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The breast cancer section is a comprehensive resource for clinical news and expert insights on breast cancer. Read more at Targeted Oncology.

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GEN-22-TTD0602 - /clinical/breast

Articles

Emanuel F. Petricoin III, PhD, Co-Director, Center for Applied Proteomics & Molecular Medicine, Professor of Life Sciences, George Mason University, discusses the use of the reverse phase protein microarray (RPPA).

Profiling Tumors with the Reverse Phase Protein Microarray

Fabrice AndrÃ©, MD, PhD, has focused his research on translational oncology and the development of novel targeted agents for the treatment of breast cancer through his research as director of INSERM Unit U981 at the Institut Gustave-Roussy in Villejuif, France.

Exploring New Genomic Targets in Metastatic Disease

Patrick Borgen, MD, chair, Department of Surgery, director, Maimonides Breast Cancer Center, discusses the Miami Breast Cancer Conference.

Overview of the Miami Breast Cancer Conference

In season 3, episode 3 of Targeted Talks, William J. Gradishar, MD, chief of Hematology and Oncology in the Department of Medicine, Betsy Bramsen professor of Breast Oncology, and professor of Medicine (Hematology and Oncology) at Northwestern Medicine, Feinberg School of Medicine, discusses the latest version of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for managing early-stage breast cancer.

Patients with early-stage breast cancer have more options than ever before, but the biggest recent updates have been for patients with estrogen receptor-positive disease, says Gradishar. This is a patient population with a high risk of recurrence, and 2 new therapies with different mechanisms of action have demonstrated the ability to reduce the risk of recurrence.

First, based on the phase monarchE clinical trial (NCT03155997), the FDA granted approval to abemaciclib (Verzenio), in combination with endocrine therapy, for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥20% in October of 2021. The study showed that CDK4/6 inhibition is effective for this patient subgroup, according to Gradishar.


For the subgroup of patients with BRCA-mutated tumors, the recent FDA approval of olaparib (Lynparza) for the adjuvant treatment for patients with 

-mutated HER2-negative high-risk early breast cancer that were previously treated with chemotherapy before or after surgery is another important update to the NCCN guideline. Approval of the PARP inhibitor was supported by findings from the phase 3 OlympiA trial (NCT02032823).


Looking ahead, Gradishar still sees room for improving early-stage breast cancer management. Ongoing drug development may offer more promising options for select subgroups in the near future.

In season 3, episode 3 of Targeted Talks, William J. Gradishar, MD, discusses the latest version of the NCCN Clinical Practice Guideline for managing early-stage breast cancer.

Unpacking the New Recommendations for Early-Stage Breast Cancer Management

In season 1, episode 3 of Targeted Talks, the importance of precision medicine in breast cancer, and how that vitally differs in community oncology compared with academic settings, is the topic of discussion. Stephanie L. Graff, MD, director of the Breast Program at the Sarah Cannon Cancer Institute HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, leads the discussion with Gabriel N. Hortobagyi, MD, FACP, professor of medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston. The experts concluded from their conversation that the future of precision medicine in breast cancer currently lies with antibody-drug conjugates.

The conversation begins with both doctors explaining the history and the current state of precision medicine in breast cancer as well as the need for targeted therapies in this space to continue the growth of precision medicine. Graff and Hortobagyi also cover the role of genomic testing in aiding in the process of giving individualized care to patients with breast cancer. Ongoing research around targeted therapies in the space was a significant part of the genomic testing conversation, as is the unanswered questions around how to perform testing on these patients in both the community and in academic settings.

The in-depth part of the talk focuses on the novel targeted therapies that are being explored in clinical trials or are newly available in the clinical setting. The doctors specifically touch upon kinase inhibitor research and its use in practice, including drugs like lapatinib (Tykerb), neratinib (Nerlynx), tucatinib (Tukysa), and alpelisib (Piqray), as well as antibody-drug conjugates like ado-trastuzumab emtansine (T-DM1; Kadcyla), sacituzumab govitecan-hziy (Trodely), and trastuzumab deruxtecan (Enhertu). Targeted therapy combinations are also mentioned.

In season 1, episode 3 of Targeted Talks, the importance of precision medicine in breast cancer, and how that vitally differs in community oncology compared with academic settings, is the topic of discussion.

