Breaking Research News from sources other than Breastcancer.org
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Acquired ESR1 Mutations Predict Poor Benefit from Further AI Therapy in Metastatic Breast Cancer
Patients with hormone receptor (HR) positive metastatic breast cancer who acquired ESR1 mutations during prior aromatase inhibitor therapy had worse survival when treated with the aromatase inhibitor exemestane compared with fulvestrant, a combined analysis of the phase 3 SoFEA and EFECT trials found. The results were recently reported in Clinical Cancer Research.
https://clinicaltrials.gov/ct2/show/NCT00065325
https://www.clinicaltrials.gov/ct2/show/NCT00253422
Turner NC, Swift C, Kilburn LS, et al. ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor positive breast cancer: A combined analysis of the phase III SoFEA and EFECT trial [published online June 16, 2020]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-20-0224
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Thanks, Lumpie. This is such good information. I'm glad we have so many eyes scouring the news.
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BMI-Related Differential Benefit of Adjuvant Docetaxel in Early Breast Cancer
Journal of Clinical Oncology
TAKE-HOME MESSAGE
This retrospective analysis evaluated the impact of body mass index
(BMI) in patients with breast cancer treated with docetaxel-based versus
non–docetaxel based chemotherapy in a large adjuvant therapy trial.
A higher BMI was associated with worse disease-free survival and
overall survival among docetaxel-treated patients. No difference was
seen in the non–docetaxel treated patients. These findings of a
differential response to docetaxel according to BMI require validation
in an independent cohort.
– Paul J. Hampel, MDhttps://www.practiceupdate.com/content/bmi-related...
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ASCO develops guideline for management of men with breast cancer
Research has led to major improvements in breast cancer diagnosis, treatment and survival. However, men with breast cancer represent only 1% of the U.S. breast cancer population and have not been emphasized in this research.
"Nearly all clinical trial participants have been women," Michael J. Hassett, MD, MPH, medical oncologist at Dana-Farber Cancer Institute and lead author of ASCO's guideline on management of male breast cancer, said in an interview with Healio. "When so few men have been included in the trials, it's hard to draw conclusions about how to treat men vs. women. Considering that more than 95% of breast cancers in men are hormone receptor positive, some have suggested that men and women with breast cancer should be treated differently."
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Many negative trials presented with 'not-negative conclusions' at oncology meetings
Increased attention should be paid to the conclusions of formally negative trials discussed during oral presentations at oncology meetings, as many convey a not-negative message, according to a research letter published in JAMA Oncology.
"During [the 2019] ASCO Annual Meeting, several trials presented were considered formally negative according to their primary analysis, but they were presented with ambiguous and not-negative conclusions," Massimo Di Maio, MD, researcher in the department of oncology at University of Turin in Torino, Italy, told Healio. "My colleagues and I later decided to perform a systemic review to better understand the real magnitude of this phenomenon. We started with ASCO 2019, but later found that the proportion of those clinical trials was not negligible. We then extended the analysis to the [European Society for Medical Oncology] meeting, covering 3 years in total."
"Our aim was to be provocative," Di Maio said. "We do not want to be considered fundamentalists of clinical research methodology, because we ... know that even in a formally negative trial there could be many potentially important findings and many ideas for further research.
"...It would be interesting to compare the conclusions included in the oral presentation of these trials with the conclusions of their final publication in a peer-reviewed journal. It was too early to perform this analysis when we wrote this letter, but this could be an interesting follow-up."
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A novel HER2-targeted antibody-drug conjugate offers the possibility of clinical dosing at trastuzumab-equivalent exposure levels
Molecular Cancer Therapeutics
Trastuzumab and the related antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due in part to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site-specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0-8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared to T-DM1 at equal payload dosing and was equally or better tolerated compared to T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.
https://www.meta.org/papers/a-novel-her2targeted-a...
DOI: 10.1158/1535-7163.mct-20-0190
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[Tests in mice show] New therapy extends breast cancer survival rate, prevents reoccurrence
A new immunotherapy developed by researchers at Northwestern University dramatically extends the survival time of mice with triple negative breast cancer, one of the most aggressive and difficult-to-treat forms of breast cancer.
In a new study, mice treated with the therapy, which comprises two immunity-boosting drugs housed inside a nanoparticle, experienced complete tumor remission for at least 100 days. All untreated mice died by day 30. None of the treated mice experienced adverse side effects or autoimmune responses...
The research will be published online this week in the Proceedings of the National Academy of Sciences...
"It's definitely prolonging survival," Callmann noted. "Even if not all mice were completely cured."
Mirkin and his team also found that the SNA-based immunotherapy protected the mice from relapsing. After the mice entered remission, the team attempted to reimplant the mice with cancer, but tumors did not grow...
The researchers believe that, in theory, SNA-based immunotherapies should be an effective treatment for many types of cancer. Mirkin's team plans to explore that next. Mirkin notes that he feels encouraged that four SNA drugs are already in human clinical trials, including a variant of the SNA used in this study in a type of immunotherapy for Merkel Cell carcinoma. That structure also was invented at Northwestern and is in a Phase 2 clinical trial conducted by Exicure, a clinical stage biotechnology startup.
