Welcome back. I"m so glad you're here to join me today. We're talking with Laosh Pushti, who is the chief of breast medical oncology here at Yale. And we're going to talk about systemic therapy. So, welcome Laosh. >> Thank you Anise, it's my pleasure to be here. >> You know, we've been learning a lot about systemic therapy. Tell me a little bit more about why it's important for breast cancer patients and how you decide which patients need systemic therapy. >> So the goal of systemic therapy is to eradicate run-away hiding cancer cells which may have left the breast before the surgeon actually removed the cancer. So [COUGH] for chemotherapy to be successful in that setting a patient needs to have micro metastatic disease, and it has to be a type of disease that is sensitive to chemotherapy. So we traditionally estimate the likelihood that someone has micro metastatic disease based on clinical pathological variables like the size of the tumor or the number of lymph nodes involved. And a little bit the grade and estrogen and progesterone receptor status and her too which are minor prognostic variables. So historically, we treated patients with systemic therapy particularly chemotherapy, if they were high risk to have micrometastatic disease. There are various algorithms that actually can integrate these variables into a pretty reliable and validated score or an actual percentage that a particular individual would have a 5, 10, 20, 30% risk of a distant recurrence without systemic therapy. The other component, the chemotherapy sensitivity has been difficult to gauge or predict based on essays, however for Positive tumors if you actually have a task which is more or less accepted as a way to estimate the chemotherapy sensitivity of Positive disease, and that is the DX recurrent score. And grade a little bit as well. So, high grade tumors are more sensitive to chemotherapy, and can see the high recurrent score, not only have the higher risk of occurrence, but they also have a higher sensitivity to chemotherapy. So, that's this ideal constellation that makes this essay very useful for Positive disease. So high recurrence score only identifies the group that is likely to have metastatic or micrometastatic disease but it also defines the cancer, that is actually sensitive to chemotherapy. So that's a way how we actually or these are the variables that we take into account. Maybe select patients for adjuvant systemic chemotherapy. So size of the tumor, the modal status, the local type DX recurrent score for Positive disease. And also other variables come into play, like patients preference, comorbidities. >> So how do you decide which chemotherapeutic regimen to give? I understand that there's a whole potpourri of different drugs that you can give. How do you decide which drug is the right one for a given patient? >> I ask my colleagues. >> [LAUGH] >> [LAUGH] So, yeah, so that's something that oncologists oftentimes debate among themselves and it's a constant source of our academic discussions and sort of off the curb consultations. There are multiple ways to approach this. One is that we would like to select a chemotherapy that is the least likely to actually have toxic side effects or side effects and adverse events in a particular individual. So, we know that certain drugs are more prone to cause neuropathy. And patients that have long-standing diabetes or prior neuropathy from other reasons are obviously at a much higher risk to have this than those who don't. Some drugs like the anthracyclins can cause, rarely, but fairly well documented that it can cause cardiovascular problems, particularly heart failure, congestive heart failure. So if someone is high risk for that, then we may have second thoughts about using a regimen that contains anthracycline. But by and large, I think the best strategy is to try to use the most effective chemotherapy regimen that exists. That a particular individual would be likely to tolerate well. So chemotherapy regimens are historically grouped into families, like first generation, second generation, third generation chemotherapy. And this roughly reflects the complexity of the regimens, the number of drugs which are involved, the length of the treatment or the intensity. And also the efficacy. So, first generation regiments are simpler, sometimes less toxic, but also less effective. >> And so when people get first generation chemotherapy, how do you decide whether they should be getting chemotherapy if they're estrogen receptor positive or whether they should just get endocrine therapy, and if they're her2-positive, how do you decide whether they should be getting a her2-targeted agent? And is that always combined with chemotherapy? >> You asked multiple questions. So the first one is how to select estrogen receptive positive patients for chemotherapy in addition to the endocrine therapy that virtually 99% of them receives. So the oncotype type DX test is probably the most helpful and most objective way to define this. Another way to define this is that the current NCCM guidelines call for chemotherapy for basically everybody who has node positive, lymph node positive disease. But this probably will change when the results from the large clinical trial become available. That tested the value of chemotherapy for a group that may have high risk or intermediate risk for recurrence because of the positive nodes. But unfortunately they also have a type of tumor that's not really sensitive to chemotherapy. And that would be the low oncotype DX risk, or intermediate low oncotype DX risk group. So these patients probably would ultimately in the future do better with trying to maximize the efficacy of the endocrine component, rather than adding on chemotherapy that really is just not