® sat down with Sanju Sinha, a PhD candidate who works with computational biologist Eytan Ruppin, MD, PhD, at the National Cancer Institute, to discuss an abstract presented at the recent American Association for Cancer Research (AACR) Annual Meeting 2021 on tumor mutational burden (TMB) as a biomarker for PD-1 inhibition. He and his team determined that in certain tumor types, the effect of TMB on therapy response varied between genders.

There are primarily 3 takeaways from our study, and it is important to note them in order. We first observed that, in melanoma, there is a marked difference between the survival between these 2 groups of low versus high TMB in males versus females. Specifically, TMB is able to stratify the responders in female patients but not able to stratify these responders in male patients. This is the first record.

The second takeaway is that we found no such differences in lung cancer, even though we had quite a large [number of patients with lung cancer]. The third takeaway is that we, indeed, found such differences, then we extended analysis to [seven] different cancer types. And these differences, very specifically, are present in 2 cancer types, glioblastoma and cancer of unknown origin. However, we must note that these differences [were recorded with an] effect size that is not significant. We do need to still repeat this analysis. We are actually encouraging other researchers to repeat this analysis in different large, independent cohorts.

Sinha N, Sinha S, Cheng K, et al. The recently approved high-TMB criteria may introduce a sex bias in response to PD1 inhibitors. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract 29.

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CancerNetwork® spoke with Sanju Sinha of the National Cancer Institute about the resulting data from his research into sex differences associated with using tumor mutational burden to predict response to PD-1 inhibition.

NCI Investigator on the Results of a Study Exploring Sex Bias Related to TMB as a Biomarker of PD-1 Inhibitors

The addition of systemic high-dose methotrexate (MTX) to intrathecal (IT) MTX treatment led to a lower incidence of central nervous system (CNS) relapse for patients with high-risk diffuse large B-cell lymphoma (DLBCL), although these data were not statistically significant, according to research published in 

“Our study on the [real world data] add to the growing body of nonrandomized data favoring the combination strategy of systemic high-dose MTX and IT MTX for the prophylaxis of CNS relapse in DLBCL,” wrote the investigators.

A total of 110 of the 145 identified patients with DLBCL who received CNS prophylaxis were included in the study’s final analysis. These patients received standard systemic therapy and were divided into 4 separate groups based on CNS prophylaxis strategy and risk categories via the CNS International Prognostic Index (IPI).

Group 1 included 46 patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy with or without rituximab (Rituxan) plus IT MTX alone. Group 2 had 12 patients receiving CHOP therapy with or without rituximab plus high-dose MTX alone. Group 3 included 41 patients who received CHOP therapy with or without rituximab plus IT and high-dose MTX. Eleven patients in group 4 received Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) chemotherapy plus IT MTX and/or high-dose MTX.

The CNS relapse rate at a 3-year follow-up was 8.6% in group 1, 8.3% in group 2, 4.8% in group 3, and 18% in group 4 (

 = .64). Using CNS IPI risk categories to evaluate high-, intermediate-, and low-risk groups, the CNS relapse rates were 16.6%, 10.1%, and 0%, respectively.

More, the 3-year overall survival rate was recorded at 69% for group 1, 75% for group 2, 80% for group 3, and 45% for group 4 (

“In this study, we have presented real-world data on 110 patients with DLBCL who received three different strategies of CNS prophylactic therapy and compared their outcomes within the limitations of a retrospective review,” wrote the investigators.

The research team acknowledges the potential for bias in this retrospective analysis but explained that the implementation of the CNS IPI to categorize risk helped to mitigate “heterogeneity in the baseline risk assessment.”

The investigators recognize that a prospective study focusing on CNS prophylactic strategy could provide valuable data, but the implementation of such research is difficult due to the rarity of CNS relapses in DLBCL.

“Our study adds to the earlier observations made in a similar retrospective study indicating a lower incidence of CNS relapse with the addition of systemic high-dose MTX to IT MTX alone,” wrote the investigators.

Faqah A, Asif S, Goksu SY, Sheikh HS. Real-World Data (RWD) on the 3-Year Follow-Up Outcomes of Different CNS Prophylaxis Strategies Across CNS-IPI Risk Groups in Patients With Diffuse Large B-Cell Non-Hodgkin Lymphoma. 