Breast Cancer Leans into the Decade of Antibody-Drug Conjugates, Experts Discuss

Two studies of patritumab deruxtecan in patients with EGFR-mutated metastatic non–small cell lung cancer and HER3-expressing metastatic breast cancer revealed promising overall response, disease control, progression-free survival rates, and more.

Patritumab Deruxtecan Elicits Clinical Activity in Some Patients With Lung and Breast Cancer

Sara Hurvitz, MD, discusses recent updates for selective estrogen receptor degraders in the treatment of patients with metastatic breast cancer and how it has impacted clinical decisions. 

Updates on SERD Trials for Metastatic Breast Cancer

Neoadjuvant chemotherapy with carboplatin has been shown to improve the pathologic complete response rate for patients with triple negative breast cancer.

HRD Biomarker Predicts Response to Neoadjuvant Chemotherapy in TNBC

During a Targeted Oncology™ Case-Based Roundtable™ event, Hope S. Rugo, MD, discussed adverse event management in patients treated with sacituzumab govitecan for triple-negative breast cancer and other therapy options. 

This is the second of 2 articles based on this event. 

Managing Sacituzumab AEs and Looking Forward to Next-Line TNBC Therapy

Aditya Bardia, MD, MPH, discussed potential second-line therapies for
patients with metastatic triple-negative breast cancer.

Second-line Options for Patients With Metastatic TNBC

Kevin Kalinsky, MD, MS, associate professor in the department of hematology and medical oncology at Emory University School of Medicine, and the Louisa and Rand Glenn Family chair in Breast Cancer Research, director of the Glenn Family Breast Center, and director of Breast Medical Oncology at the Winship Cancer Institute, discusses the disparities seen between non-Hispanic Black women and non-Hispanic White women with hormone receptor (HR)-positive HER2-negative breast cancer on endocrine therapy.

In a subgroup analysis of 5,000 patients with HR-positive/HER2-negative breast cancer either on chemotherapy plus endocrine therapy or endocrine therapy alone, patients had better results, including disease free survival (DFS), on endocrine therapy but these results did not extend to all patients equally. While 6% of the patients involved were non-Hispanic Black women, this still underscored the under representation of this patient population in clinical trials. Moreover, this patient group had poorer results when compared with non-Hispanic White patients.

In an interview with Targeted OncologyTM Kalinsky discussed how these results open more questions for researchers to answer. He added that they need to understand why these disparities exist and address the poor results for this patient population.

 This is despite having a higher rate of non-Hispanic black vs non-Hispanic white women agreeing to their randomization and despite the fact that at 1 year we saw that patients were equally adherent to their endocrine therapy in both of those subgroups. We also did note that non-Hispanic Black women had a higher rate of grade 3 tumors, and a higher BMI, and that magnitude of difference when we look at invasive [DFS] and distant relapse-free survival between the 2 groups when we incorporated the body mass index into the multivariable analysis the magnitude of that benefit had dampened a bit.

 I think that this was a, hopefully, informative analysis. There are several questions that come out of this; specifically, why is this happening? And there are additional studies that will be reviewing adherence beyond a year and looking at other social determinants of health. These results are like what was seen in [TAILORx trial [NCT00310180]] within the first 5 years of follow up in that analysis in a node-negative population, so there does seem to be this consistent finding. I just think that the next steps are for us to continue to understand why this is happening.

Videos

Looking at a subgroup analysis of patients with hormone receptor-positive and HER2-negative breast cancer on endocrine therapy, researchers saw promising results but worrying disparities between non-Hispanic White patients and non-Hispanic Black patients.  


News

Discussing Racial Disparities Among Patients with HR+ Breast Cancer 

Seth Wander, MD, PhD, Massachusetts General Hospital, discusses what research and topics excite him when evaluating future treatments for patients with breast cancer.

In his own research, Wander is focused on examining CDK4/6 inhibition for patients with hormone receptor-positive metastatic breast cancer (MBC) with 

 mutations and fusions. During a presentation at the 2022 American Association for Cancer Research Annual Meeting, research was presented by Jamie Brett, fellow at Dana-Farber/Mass General Brigham Hematology/Oncology program, discussed findings from a study which evaluated patients with MBC who had used a CDK4/6 inhibitor within 30 days of circulating tumor (ct)DNA testing. Then, patients were analyzed for time-to-next-treatment to evaluate the CDK4/6 inhibitors. What they found was that treatment CDK4/6 inhibitors proved to be effective in this patient population.