working on their particular tumor. So for Positive patients, probably the best way to decide is using oncotype DX recurrence score. And another way to use that is if somebody has multiple lymph nodes, then you really want to err on a safe side, even if the chemotherapy's not that likely to work. >> And what about her two patients? >> For her two positive patients, it looks like that if you compare endocrine therapy versus chemotherapy and herceptin. The chemotherapy and herceptin combination is more effective as [INAUDIBLE] treatment. So parts of it relates to the biology of the disease. So if you are an Positive Her2 positive disease, it's not so dependent on Than just an Positive Her2 negative subtype. So because of that most of the Her2 positive patients receive chemotherapy with herceptin. Very important recent development was the identification of minimalistic chemotherapy regiment that is usually quite well to a really it short 12 weeks. And includes weekly pofitaxle along with herseptin that produces very high survival rates when combined with this thermal care endocrine therapy for a subset of the Positive patients. And that subset is less than two-centimeter tumors that are And Her2 positive. And this particular study only included node negative patients. >> Mm. >> And most of the patients were 65 or above, that's actually a substantial sort of minority of the Her2 positive group and for them this was really an important study. So if someone is around 65 or older, is a less than two centimeter tumor which very often the case with this screen detected cancers. And it has a strongly Positive cancer then they actually could get only 12 weeks of chemotherapy with herceptin and their five years survival rates were well above 95%. >> Wow, [CROSSTALK] one of the things that we talked about in the course was the timing of chemotherapy. Whether to have chemotherapy before surgery or after surgery. How do you decide whether patients should have neoagiment chemotherapy before surgery, or agiment chemotherapy, after. >> So neoagiment in chemotherapy today has to input [INAUDIBLE] the case that the particular sequencing it entails. One is that patients end up in a smaller surgery. So that was the initial observation that really introduced neoagiment therapies. That people who presented the [INAUDIBLE] advanced breast cancer were made operable by receiving chemotherapy. Subsequently a few years ago, actually many years ago at my former colleagues in surgery, we have shown that patients, even if they are operable and presented a relatively small tumor, if they receive regional chemotherapy, they end up with a smaller volume being resected. And we assume and we believe that that actually is beneficial because they are not with they with the batisiquisatimatica. The other input information that neoagiment chemotherapy gives is the prognostic information. Patients with extensive residual disease have poor prognosis. So what is happening now, and what's really exciting, is that there are a series of clinical trials that are designed for patients with residual disease. So this really capitalizes on this observation that there are many many patients who are cured with the current existing therapies for those you don't really new drugs anymore. But we can either defy the group who is not having a good prognosis despite getting the best current standard neoagiment chemotherapy followed by whatever is appropriate. Because they had a high rate of recurrence, so for that group, Duke actually had the best state of the art chemotherapy as a neoagiment pre-operative treatment, yet they have residual disease. They actually will have options to go on the back-up sort of agiment treatment regimen. And what this will be, will really be defined by the currently ongoing, sort of, post neoagiment, agiment, clinical trials. So, for triple disease, currently there is a study that uses a drug that we normally don't frequently use in the neoagiment setting. So that's a clinical trial that's open already for patients with residual disease, breast cancer of who have residual disease after the neoagiment chemotherapy with tech center. There's another study which will open shortly which will use a in that setting. It's just approved by the NCI and supported. So that's really a very exciting opportunity. For the Her2 positive patients we had TDM1. So there's a large study that compares extent of care continuing with herceptin single agent versus getting TDM1. Which has shown its efficacy and it's approved in the metastatic setting for patients who failed or progressed on herceptin [INAUDIBLE]. >> So for our audience tell everyone what TDM1 is. >> So TDM1 is an antibody drug conjugate, and it's a very finicky one, because it's really Herceptin or Trastuzumab, and the microtubule binding cytotoxic drug. And it has shown improved survival in patients who progressed on hercepton and and it's a better treatment than [INAUDIBLE] for example. >> So that's why it's only useful in Her2 positive patients? >> Right. Because it's really conjugated to. >> So the other question, and you brought this up, is the whole future of medical oncology and breast cancer and immunotherapy, which is the buzz word that we hear about all the time. And you mentioned immune checkpoint inhibitors. Tell us about the future of immuno-oncolgy and breast cancer. So I think this probably will be the paradigm shifting sort of new therapy that's just really hit the clinical trial phase. So there are two clinical trials, most of them at phase one studies, intrapulmonary metastatic breast cancer of heavily pretreated patients. All these studies we were very involved with Merck, another study by Genentech, and most of these study shows that 20% of the activity response rate