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The 3-year follow-up analysis of 4 treatment groups who received CNS prophylaxis found a decreased incidence of CNS relapse for patients with high-risk diffuse large B-cell lymphoma, although the data were not statistically significant.

Real-World Data Suggest Systemic High-Dose and Intrathecal MTX Lower CNS Relapse Incidence for DLBCL

 What are some of the unmet needs in the treatment of early stage hormone receptor–positive breast cancer?

 Although we’ve made considerable progress, we have quite a bit of work to do. We have data with CDK4/6 inhibitors in the adjuvant setting, and we’re trying to understand why we’re seeing seemingly different results from some of these agents, as well as learning whether the differences that we have seen will hold up with time. That’s an important area that requires further clarification.

It’s critical for us to get a better understanding of what’s happening in the younger patient population that is getting a benefit from chemotherapy, and whether it’s really the benefit of the chemotherapy or the induction of ovarian suppression. That’s going to be a really important area for us to clarify. Perhaps it will result in more widespread use of ovarian suppression, or we’ll identify that it really is a benefit of chemotherapy and that these patients should be treated. This is certainly an unmet need.

It’s also really important to understand the toxicities associated with our therapies and how to better mitigate those toxicities, especially endocrine therapy. Many patients suffer with adverse effects on these treatments. While it’s great to see the availability of a tool such as the Breast Cancer Index come into more widespread use to spare women some of the toxicities, for those women where we identify that there really is a benefit, we need to do better in helping them manage some of these more common adverse effects because they significantly impact quality of life.

 Absolutely. Thank you so much, Dr Mahtani. I hope that you found this information to be valuable in your clinical practice. Thank you all for watching this 

An overview of unmet needs surrounding current treatment patterns for early-stage HR+ breast cancer. 

Optimizing Treatment Outcomes in HR+ Breast Cancer

 What are the data that are supporting the use of the Breast Cancer Index [BCI] in patients with early hormone receptor–positive breast cancer?

 We have extensive clinical evidence of the test validity and utility for the predictive ability of the assay data in around 2000 patients treated in trials, including MA.17R, Trans-aTTom, and the IDEAL trial. Those trials have shown BCI to be a consistent and reproducible predictor of who will benefit from extended endocrine therapy, with about a 65% relative risk reduction shown in patients who have a gene signature that is basically a molecular assessment of the estrogen signaling pathway. The result is very easy, in that it’s very plainly reported as yes or no: yes meaning your patient will benefit from extending therapy, no meaning your patient will not benefit.

Similarly, the prognostic ability of the assay has been validated in a large number of patients—around 2000—including pre- and postmenopausal, node-positive, and node-negative patients. The assay has been shown to provide an individualized risk of distant recurrence from years 5 to 10. This information can help inform the patient as well as the physicians’ perception of their risk of recurrence above and beyond clinical pathology features. I’ve been really surprised to see some of the assumptions that I’ve made in my practice using clinical pathology factors challenged by the results of the BCI, which have shown some patients with N1 disease having a low rate of distant recurrence. At the same time, in some patients who I expected to have a quite good prognosis, their N0 has a higher risk of distant recurrence. This has been very useful in my practice in helping patients make this decision.

 To shift gears to the patients, how do you think the addition of the Breast Cancer Index to the NCCN [National Comprehensive Cancer Network] Guidelines will impact patient outcomes?

 It has to do with getting the message out that this assay is available and understanding how it can impact decision-making. We need to create awareness in physicians that it is a test that has been endorsed by the NCCN. In that regard, it will have a big impact in that patients who are not really benefiting from endocrine therapy may choose to not continue that treatment and not suffer those adverse effects.

Thoughts regarding how the addition of the Breast Cancer Index to the NCCN guidelines for HR+ breast cancer may likely impact extended adjuvant therapy and patient outcomes. 

Utilization of The Breast Cancer Index for HR+ Breast Cancer

Combination therapy with durvalumab (Imfinzi) and tremelimumab plus chemotherapy resulted in a statistically significant improvement in overall survival (OS) versus chemotherapy alone in patients with stage IV non–small cell lung cancer (NSCLC), according to the sponsor of the phase 3 study, AstraZeneca.

In addition to a reduction in the risk death, the randomized, open-label, multicenter POSEIDON trial (NCT03164616) indicated a significant progression-free survival (PFS) benefit with the PD-L1/CTLA-4 inhibitor combination versus standard of care. This is the first phase 3 trial to demonstrate an OS benefit with tremelimumab.