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Antibody-drug conjugates in breast cancer: the chemotherapy of the future?
Current Opinion in Oncology
Abstract
Antibody-drug conjugates (ADCs) represent an interesting new class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies. The aim of this article is to review the efficacy and safety of ADCs in breast cancer. Following the approval of T-DM1 both in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel anti-HER2 ADCs have been investigated. Some of these compounds, such as the recently FDA-approved trastuzumab deruxtecan, have shown relevant activity in T-DM1-pretreated patients, possibly thanks to the so-called bystander effect, namely the ability to exert cytotoxic activity also against antigen-negative cells. Such feature allows to overcome the HER2 intratumoral heterogeneity in breast cancer and could explain in the preliminary activity demonstrated also in HER2-low breast cancers. However, several ADCs targeting other cancer-associated antigens than HER2 are under development, representing a promising strategy for the treatment of triple-negative tumors, exemplified by the encouraging results of sacituzumab govitecan. ADCs are innovative and effective therapeutic drugs in breast cancer. Research efforts are ongoing to identify novel targets and combination with other treatment modalities, particularly with immunotherapy, to further improve patients' outcomes.
https://www.meta.org/papers/antibodydrug-conjugate...
DOI: 10.1097/cco.0000000000000656
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As always, Lumpie, we appreciate you!!!!!
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T-DM1 in Patients With HER2-Positive Metastatic Breast Cancer and Brain Metastases
- Annals of Oncology This exploratory final analysis of a phase IIIb trial was designed to evaluate the benefit of trastuzumab emtansine (T-DM1) for patients with HER2-positive breast cancer and brain metastases. Reduction in the sum of major diameters of brain metastases >30% occurred in 42.9% of patients. Significant intracranial responses were observed among 49.3% of those who had not received brain metastasis–directed radiotherapy.T-DM1 has good activity in this population, and further study is warranted.
https://www.practiceupdate.com/C/103466/56?elsca1=emc_enews_topic-alerthttps://www.annalsofoncology.org/article/S0923-7534(20)39930-0/fulltext# DOI:https://doi.org/10.1016/j.annonc.2020.06.020CONCLUSION: This exploratory analysis of patients with HER2-positive MBC and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting.
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I found this article about specific mutations
MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1100-5
I’m sharing it with my MO because I have MRE11a somatic mutation.
Dee
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'Liquid biopsy' tech contributes to successful clinical trial for detecting breast cancer recurrence
"These circulating markers were more predictive of relapse than any other commonly used clinical marker on the planet," Radovich said. "It's more predictive than tumor size, grade, stage or lymph node status."
"This is the largest clinical study ever published on the use of circulating markers and minimal residual disease," Radovich said. "This really puts it on the map."
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fascinating
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I’m glad liquid biopsies are getting traction!
I have had 2 liquid biopsies with zero results, since metastatic. Very odd but I guess it happens. Had to move onto a tissue biopsy.
Dee
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Neratinib Plus Capecitabine in HER2+ MBC Previously Treated With ≥2 HER2-Directed Regimens
- Journal of Clinical Oncology This international, randomized, phase III trial was designed to evaluate capecitabine with either neratinib (an irreversible pan-HER TKI) or lapatinib (a reversible dual EGFR and HER2 TKI) in 621 patients with HER2-positive, metastatic breast cancer, including approximately 16% with brain metastases. Patients must have been previously treated with two or more HER2-directed regimens for metastatic breast cancer, although only 35% had received prior trastuzumab, pertuzumab, and T-DM1. Neratinib plus capecitabine led to a significantly improved progression-free survival (a co-primary endpoint) compared with lapatinib plus capecitabine (HR, 0.76; mean PFS difference of 2.2 months). There was no significant difference in overall survival (a co-primary endpoint) between groups (mean, 24.0 vs 22.0 months). Time to CNS disease intervention and duration of response also favored the neratinib treatment group. Diarrhea and nausea toxicities were numerically higher in the neratinib group, but discontinuation rates and quality-of-life assessments were similar.This trial is the first to demonstrate superior clinical outcomes of a particular HER2-directed TKI compared with another in the metastatic setting, and establishes neratinib plus capecitabine as an appropriate treatment option for this patient population.
DOI: 10.1200/JCO.20.00147 Journal of Clinical Oncology0 -
Fascinating about the liquid biopsies. Thanks, Debbie for sharing.
Thanks too, Lumpie, for the Neratinib trial. Always on the lookout for tx possibilities.
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Lumpie I ran across this today and thought it might be of interest to someone.
Here's another https://www.goodnewsnetwork.org/cancer-vaccine-eliminates-97-tumors-amazing-success-human-trials-next/
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Gussy: Thanks for sharing that - it does sound interesting.
