow cells to um And Travis 8 to the circulation. And here red cells to burst into the extra vascular space. In this pre clinical model we demonstrated that the tie two inhibitor rubasinghe. It can decrease the amount of deck strand bursting uh and can also decrease the amount of circulating tumor cells in the circuit in the in the blood and can when added to chemotherapy reduced the number of lung metastases here you see lung metastases on the left and untreated animal and after treatment for a blockage of reduction in the number of metastases. And you also see an effect on the primary tumor, possibly through its anti angiogenic effect. So based on this we performed a first in human trial combining with masculine plus anti tubal in therapy using this drug Avastin, which was initially developed as a pcr able inhibitor and used in leukemia. And it was found that it wasn't a great leukemia drug but it's a very good inhibitor of tie to. And in this study it was found that there was an increase in engine poet and to which is a far more dynamic biomarker of tie to blockade. When we use this with paclitaxel rebellion. We saw in some patients striking anti tumor effect. This is a patient with a large fun getting breast mass which completely resolved with therapy and we saw pharmacy dynamic effects with decreasing um circulating tumor cells and increased and reporting to. We also saw a dose dependent effect Of an increase in ocular pressure. We saw this with 100 mg dose of Avastin compared with baseline in the orange here and a lesser increase in intraocular pressure At the 50 mg dose level. Why is this? And is this a pharmacare dynamic biomarker? Well, it turns out that tie to um are is located in epithelial cells of the slims canal Deletion and that deletion of protein one and 2 and tied to adult mice results and severely impaired. Uh So schon canal integrity and Transito sis resulting in increased intraocular pressure, which is a hallmark of open angle glaucoma. So this might be a problem endemic biomarker that we can use And we're currently pursuing other inhibitors of tie to that may have less off target effects compared to the ones we saw in our face Our Phase one Trial. Finally, I'll conclude with equity, a discussion of equity and Um certainly the COVID-19 pandemic has uncovered um racial and ethnic disparities and healthcare outcomes. As you can see here, um mortality rates for blacks or african non hispanic blacks or african americans. Hispanics or Latinos are substantially higher compared to covid related mortality for whites and in our experience at Montefiore. Nearly 6000 patients who presented with covid over a one month period of time of whom 16% of patients succumb. Uh we found that Hispanics and non hispanic blacks had substantially more morbidity ease than non hispanic whites. And after controlling for age, gender, socioeconomic status and comorbidities compared with non hispanic whites. There actually were somewhat lower mortality rates in Hispanics and non hispanic blacks uh indicating that um that addressing these disparities and comorbidities could help result in better outcomes. We also saw a very high case fatality rate early on in the pandemic for patients with cancer proposing another barrier. Well, these racial disparities are well known and well documented in a variety of cancer types, but particularly for breast cancer. And as you can see, And as I showed you before, cancer mortality rates are declining substantially over the last 40 years. But there remains this racial divide um between between blacks and whites. And there are many reasons for this and this includes more advanced age at presentation, higher rates of triple negative breast cancer morley for form of breast cancer, higher obesity rates, more comorbidities. Disparities and care and other social determinants of health and certainly addressing the social determinants of health are necessary, but it isn't really sufficient for addressing some of these disparities. Well, there is some evidence that at least in respect of breast cancer may not be because we seem to consistently observe racial disparities and extreme receptor positive breast cancer and clinical trial cohorts. And we focused on clinical trial cohorts because these are patients who are healthy enough to participate in cancer. Clinical trials have access to good health care and are getting state of the art care in the context of a clinical trial. And when we looked back at racial disparities now come in in one of the trials, I initially showed you that showed the value of a given paclitaxel. 8% of these patients were black. These patients at stage 2-3 disease. We see it we saw about a 1.6-fold increase in recurrence risk, specifically in black woman who had a positive her two negative disease. This was by self identified race. And we did not see this in other health care and other breast cancer subtypes. We saw the same thing in another study where patients received chemotherapy. Here there was a 1.5-fold increase specifically in er positive her two negative disease but not the other subtypes. And this wasn't patients who had um african american ancestry defined by ancestry, informative markers. We then looked at the Taylor X population. Again, these were patients who had the lowest risk disease, even positive, her two negative. They all had the 21 gene recurrence score. And here we also saw racial disparities uh by self identified race. We then looked at our at our cohort at Montefiore Einstein were about a third of our patients were