Moving forward within the breast cancer space, experts including Wander look forward to seeing more novel agents come into play and seeing the different ways that they can be used, including CDK inhibitors, antiestrogens, antibody drug conjugates, and more.

We're starting to see more data on some of these novel anti-estrogen agents that are moving through the various clinical pipelines. As it relates to some of our work, it's always interesting to see new emerging insights related to genomic predictors of response and resistance to CDK inhibitors and antiestrogens.

 In the broader breast cancer field in general, there's lots of other exciting areas that are upcoming, including the use of antibody drug conjugates in areas that we haven't yet had experience using. For example, in hormone receptor-positive disease as well as in HER2-low or negative disease. We are going to learn a lot more about that over the course of the next year, both in patient populations as well as in the translational and preclinical space.

Seth Wander, MD, PhD, discusses what research and topics excite him when looking to further evaluate future treatments for patients with breast cancer. 


Excitement Shown With CDK4/6 Inhibitors and More in Breast Cancer Research 

Erika P. Hamilton, MD, lead investigator and director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, discusses the updated safety analysis of the DESTINY-Breast03 trial (NCT03529110) and the patients who were enrolled in the study.


findings of the DESTINY-Breast03 trial at the 2022 American Society of Clinical Oncology (ASCO)

 Annual Meeting. During her session, she compared the safety of trastuzumab deruxtecan (Enhertu) with trastuzumab emtansine (TDM-1) for patients with HER2-positive unresectable or metastatic breast cancer.

In the trial, patients were randomized in a 1:1 ratio to receive either trastuzumab deruxtecan (n = 257) or trastuzumab emtansine (n = 261). While the efficacy data from the study was from a primary data cutoff of May 21, 2021, the updated safety findings were from a cutoff of September 7, 2021.

This was the safety update for DESTINY-Breast03. As you recall, trastuzumab deruxtecan was initially approved based on DESTINY-Breast01 [NCT03248492]. DESTINY-Breast03 was a study that brought it up into an earlier-line setting, so patients that had seen trastuzumab and/or a taxane in the metastatic setting or relapsed within 6 months of neoadjuvant or adjuvant therapy. Based on DESTINY-Breast03, trastuzumab deruxtecan got a new expanded indication in earlier-line settings in May 2022.

As opposed to the plenary [session], where DESTINY-Breast04 [NCT03734029] looked at patients who had HER2-low expression [and unresectable and/or metastatic breast cancer], this was a study of that 15% to 20% of patients with breast cancer who we know have too high [expression]. That's 3+ by immunohistochemistry, or fluorescence in situ hybridization–positive.

This study, opposed to DESTINY-Breast01 that was with very heavily pretreated patients, looked at patients in the so-called second-line setting. They had seen trastuzumab and a taxane in the metastatic setting or relapsed within 6 months of receiving HER2 directed therapy in the neoadjuvant or adjuvant setting.

Erika P. Hamilton, MD, discusses the updated safety analysis of the DESTINY-Breast03 trial and the patients who were enrolled in the study.

Update of DESTINY-Breast03 Emphasizes Safety of Trastuzumab Deruxtecan in mBC

Rachel Würstlein, MD, Universität München, lead investigator of the KAMILLA study (NCT01702571), discusses the use of trastuzumab emtansine (T-DM1) following the KAMILLA trial which evaluated the agent in patients with HER2-positive locally advanced or metastatic breast cancer who have brain metastases.

KAMILLA was a 2-cohort, open-label, multicenter trial. Investigators aimed to evaluate the safety and efficacy of T-DM1 in patients with metastatic breast cancer. In the trial, over 2000 patients were enrolled and 182 patients were included in the Asian cohort.

In the KAMILLA trial, patients with HER2-positive locally advanced or metastatic breast cancer who had brain metastases received T-DM1 at a dose of 3.6 mg/kg given intravenously every 3 weeks until they experienced unacceptable toxicity, withdrew consent, or had disease progression. The median treatment duration was 4.9 months (range, 0-44 months) in patients with brain metastases.

Findings from the exploratory analysis of T-DM1 in the trial revealed that this patient population had promising activity as well as tolerability on the therapy. In addition, findings confirmed the safety and efficacy of T-DM1, and there were no new safety signals demonstrated.