“We are pleased to see the POSEIDON phase 3 trial demonstrate, for the first time, a significant and clinically meaningful overall survival benefit for Imfinzi plus tremelimumab with chemotherapy in metastatic non-small cell lung cancer,” Dave Fredrickson, Executive Vice President of the Oncology Business Unit at AstraZeneca, said in a press release. “We were particularly pleased by the safety profile. We’ve seen encouraging uptake of novel combinations in this setting and believe this new approach will add a further option for patients with high unmet medical need. We look forward to discussing next steps with regulatory authorities.”

The trial included 3 treatment arms, with patients receiving standard chemotherapy either alone, in combination with durvalumab, or with durvalumab/tremelimumab. A prior analysis of all 3 arms demonstrated an acceptable safety profile for each, with the tremelimumab combination having a broadly similar profile to that of durvalumab and chemotherapy.

The primary end points of the trial are OS and PFS in the durvalumab plus chemotherapy combination arm. Secondary end points include OS and PFS with the durvalumab/tremelimumab combination.

Patients received durvalumab at a fixed dose of 1500 mg every 3 weeks with chemotherapy, then every 4 weeks until progression. Tremelimumab was administered at 75 mg every 3 weeks for 4 cycles with chemotherapy, and extra doses were given as maintenance following chemotherapy. Chemotherapy alone was given for up to 6 cycles. Maintenance pemetrexed was allowed in non-squamous patients if given during induction.

Eligible patients had histologically or cytologically documented stage IV NSCLC, a confirmed PD-L1 status prior to randomization, no activating EGFR or ALK mutations or ALK fusions, no prior therapies for metastatic disease, and a WHO or ECOG status of 0 or 1. Both squamous and non-squamous histology were allowed.

According to the company, data from the trial will be made available at an upcoming medical meeting. In addition to this indication, the combination is being explored in lung, bladder, and liver cancer settings.

Imfinzi and tremelimumab with chemotherapy demonstrated overall survival benefit in POSEIDON trial for 1st-line Stage IV non-small cell lung cancer. News release. AstraZeneca. May 7, 2021. Accessed May 7, 2021. https://bit.ly/3tqfiQs

Data reported from the phase 3 POSEIDON trial are the first to demonstrate a statically significant overall survival benefit with tremelimumab.

Tremelimumab and Durvalumab Combo for Stage IV NSCLC Reaches Significance for OS 

 When do you do genomic testing in your patients with hormone receptor–positive breast cancer? Do you test all of your patients? Why or why not?

 That’s a great question. It’s important to first recognize how far we’ve come. Many of us forget that not too long ago, we were giving chemotherapy to the majority of women with localized breast cancer, regardless of lymph node status, menopausal status, or receptor status. The availability of genomic assays to help us make that decision has allowed us to tailor our treatments much better and spare women the toxicities if they’re not benefiting from our treatments.

In my practice, I would order an assay only when the information will potentially change my decision. For example, in a patient with more than 3—some might say more than 2—positive nodes, I wouldn’t use the information. I would default to the use of chemotherapy. I wouldn’t send any assay in that situation. Similarly, it’s not useful to order the assay for a patient who is not suitable to receive chemotherapy, has multiple comorbidities, is receiving multiple other medications, or you don’t think will make it through chemotherapy without some significant toxicity. But for the patient for whom there’s some clinical equipoise—for example, a healthy pre- or postmenopausal woman with a clinically high-risk tumor, where the feeling really is to use chemotherapy—the results of a genomic assay can be very helpful in clarifying prognostic information. Most important, it helps us identify whether chemotherapy is likely to be a benefit and impact that risk.

Shifting to the decision about extended adjuvant endocrine therapy, if a patient is tolerating treatment well, has good bone density, is really committed to the decision to continue for the entire 10 years of therapy, and would be uncomfortable with the thought of going off-treatment, then I don’t know that I would order any assay. Unfortunately, not many of our patients are in that situation, because many of these women are suffering with adverse effects of these treatments. In my clinic, I frequently discuss how to manage the toxicities of endocrine therapy. We know that the information we would normally use to make that decision, namely clinical pathology factors, aren’t always reliable in predicting who’s going to benefit from continuing therapy. In terms of how I’m using these assays, I’m frequently using the Breast Cancer Index to make that extended adjuvant endocrine therapy decision.