which is actually better than with most chemotherapy drugs per use in that setting, third, fourth, fifth line therapy. But the most remarkable feature of this studies was that both of them showed the dose responded at an incredibly long duration of treatments. So incredible that actually in the Merck study, the five patients who responded, three of them are still on the drug over a year. So, this has never been seen before with chemotherapy. And what really makes this sort of really encouraging is that the same observations are panning out in other disease types, lung cancer, gastric cancer, colorectal cancer, subset of colorectal cancers, bladder cancer. So this is really an across the boards phenomenon that about 20, 30% of patient respond and those who respond had this really long duration. In fact the, in a Melanoma, Metastatic Melanoma there are patients who, in Metastatic Melanoma had participated in initial phase one study, eight years ago and they are still cancer-free, progression-free, for life. >> And so these immunotherapies, is that really just recharging your immune system against cancer? Would you ever see a day when we wouldn't need to use chemotherapy, and we can just rev-up your immune system to fight cancer alone? >> [COUGH] So like any treatment modality, how to use a new drug, optimally. It will need to be worked out through clinical trials and it will take, that's what's going to be really the main strain and will occupy, I think, medical oncology for the coming ten years. So we did this with chemotherapy drugs, with one drug to begin with and then two and three and four and five and they combine them and figure out that that there is a max plateau that you can get at and what drugs are safe to combine, so I think the same will pan out or will play out again with the endocrine with the immune modulating drugs. So there are several types of them and then you can, there is good reason to combine them with chemotherapy, with endocrine therapy, with Her2 other therapies. So one reason why probably chemotherapy will stay even when the immune checkpoint inhibitors become a mainstay of treatment is because chemotherapy itself sort of produce these new antigens or release these antigens into the micro environment that the immune system then recognizes. So you could think of chemotherapy as a priming. >> Yeah. The two may be synergistic. >> That's right. Yeah. The really exciting thing within the immunotherapy field in breast cancer and the metastatic studies and it looks like if we can reproduce what happened in melanoma that finally we can say that actually there are some patients in metastatic disease who we can keep alive for a decade or eight years. That will be fantastic. The other exciting thing is that these drugs are moving from the really early Phase I sort of phase into the neoagiment phase. The very idea that by using chemotherapy as a priming, we can increase the response rates that really are associated with this good outcome by adding in and administering simultaneously the immune checkpoint enablers and sort of capitalize on the activity of the human system. And, the third piece is to use these drugs, in the post neoagiment setting. Where, I set off agiment therapy as a maintenance treatment. >> Tell me, just lastly, as we wrap up, about toxicity, and how you think, in the future, we're going to modulate toxicity of our regimens. because a lot of people are worried about chemotherapy, because they're losing their hair and getting numbness in their fingers. >> So I think the best way to actually modulate toxicity is not to give therapy. >> [LAUGH] >> And we're getting really smarter and smarter to select individuals for treatment. So this new mention of medicine paper that came out today which is I guess September the 28th, 2015 have shown that Positive patients with the recurrent score of less than ten really don't need chemotherapy. They just, they can only be so good, but they just don't need that. So we try to re-identify the subpopulation who don't need the chemotherapy, so they won't have side effects. For those who need chemotherapy, I think one tendency's to really sort of identify the group who can actually, then we can scale back treatment. Like I refer to in the HER2-positive space, just giving the weekly Taxol, along with the Herceptins, so that 12 weeks is enough for them. And I think we are getting smarter and smarter in identifying the groups based on their age, their clinical pathological and molecular features. Where we can roll back the treatment, so, that remaining group who really needs the most intense chemotherapy regimens. Thanks for God there are better drugs, palliative drugs. So then you have advances continuously in antiemetic drugs. And really amasasore or nausea vomiting shouldn't be a problem anymore. Hair loss remains an issue, and it's an issue that is very sort of hard to see how we could actually tackle. Other then providing psychosocial support, or neuropathy is another area where relatively little progress has been made. But there are drugs to help. With the, with the symptoms particularly the faint, pain, numbness. And there may be some interesting compounds that actually could prevent neuropathy but they are in the very early stages of development. >> Yeah. >> And of course we can deal with neutopedic fever by using gross metho support by which is been a main stay of therapy to prevent this potentially really serious and life threatening complication. Which is the white cell counts and infections. >> Well it sounds like there's a lot going on in the medical oncology space in breast cancer and tremendous advances have been made and more yet to come. So thank you so much for joining me as my guest today. >> It's my pleasure. Thank you.