 It’s an interesting question to think about what’s going to happen now with T-DM1. There is a well-described track in metastatic breast cancer in the second-line or further. But as we already know, also in the past-neoadjuvant treatment, we have been working on this question [and I believe] it’s time to move it to the neoadjuvant setting. We have to define the patient population. There have been some interesting presentations at [last] year’s ASCO, and I think safety populations like this are the backbone to start use of these tracks in the earliest setting. I think that it is now been moved from metastatic to first-line and we’ll have it also in the neoadjuvant setting.

Rachel Würstlein, MD, discusses the use of trastuzumab emtansine following the KAMILLA trial which evaluated the agent in patients with HER2-positive locally advanced or metastatic breast cancer who have brain metastases.


Next Steps for Trastuzumab Emtansine After the KAMILLA Trial

Adam Brufsky, MD, PhD, FACP, professor of medicine at the University of Pittsburgh School of Medicine, associate division chief for the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine's Department of Medicine, medical director of the Magee-Women's Cancer Program, associate director for clinical investigations at UPMC Hillman Cancer Center, and codirector of the Comprehensive Breast Cancer Center, discusses the real-world efficacy of letrozole (Femara) in combination with palbociclib (Ibrance) as treatment of patients with estrogen receptor-positive, HER2-negative, advanced breast cancer, based on race and ethnicity.

Patients with ER-positive, HER2-negative, advanced breast cancer were evaluated on this treatment in the phase 3 PALOMA-2 study (NCT01740427), explained Brufksy. Overall, there was no survival benefit shown in the overall study population when palbociclib was added to letrozole. However, a 

progression-free and overall survival was shown in patients who identified as Black or Hispanic

 Obviously, real-world analyses can’t replace randomized clinical trials. But it can add a lot of data to it. Randomized clinical trials, as much as we love them, especially since the NSAB over the last 50 years has really changed the practice of breast oncology, only refer to the patients in the trial. And the patients had to be very restrictive. In their entry criteria, the treatment is very restricted, you can’t violate or have the lab values be abnormal for more than a couple of weeks. I think people have tried a lot of times.

 Another thing is that these trials take so long to conduct in breast cancer, because people rightfully live such a long time, that the standard-of-care for the placebo arm changes. So, you have all these issues. For that reason, I think a lot of us have gotten very interested in real-world analyses. I think the 21st Century Cures Act from the FDA, that was an act of that, again, I think, within the last 5 years or so, really allows for the use of real-world evidence that is from databases, or charter reviews, or things like that to be at least considered in drug approvals, or label expansions. It doesn't replace a randomized clinical trial. I think it fills in the data, in particular groups that maybe were under-represented in the trial like elderly or various minority groups, African Americans, for example. I think that looking at those subgroups in the real-world analysis helps us out.

 We did a real-world analysis of first-line palbociclib and letrozole from the Flatiron database, which is a large database of about 2.8 million records. When we did this analysis, a bunch of investigators got together with Pfizer, and we analyze looks at me and I was about 1,300 or 1,400 patients per, or even higher who receive letrozole only, starting in 2015 and going up to 2020, or letrozole with palbociclib. And we did a variety of physical techniques to try to eliminate confounding and bias to the best we could do. There's always going to be confounding and bias, but we use things like inverse probability treatment waiting, and propensity score matching to try to match them as closely as we could. When we did that, we found not only a progression-free survival benefit that was very similar to that seen in PALOMA-2, but there was an overall survival benefit that was totally significant. So even though the randomized trial didn't show any benefit in terms of overall survival with Palbociclib, the real data did. And so, this kind of consistent with the idea that there probably are going to be differences between the 3 CDK4/6 inhibitors, and the issue is how clinically significant those differences are. And I think that's still a matter of open debate amongst breast oncologists.

Adam Brufsky, MD, PhD, FACP, discusses the real-world efficacy of letrozole in combination with palbociclib as treatment of patients with estrogen receptor-positive, HER2-negative, advanced breast cancer, based on race and ethnicity.

RWD Show Survival Advantage of Frontline Letrozole Plus Palbociclib in Minorities With aBC

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the findings from the ELAINE-1 trial (NCT03781063).

In the study, investiagtors evaluated lasofoxifene vs fulvestrant (Faslodex) in patients with locally advanced/metastatic breast cancer and an estrogen receptor 1 (

) mutation. Patients must have progressed on aromatase and CDK 4/6 inhibitors.

According to findings presented at ESMO 2022, 

treatment with lasofoxifene elicited a durable complete response

 (CR) which could be characterized as complete clinical remission.