black. And here we saw a 1.8 fold increase in risk and specifically in your positive her two negative disease, not the other subtypes. And we also looked at the national cancer database. Um And here we see a 1.25-fold increase in mortality by self identified race. When we took a deeper dive into Teller X. We found that these racial disparities were not explained by earlier discontinuation of endocrine therapy. Clinical pathologic characteristics, differences in the 21 gene recurrence score, insurance coverage or the neighborhood deprivation index indicating there's something going on here that we can't put our finger on. In order to address these disparities. We've initiated trial which is now nearly complete where we try to identify address the neuropathy that seems to be taxing induced neuropathy which is a major side effect of taxing associated adjuvant chemotherapy. And we previously demonstrated that uh women of african american ancestry and this is with ancestry informative markers have or more likely to get Grade 2-4 neuropathy from taxing. Then your women of european american ancestry and they also had worse outcomes. And we've identified um specific genotype associated with um a higher risk of Grade 2-4. Treatment associated neuropathy um which can be distinguished from a low risk phenotype. And we've now nearly completed a cruel about 240 patients in this N. C. I. Sponsored trial for patients receiving one of two types of taxing therapy where we're attempting to prospectively validate the ability of this germline predictor of Taxol induced neuropathy to identify patients of african american ancestry who are most likely to develop uh neuropathy. The notion here is that we might be able to use this genotype to to direct patients to a specific type of chemotherapy associated that they may need to help reduce their breast cancer recurrence. Um But uses a type of chemotherapy that may be less associated with neuropathy. So this is my final slide and it concludes the history of the progress and precision and localized breast cancer. Um in 1976 when Dr Bandana made his first seminal report. Compared to today at that time screening for breast cancer was not a proven value. Local therapy consisted of mastectomy and axillary dissection. There were no systemic therapies that were proven to be a value in reducing the risk of distant recurrence and there were no biomarkers. Today. We have effective screening tools such as digital mammography, an average risk patients or M. R. I. And high risk patients who have genetic mutations that can identify breast cancer. That's early stages of disease where it's more amenable to cure with local therapy alone. We're using less surgery rather than mastectomy and using wide excision and sampling 123 sentinel lymph nodes rather than doing level one and two axillary dissection which is associate with less morbidity and we're using better radiation techniques treating either the whole or partial breast which results in better local control without sacrificing local control and lower long term toxicities. We now have a slew of systemic therapies that can help reduce the risk of systemic recurrence, including anti estrogen therapy, chemotherapy, anti her two therapy immune checkpoint blockade and coming down the pike antibody drug conjugate. Um And we now have biomarkers that can identify tumors that express er PR and Her two that can guide the use of a german endocrine therapy. And her two directed therapy, we can identify germline biomarkers that are associated with increased a breast cancer risk that might identify patients who can have prophylactic surgery, prophylactic mastectomy or Affleck. To me too markedly reduced the risk of developing cancer in the first place or guide the use of achievements of therapies such as part prohibit Urz. We also have somatic gene expression essays um that can guide the use of targeted therapies such as the CIA inhibitors which I did not get into. And finally we have blood based biomarkers such as circulating tumor cells and circulating tumor DNA which we can use for surveillance or guiding uh the use of systemic therapies in patients with advanced stage breast cancer and um in the future early stage breast cancer. Thank you for your attention. Thank you very much. Dr. Sparano. This is a terrific talkin, you know, coming from 1976 to 2022, we've got a lot of reason for optimism. Thanks to you and your colleagues in this terrific work. Um There are already a couple of questions in the chat. Um dr Greenberg starts off with. Has anyone seen enough What moving around? Has anyone seen enough male breast cancer patients to compare with female patients in any of these areas that you've described? Well for every for every 1000 breast cancer, there's one um um man who developed breast cancer. I have a number in my in my practice now. Um we we uh breast cancer men tends to occur in older men Um more likely to be estrogen receptor positive and her two negative. Very very not infrequently, I should say, associated with germline pathogenic germline variants in the BRCA two gene, otherwise the principles of management of male breast cancer are quite similar to the management of breast cancer. Uh in in women with the exception that for anti estrogen therapy, tamoxifen is really the preferred agent compared, say with aromatase inhibitors which cannot be used and then without the use of um in uh analog which can induce significant, you know, morbidity. And and my second question, has anyone compared two or more of the gene platforms