Breaking Research News from sources other than Breastcancer.org

BlueGirlRedState

Lumpie - thank you for your posts on lymphedema and AIs. AIs definitely have SEs, and I don't think DRs know much about managing them. I have BC for the third time, twice left breast, and now R-axilla. Even though Ibrance is shrinking the tumor, oncologist suggested I look at surgery, which terrifies me. I think the risks and SEs will be much worse than bi-lateral was. Tendons, nerves, muscles - and I already have lymphedema from the tumor. Just had a CT Thursday, really hoping for more shrinking. Radiation might be out since I had that in 2009 on Left side, whole breast.

BevJen

BlueGirl,

If you were not radiated on the R side, radiation might still be a possibility. And they are getting much better at targeting radiation. So don't give up on that thought!

santabarbarian

consider proton rads - very targeted

Lumpie

Novel Therapies in the Management of HER2-Positive Breast Cancer

Interview with Reshma L. Mahtani DO

9 minute video offers overview of treatment options for both early stage and MBC HER2+ disease. There is discussion of new therapies and Dr. Mahtani briefly mentions HR+, HER2+ disease. Transcript provided, too.

https://www.practiceupdate.com/C/101965/56?elsca1=emc_enews_topic-alert

Lumpie

Karenfizedbo15: Thanks for sharing insight on NHS situation. I hope that all of our health systems will pay more attention to patient concerns!

Lumpie

On the use of DNA as a linker in antibody-drug conjugates: synthesis, stability and in vitro potency

Here we present the synthesis and evaluation of antibody-drug conjugates (ADCs), for which antibody and drug are non-covalently connected using complementary DNA linkers. These ADCs are composed of trastuzumab, an antibody targeting HER2 receptors overexpressed on breast cancer cells, and monomethyl auristatin E (MMAE) as a drug payload. In this new ADC format, trastuzumab conjugated to a 37-mer oligonucleotide (ON) was prepared and hybridized with its complementary ON modifed at 5-end with MMAE (cON-MMAE) in order to obtain trastuzumab-DNA-MMAE. As an advantage, the cON-MMAE was completely soluble in water, which decreases overall hydrophobicity of toxic payload, an important characteristic of ADCs. The stability in the human plasma of these non-engineered ONbased linkers was investigated and showed a satisfactory half-life of 5.8 days for the trastuzumabDNA format. Finally, we investigated the in vitro cytotoxicity profle of both the DNA-linked ADC and the ON-drug conjugates and compared them with classical covalently linked ADC. Interestingly, we found increased cytotoxicity for MMAE compared to cON-MMAE and an EC50 in the nanomolar range for trastuzumab-DNA-MMAE on HER2-positive cells. Although this proved to be less potent than classically linked ADC with picomolar range EC50, the diference in cytotoxicity between naked payload and conjugated payload was signifcant when an ON linker was used. We also observed an interesting increase in cytotoxicity of trastuzumab-DNA-MMAE on HER2-negative cells. This was attributed to enhanced non-specifc interaction triggered by the DNA strand as it could be confrmed using ligand tracer assay.

https://www.nature.com/articles/s41598-020-64518-y.pdf

https://doi.org/10.1038/s41598-020-64518-y

Nature Scientific Reports | (2020) 10:7691 {open access}

{This article is pretty technical. I think that there is press reporting on it, too, which may be more reader friendly. I will post that if I can find it. In short... many of us are familiar with antibody drug conjugates, like Kadcyla aka T-DM1. It combines two drugs: Traztuzamab and DM1. They are "linked." Making the link stable is challenging. This article discussed a different method of linking drugs which may be more stable and may allow the linkage of more than two drugs.}

Lumpie

New class of precision medicine strips cancer of its DNA defenses

A new precision medicine targeting cancer's ability to repair its DNA has shown promising results in the first clinical trial of the drug class. The new study, designed to test the drug's safety, found that half of patients given the new drug either alone or with platinum chemotherapy saw their cancer stop growing, and two patients saw their tumours shrink or disappear completely.

A new precision medicine targeting cancer's ability to repair its DNA has shown promising results in the first clinical trial of the drug class.

The new study, designed to test the drug's safety, found that half of patients given the new drug either alone or with platinum chemotherapy saw their cancer stop growing, and two patients saw their tumours shrink or disappear completely.

Damage to the DNA in cells is the root cause of cancer -- but it is also a fundamental weakness in tumours, and cancer cells can be killed by further damaging their DNA or attacking their ability to repair it. The new phase I trial tested the first in a new family of drugs blocking a key DNA repair protein called ATR. Phase I trials are designed to assess the safety of new treatments, and it's unusual to see a clinical response at this stage.

The drug's benefit in blocking DNA repair was even more marked in patients also given chemotherapy, which works by causing DNA damage. In these patients, 15 of 21, or 71 per cent saw their disease stabilise -- suggesting that chemotherapy boosted sensitivity to berzosertib.

https://www.sciencedaily.com/releases/2020/06/200622160339.htm?fbclid=IwAR2L7QGr56qy5iFDCXOIb__NY9bqwtRN4hxwN8f6PB1ugKmAiZkFrNnAGIQ

Story Source: Materials provided by Institute of Cancer Research.