The results of the trial demonstrated that lasofoxifene led to a median progression-free survival of a little over 6 months compared with fulvestrant, which had a median progression-free survival of 4 months. This corresponded to a hazard ratio of 0.699 and this result was not statistically significant but a clear signal that lasofoxifene may have some benefit.

Some of the secondary end points that were looked at also provided evidence for that signal, including overall response rates where lasofoxifene led to a response rate of greater than 13% vs fulvestrant at a little less than 3%. Similarly, clinical benefit rate was also prolonged. Again, both the response rate and clinical benefit rate did not meet statistical significance, but these are favorable signals are something that should be evaluated in larger studies.

The most interesting finding from the ELAINE-1 clinical trial was the fact that when we looked at a pharmacodynamic signal in these 

 mutations in the mutant allele fraction, what we found was that lasofoxifene was effectively targeting these mutant allele fractions with a dramatic decrease of all the variants with a greater decrease with lasofoxifene than with fulvestrant.

 alteration, which we know is a very difficult alteration to treat. Clinically, this mutant in was a stratification factor in ELAINE-1. What we found was that in patients treated with lasofoxifene, there was a dramatic decrease in the 

 alteration at the 8-week mark. In contrast with fulvestrant, there was an increase which give us good evidence of what I would say is an on-target effect of lasofoxifene. It provides further evidence that this drug should be studied further in combination with other targeted therapies.

Matthew P. Goetz, MD, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discusses the findings from the ELAINE-1 trial.

Durable CR With Lasofoxifene in ESR1+, ER+/HER2- Metastatic Breast Cancer

Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute and medical oncologist at Tennessee Oncology, discusses the next steps following the successful outcomes of the phase 3 DESTINY-Breast03 trial (NCT03529110) of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive breast cancer.

Based on the primary analysis of the study, trastuzumab deruxtecan showed a 72% reduction in the risk of progression or death versus trastuzumab emtansine (TDM-1) in these patients and adverse events were manageable. These patients must have received a prior trastuzumab (Herceptin)-based regimen, but Hamilton says there are now trials investigating earlier use of trastuzumab deruxtecan in the frontline, adjuvant, and neoadjuvant settings, with the latter 2 showing whether this will be a curative option for patients.

Another area that needs to be investigated is the sequencing of current agents once trastuzumab deruxtecan is used in the second line. Other agents used in HER2-positive disease including capecitabine (Xeloda), tucatinib (Tukysa), and trastuzumab (Herceptin) will need to be investigated in terms of their efficacy following the newer agent and what the optimal sequence is. The role of TDM-1 as a subsequent treatment after trastuzumab deruxtecan will also need to be determined.

 We are going to continue to bring trastuzumab deruxtecan up into earlier settings, meaning there are ongoing trials in the first-line with trastuzumab deruxtecan as well as both neoadjuvant and adjuvant studies, so studies where patients are in the curative setting. We're excited to see, with how fantastic the results have looked in DESTINY-Breast03, what we might see in earlier lines.

One big remaining question is how do we sequence the drugs we have? If we're conceivably using trastuzumab deruxtecan in the second-line, we have drugs like capecitabine [Xeloda], tucatinib [Tukysa], and trastuzumab that we can use [in the] third-line. We have TDM-1 that we are not…using in the first or second line now. So how do we sequence these and what are the activities of our existing HER2 drugs going to be after patients have already seen trastuzumab deruxtecan? Because we don't have a lot of data on that.

Erika P. Hamilton, MD, discusses the next steps following the successful outcomes of the phase 3 DESTINY-Breast03 trial of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive breast cancer.

HER2-Positive Breast Cancer

Next Steps Following DESTINY-Breast03 for HER2+ Breast Cancer

Erica Stringer-Reasor, MD, an assistant professor of medicine at the University of Alabama at Birmingham, discusses the leptomeningeal metastases in patients with breast cancer and an FDA-approved targeted therapy/chemotherapy combination that is being studied as a treatment.

Leptomeningeal metastasis is a rare but aggressive form of breast cancer with very limited treatment options. There are not many randomized studies or single arm studies evaluating this purely due to the rareness of this disease.

Erica Stringer-Reasor, MD, discusses the leptomeningeal metastases in patients with breast cancer and an FDA-approved targeted therapy/chemotherapy combination that is being studied as a treatment.

BREAST CANCER

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