For others who want highlights:
Larotrectinib is an oral drug that received accelerated breakthrough status after it displayed remarkable success in treating adult and pediatric cancers that currently have no satisfactory alternative treatments or have progressed following treatment. This is the second ever FDA-approved drug that treats cancers based on a certain genetic trait, regardless of the patient's age or cancer type, and it is the first drug to ever treat cancers that contain the specific NTRK gene that is present in several common forms of adult cancer and many forms of rare pediatric cancers. NTRK fusions are rare, but can occur in salivary gland, lung, breast, and thyroid cancers, as well as soft tissue sarcoma – and prior to this week's FDA approval, there had been no treatment for many of the cancers that frequently expressed this mutation.
Here is the FDA announcement: https://www.fda.gov/news-events/press-announcements/fda-approves-oncology-drug-targets-key-genetic-driver-cancer-rather-specific-type-tumor
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Lumpie, do you know if any of the common genetic tests (foundation etc) look for the mutation that Larotrectinib targets?
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Yes. Looks like Foundation One screens for it.
Here is their list:
I also found all 3 NTRK alterations on the Strata Oncology test list - so it appears that Strata tests for these alterations as well.
Addendum: These tests generally recommend drugs that treat cancer with the genomic finding. So it would be interesting to hear whether this drug is now being recommended. I looked at my results from Strata but, since I did not have any of these alterations, I didn't get any associated recommendations. Strata (in theory) tells you drugs in clinical trial for the alteration, but... that part did not appear to be a perfect process. I know of one drug off the top of my head that was in stage 3 trials at the time my test was run but was left off the list of clinical trial drugs (DS-8201a AKA Enhertu). In fact, they did not recommend any clinical trial drugs. In fairness, Strata was still in clinical trial phase at that point so maybe they had not fully implemented that function yet.
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Thank you! You're a gem keeping us utd on all this!
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Lumpie, thanks so much for this.
Two things: I went back and checked the list of genes for which Foundation One tested in Jan of 2019 on my own results, and it appears that the number is the current number tested is the same on the link you provided. I was hoping that they might have added a lot of new genes, but it doesn't appear to be the case. Here's the list from my Jan 2019 test. Maybe I didn't look carefully enough:
Second, on my own test results, I found that I have NTRK1 amplification. I got excited and thought that this might be an option for me. However, per the article below I found, this drug works most specifically to fusions rather than other modifications:
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Interesting article from Science News today about the effectiveness of an immunotherapy plus a vaccine currently being trialed (phase 2) at Duke -- currently for Her2+ use.
https://scienmag.com/investigational-breast-cancer...
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JoynerL - That list is huge. I need to go back and look at results from genetic test my DR ordered Sept 2019. No known markers were found, but I thought she said 20-30 known markers were looked at. Your list looks much larger. I think she said the test was specific to BC. Insurance so far has denied to claim, saying it is not relevant to diagnosis or treatment. I think the lab is going to pick up most of the cost.
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BlueGirlRedState,
Foundation One testing is genomic testing -- testing of the tumor and changes within the tumor (tumor cells can change during cancer evolution) -- not genetic (what you are born with) testing. I had trouble in 2016 getting my insurance to pick up genetic testing. Genomic testing, on the other hand, is FDA approved and I know that Medicare covers it -- that means that most insurance companies, that take their cues from Medicare, will cover as well.
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This article is relevant for both early and advanced cancers, with some interesting info relevant specifically to tamoxifen users. This is only an abstract but if you follow the link to the publisher ("Nature") there's somewhat more info as well as an option to purchase the article itself for $8.99, which seems pretty reasonable to me, particularly compared to some fees for such articles.
"Fasting-Mimicking Diet and Hormone Therapy Induce Breast Cancer Regression"
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you can see the text for free here https://www.researchgate.net/publication/342967885_Fasting-mimicking_diet_and_hormone_therapy_induce_breast_cancer_regression
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BevJen - Thanks for that link. I find the vaccine studies fascinating and promising. Nothing better than out immune system to fight bad cells. We just have to teach the body to recognize Cancer cells as bad and attack them. 😃
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Indigenous American Ancestry Tied to HER2+ Breast Cancer
Higher proportion of Indigenous American ancestry associated with a greater incidence of HER2+ breast cancer
- HealthDay TUESDAY, July 28, 2020 (HealthDay News) -- Indigenous American (IA) origin could partly contribute to the higher incidence of human epidermal growth factor receptor 2-positive (HER2+) breast cancer in Latinas, according to a study recently published in Cancer Research.Katie M. Marker, M.P.H., from the University of California in San Francisco, and colleagues evaluated genomewide genotype data for 1,312 patients participating in the Peruvian Genetics and Genomics of Breast Cancer Study to estimate genetic ancestry. The association between HER2 status and genetic ancestry was evaluated with findings replicated in 616 samples from Mexico and Colombia.The researchers found that the odds of having a HER2+ tumor increased by a factor of 1.20 with every 10 percent increase in IA ancestry proportion. In samples from Mexico and Colombia, this association between HER2 status and IA ancestry was independently replicated."The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants," the authors write.https://www.practiceupdate.com/C/104315/56?elsca1=emc_enews_topic-alerthttps://cancerres.aacrjournals.org/content/80/9/1893DOI: 10.1158/0008-5472.CAN-19-3659 Published May 2020
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Thank you, moth, for the Research Gate link to the article
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