 You just mentioned the Breast Cancer Index. How do you decide which assay to use for a given patient?

 It depends on what decision you’re trying to make. For patients for whom I’m making the decision regarding the use of chemotherapy, I’m typically using the 70-gene assay or the 21-gene recurrence score. Although there are certainly other assays that are available, those are the 2 that I’m most familiar with and comfortable using. That’s really the key: The physician has to feel comfortable explaining the results to the patient and making a difficult decision and conversation as easy as possible.

The NCCN [National Comprehensive Cancer Network] Guidelines detail where these assays are prognostic vs predictive. That information is certainly available to help guide physicians’ decision-making in terms of which assay to choose. The NCCN lists the 21-gene assay as the preferred, given the predictive and prognostic information that can be gleaned from it. But in my practice, although I recognize that MINDACT was not a study that was powered to identify a chemotherapy benefit, it has been useful in identifying a group of patients who have a sufficiently high distant metastasis-free survival that chemotherapy is not likely to improve that significantly. I’ve utilized the 70-gene assay quite frequently, and I’m very comfortable with that assay and having that discussion with the patient.

At my institution, we’re participating in the FLEX Registry. This registry utilizes MammaPrint and BluePrint. The study’s primary aim is to create a large-scale population-based registry of full genome expression data matched with clinical data to investigate new gene associations and prognostic and predictive value. We’re very excited about the possibility of interrogating that database, which will hopefully answer many questions. Finally, in terms of making that endocrine therapy decision of whether to extend, I’ve utilized the Breast Cancer Index quite a bit. This is an assay that’s been endorsed by NCCN and given the distinction that it’s the only 1 that provides predictive information on endocrine therapy benefit.

Dr Reshma L. Mahtani, of Sylvester Comprehensive Cancer Center, describes when and for whom she recommends genomic testing for HR+ breast cancer. 

Genomic Testing for HR+ Breast Cancer: Best Practices

 What are genomic assays, and what is their current role in early stage breast cancer?

 Genomic assays aim to give us a more in-depth understanding of the biology of the individual’s tumor by looking at various levels of gene expression. The information can aid in further prognostication beyond clinical pathology factors alone. Most important, it can help us predict the benefit, or sometimes the lack of benefit, of our treatments, like chemotherapy and endocrine therapy. We’ve come a long way in the treatment of early stage breast cancer by incorporating various assays to help guide our decision-making and, most important, assist in helping patients be spared the toxicities of our treatments.

 Absolutely. How has the NCCN [National Comprehensive Cancer Network] updated its guidelines for the use of genomic assays for early stage disease? What is the significance of this shift in terminology?

 We’re fortunate to have several gene expression assays available to help guide us in the adjuvant setting. The NCCN Guidelines detail recommendations on the use of several of these, including the 21-gene assay, the 70-gene assay, Prosigna, as well as EndoPredict. The guidelines were updated to incorporate information from recently reported studies, such as RxPONDER as well as the 8-year data from the MINDACT trial. There was specifically a comment that we don’t know whether the benefit of chemotherapy that we’re seeing across some of these studies in younger patients is related to the possible chemotherapy-induced ovarian suppression. This will be an important area for us to clarify going forward in our younger patients. In terms of shifting the terminology as we talk about systemic therapies, now included is a discussion about extending adjuvant endocrine therapy and the endorsement of the Breast Cancer Index as an inclusion in the NCCN Guidelines update.

 How do the updated guidelines regarding the use of genomic assays affect the management of early stage hormone receptor–positive breast cancer in the extended adjuvant setting?

 The NCCN panel recently expanded the guidelines for breast cancer by recognizing the Breast Cancer Index as the only gene expression assay for prediction of benefit from extended endocrine therapy. This recommendation includes both node-negative and node-positive patients across antiestrogen therapies, including tamoxifen and aromatase inhibitors. This recommendation is based on various data sets that have validated the assay, which is also prognostic. The endorsement will hopefully publicize the value of the assay for clinicians who may not be aware of its availability.

A review of recent updates to genomic testing guidelines by the National Comprehensive Cancer Network and important takeaways that impact treatment decisions for HR+ breast cancer in the extended adjuvant setting. 