in the same patient, That's an important question. Um They yes, they have been used. It's not uncommon that if patients have a high recurrence score, They may have say Amanda Print SA 17 essay as a tiebreaker. Uh and um in those circumstances? I think it's important. And as I've shown you, they just briefly touched upon it. There are several gene expression essays that have been shown to provide prognostic information. The 21 gene recurrence score is the only one that seems to show predictive information for Chemo benefit. That may not just be a function of the essay itself. And what drives of the prognosis and prediction in the essay. Because most of these essays are really driven by Estrin sectors reflecting reflecting extra receptor signaling and proliferation but may be a function of the populations that they were validated in getting access to these clinical trial cohorts uh is very challenging and there are very few of them and the ones that provide most value are the ones that were patients were randomized to one treatment or or another treatment. So, um I think the most important point take home point is number one. These essays do not classify patients in the same way as high or low risk point. Number two is that fewer patients are classified as high risk. Using the 21 gene recurrence score, it's about 20% Compared with the other essays, which is in the range of 35-40%. And if the purpose of two of using these essays is to spare the use of chemotherapy, obviously one would want to use it in a population that assigns the fewest patients to the high risk category. And thirdly, if one is going to use these essays for guiding the use of chemotherapy. My opinion is that one should use the essay where there's the highest level of evidence supporting their intended use. So that's an indirect way of addressing that question. Without calling out a specific um gene expression essay. Okay. Um a couple of typos in the next one but I'll take a crack at it. There's obesity of postmenopausal women show increased recurrence and invasion um s of estrogen and macrophages. Um Yeah that's an excellent question. Um We um one of the points I tried to make in the talk is that oftentimes you know, we designed a prospective clinical trials that are done in the N. C. I. System to address the specific question. But oftentimes we learn more from the secondary analyses from those trials. Um And I showed you a couple examples of those um About 10 years ago we published a report In the same trial I showed you earlier the E1199 trial demonstrating that obesity was associated with a higher risk of recurrence. Which wasn't a new observation in early breast cancer. Because 40 previous studies had shown that what was different about our the result was that we identified an interaction between obesity and high recurrence rate and er positive her two negative disease that report which got a lot of attention then triggered a meta analysis by the early breast cancer collaborative trial list group. Um and in this meta analysis including about 100,000 patients. We found a very similar interaction that is an interaction between obesity and high recurrence rate specifically and positive? Um Her two negative disease? The reason and more so in younger patients than in older patients. And that may be for several factors that may be inflammatory cytokines that are driving. This aisle six is an example of an inflammatory cytokine that I showed you um that's associated with higher recurrence rate. Um And there may be multiple factors, other factors such as estrogen and say hyper insulin e mia that could be driving this. Regarding the macrophages. I've shown you a potential essential role of macrophages and um in driving metastases and this is a major area of investigation now of therapies that are they're targeting macrophages to try and prevent um metastases. I also see a question about tills or tumor infiltrating lymphocytes. Those have shown to be prognostic and ah localized triple negative breast cancer. Higher till expression is associated with a better uh prognosis. However, because of issues related to um we analytic validity and reproducibility. Uh these have not yet been integrated into the um prognostic classification for early breast cancer. Alright, we've hit we're actually past the end of the hour so if anybody has to leave, please do. But we'll try to get this last question from DR Chen answered by Dr Sparano. How are the activated macrophages participating in the metastases this tie two inhibitor target the tumor. Is it mainly interfering with macrophage response. Yes. I showed you the example of our efforts to do exactly that using the drug. Um It turns out that that drug uh which which binds to the tie two receptor on this tie to hy vee jet high uh macrophage um and had the clinical effects that I showed you including pharmacy dynamic effects with reflecting reflected by increased intra ocular pressure. That drug also had off target effects it hits the tanker raises and because of that it was associated with musculoskeletal toxicity. So the company, the company that's developing that drug is developing a second generation tie to Canada's inhibitor that has less off target effects on the tanker raises. And we hope to be pursuing clinical trials and and resuming that therapeutic strategy. Okay well thank you so much dr Brown for this terrific talk and update and we look forward to hearing more again in the future. Thank you for the opportunity to share my work. Alright, be well everybody. Thank you