NCCN Updates to Genomic Testing in HR+ Breast Cancer

Compared with trastuzumab (Herceptin), adjuvant trastuzumab emtansine (T-DM1; Kadcyla) did not increase the risk of central nervous system (CNS) recurrence while offering a clinical benefit for patients with HER2-positive early breast cancer across subgroups, according to data published in 

The subgroup analyses in the KATHERINE trial (NCT01772472) included patients with residual invasive disease after neoadjuvant chemotherapy plus trastuzumab, focusing on small tumors and particularly high-risk disease.

Patients were enrolled and randomized to receive either adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) over a period of 14 cycles.

The research team found there was a decreased risk of recurrence or death for patients treated with T-DM1 compared with trastuzumab, including those who received anthracycline-based neoadjuvant chemotherapy (HR, 0.51; 95% CI, 0.38–0.67) or nonanthracycline-based neoadjuvant chemotherapy (HR, 0.43; 95% CI, 0.22–0.82), presented with cT1, cN0 tumors (0 versus 6 invasive disease-free survival events [IDFS]), or presented with high-risk tumors.

While there was no observed association between T-DM1 and a difference in the risk of CNS recurrence, the data showed that the CNS was more commonly the first site of recurrence for patients in the experimental arm (5.9%) compared with the trastuzumab arm (4.3%).

“In KATHERINE, there was a numerically higher incidence of CNS recurrence as the first IDFS event in the T-DM1 versus the trastuzumab arm. The data presented here suggest that this increased incidence is a result of competing risk as observed in trastuzumab trials,” wrote the investigators. “Specifically, substantial reduction in the incidence of non-CNS recurrences as a first event observed with T-DM1 resulted in an increased likelihood of a CNS recurrence as a first event and as the only site of recurrence.”

Focusing on treatment-emergent peripheral neuropathy, patients receiving T-DM1 had a higher incidence rate (32.3%) compared with patients receiving trastuzumab (16.9%). More, an increase in all-grade peripheral neuropathy was observed for patients with baseline peripheral neuropathy who were treated with T-DM1 (36.3%) versus those without baseline peripheral neuropathy (31.1%). For patients treated with trastuzumab, similar rates were observed with (17.5%) or without (16.8%) baseline peripheral neuropathy.

“In our analysis, patients with baseline peripheral neuropathy (grade 1) who received T-DM1 had a higher incidence of grade 2 and 3 peripheral neuropathy,” wrote the investigators. “However, regardless of treatment group, baseline peripheral neuropathy was associated with longer duration and lower resolution rates of peripheral neuropathy, suggesting that pre-existing peripheral neuropathy is a risk factor irrespective of HER2-targeted treatment type.”

Overall, baseline peripheral neuropathy was associated with extended median duration of peripheral neuropathy (105-109 days longer) and lower resolution rates of neuropathy (65% vs 83%) regardless of treatment arm.

More, an association was found between prior platinum therapy and increased grade 3/4 thrombocytopenia for patients receiving T-DM1 (13.5%) compared with those treated with trastuzumab (3.8%).

Limitations of the research included statistical and methodological issues, although the investigative team was reassured with the results as they aligned well with previously reported data in this area of research.

Moving forward, the investigators emphasized that these data have the potential to support clinicians in their use of adjuvant T-DM1 as the new standard of care for patients with this tumor type.

Mamounas EP, Untch M, Mano MS, et al. Adjuvant T-DM1 versus Trastuzumab in Patients with Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer: Subgroup Analyses from KATHERINE. 

. April 28, 2021. doi:10.1016/j.annonc.2021.04.011

The KATHERINE trial found a clinical benefit without increasing the risk of CNS recurrence for patients with HER2-positive early breast cancer treated with T-DM1.

Subgroup Analyses of KATHERINE Trial Promote T-DM1 Use in High-Risk Groups

 program titled “Individualizing Extended Adjuvant Therapy in HR+ Breast Cancer.” Our discussion is going to focus on adjuvant therapy in hormone receptor–positive breast cancer. Dr Mahtani, what are the options for extended adjuvant therapy in patients with early stage hormone receptor–positive breast cancer?

 We should start by defining extended adjuvant hormonal therapy for women with early stage breast cancer as indicated in those who have completed 5 years of tamoxifen, or a sequence of tamoxifen and an aromatase inhibitor. There’s an option to continue on with additional endocrine therapy, typically for an additional 5 years. The idea in considering additional treatment is that, for some patients, the risk of recurrence continues well beyond the 5 years postdiagnosis. Given that many recurrences occur after 5 years, it may be useful to consider extended therapy for some patients. The trials that have evaluated additional therapy after those first 5 years have consistently shown about a 3% to 5% absolute benefit in preventing recurrences. However, this benefit should be balanced against the toxicities that many women who are on extended endocrine therapy face. We typically decide whether to extend the therapy based on clinical pathological features, such as nodal status and tumor size. This information can certainly be prognostic, but the challenge is that it’s not always predictive in terms of who’s going to benefit. That’s where we really need an additional piece of information.

The rationale for treating early-stage HR+ breast cancer with extended adjuvant therapy and factors that impact treatment selection. 

Extended Adjuvant Therapy for HR+ Breast Cancer 

 program titled “Individualizing Extended Adjuvant Therapy in HR+ Breast Cancer.” Our discussion is going to focus on adjuvant therapy in hormone receptor–positive breast cancer. Welcome. Let’s begin. Dr Gadi, what’s the difference between adjuvant and extended adjuvant therapy in patients with early stage hormone receptor–positive breast cancer?

 Before I start answering that question, I want to make 1 disclosure. I’ve spent my career focused, to some degree, on diagnostics development. I’m a founder of a company called SEngine Precision Medicine. I have intellectual property in a company called Chimerasite, I have received research funding from Agendia, and I served as a consultant speaker for Hologic.

In regard to the differences between adjuvant therapy and extended adjuvant therapy in breast cancer, we have multiple types of breast cancer. With regard to hormone-positive breast cancer in particular, many of us intuitively have known, based on our clinical practice, that these are patients who have a long horizon for being at risk for a recurrence. These recurrences can happen quickly—a few years after the initial therapy—but we know there’s a long tail, so there are folks who can recur as many as 10, 15, 20, 25 years later. Because of that, we are developing segments of time in which to think about these patients. In the early stage setting and soon after, the first 5 years, we call the adjuvant setting. Then there is this component of time we are terming extended adjuvant setting in hormone-positive disease, which extends from that fifth year and beyond.

 What is the goal of each type of treatment?

 In the early stage treatment, when we think about cancers in the first 5 years, we’re worried about cancers that are oftentimes highly proliferative, having features that would predict an early recurrence. The idea is using a combination of multiple types of therapies. But in terms of the systemic therapies—focused on antiestrogen therapies, chemotherapy, and novel biologics in the context of 

 [human epidermal growth factor receptor 2]–positive disease—the goal of all those therapies is to say that at the end of 5 years after the initial diagnosis, the patient is free of disease. Those are the tools we typically try to look at in that immediate 5 years. As an extension in the extended phase of things, these are cancers that probably have been hibernating and lurking in this stage. Whatever molecular programs take place to turn them on again after that fifth year, we ask, “What are the tools we might have available to prevent that from happening for these slumbering cancer cells?” The main focus has been looking and focusing on endocrine therapies, antiestrogen-type medicines for that fifth year and beyond.

 You just mentioned the endocrine therapies. What are the current treatment options for both treatment types?

 In the early stage setting, the primary methods we use are either estrogen receptor blockade, or aromatase inhibition. In terms of estrogen receptor blockade, the drug we primarily use in this country is tamoxifen, which binds to the estrogen receptor and prevents the estrogen receptor from landing on its typical sites within the nucleus of the cancer cell and promoting growth to the cancer cell. With the aromatase inhibitors, we block that enzyme. By doing so, we block the terminal step of turning pre-estrogens into active estrogens. When we do this in the peripheral tissues, it makes it really difficult for cancer cells to survive in these other organs. As a result, they die over time. Those are the 2 mechanisms we focus on. Both can be used in the first 5 years. Certainly, in premenopausal women, we don’t use the aromatase inhibitors because there can be certain toxicities and there may also be diminished benefit of those medicines. To make them feasible in that premenopausal patient population, we combine those aromatase inhibitors with drugs that suppress the ovarian function. When we combine the 2 together, they work quite well in terms of preventing recurrences from happening, especially in high risk, early stage cancers in young women.

The goals of adjuvant therapy versus extended adjuvant therapy for early-stage HR+ breast cancer and current treatment options available for each approach.