Lumpie

BlueGirlRedState: I am so sorry about your dilemma. I loathe ambiguity... part of the reason I research ad nauseam. Surgery is scary. It seems to me that lymphedema results more often from removal of nodes than lesions, so if they are only talking about removing a tumor, that may be an advantage. My impression is that they are moving toward more neoadjuvant therapy so that less, or less extensive, surgery will be necessary. I think that if they find a way to do less node removal, there will be less lymphedema. I hope all goes well for you.

Lumpie

Trial Assessing Atezolizumab in Triple-Negative Breast Cancer Misses Endpoint

Genentech announced that the phase 3 study of atezolizumab in combination with paclitaxel for the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC) did not meet its primary end point in the PD-L1-positive population.

Findings showed that the study did not meet statistical significance for PFS and also demonstrated a negative trend in overall survival (secondary end point) for patients in the atezolizumab plus paclitaxel arm. The study, however, was not powered for overall survival and data was immature at the time of analysis. The safety profile of atezolizumab was consistent with that seen in previous studies and no new safety signals were reported.

Atezolizumab is marketed under the brand name Tecentriq and is currently approved in combination with Abraxane (paclitaxel [protein-bound]; Celgene) for the treatment of unresectable locally advanced or metastatic TNBC in patients whose tumors express PD-L1. In June 2020, Genentech announced results from the IMpassion031 study evaluating Tecentriq plus Abraxane in patients with previously untreated, early TNBC. Results showed the combination therapy demonstrated a statistically significant and clinically meaningful improvement in pathological complete response, regardless of PD-L1 expression (primary end point).

https://www.cancertherapyadvisor.com/home/cancer-topics/breast-cancer/trial-assessing-atezolizumab-in-triple-negative-breast-cancer-misses-end-point/?utm_source=newsletter&utm_medium=email&utm_campaign=cta-update-hay-20200811&cpn=&hmSubId=nIej-0ANyLQ1&hmEmail=02k_9hvA1kiS6nmG9LnGT5WH-O6RhZf90&NID=&email_hash=f6f19b3bf12938acdd2c69cb86958025&dl=0&mpweb=1323-101775-6515878

Reference

1. Genentech provides update on phase III study of Tecentriq in combination with paclitaxel for people with metastatic triple-negative breast cancer. https://www.businesswire.com/news/home/20200806005915/en/Genentech-Update-Phase-III-Study-Tecentriq-Combination. Accessed August 7, 2020.

BevJen

Lumpie,

Thanks for posting. My center has been doing a trial with tecentriq for those with hormone positive cancer (no longer enrolling). I wonder what the implications are for that cohort. Atezo/tecentriq was all over my Foundation One report as a possible drug for me.

BlueGirlRedState

The other night I heard an interview from this ND, Nalini Chilkov, and was impressed. Her website might not be as impressive as the interview. https://www.integrativecanceranswers.com/dr-nalini-chilkov/ She stressed how she works with the oncologosts, has them focus on the cancer while she focuses on the patients health from the cancer and effects on treatments on health, making sure what she does is not interfering with what the oncologist does. If she was not in southern California, I would probably consult with her to see if she would take me on as a patient. . Another interview with Dr. Ralf Kleefon the same program was also interesting where hyperthermia is used sometimes in combination of lower doses of chemo drugs than the standard calls for. The particular treatment is ony allowed in 3 countries in Europe at this time, Germany, Austria, Sweeden. Here is an article, not the interview https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469443/ It is tempting to try something other than the "standard of care" when you start having doubts about the standard.

santabarbarian

Check out Dr Keith Block , The Block Center, chicago. He is MO who is ALSO an integrative doc. I thought he was wonderful.

Lumpie

Serial Analysis of CTCs in Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy

Journal of the National Cancer Institute

These authors evaluated the prognostic significance of circulating tumor cells (CTCs) in 469 patients with metastatic breast cancer receiving first-line chemotherapy who had serial samples available. The authors improved on the current model of baseline CTC measurement by identifying four CTC trajectory patterns. Progression-free and overall survival were most favorable in patients with undetectable CTCs. In the remaining patients, the model was able to stratify patients into low–, intermediate–, and high–CTC trajectory risk groups. The CTC trajectory performed better as a prognostic model than baseline CTC status or combined CTC status at baseline and end of cycle one.The findings from this large dataset with subsequent validation offer promising and generalizable results. CTC trajectory patterns may serve as a powerful prognostic biomarker to guide treatment decisions in women with metastatic breast cancer.

https://www.practiceupdate.com/C/104907/56?elsca1=emc_enews_topic-alert

https://academic.oup.com/jnci/advance-article-abstract/doi/10.1093/jnci/djaa113/5889954?redirectedFrom=fulltext

https://doi.org/10.1093/jnci/djaa113

debbew

The secret of lymph: How lymph nodes help cancer cells spread

For decades, physicians have known that many kinds of cancer cells often spread first to lymph nodes before traveling to distant organs through the bloodstream. New research from Children's Medical Center Research Institute at UT Southwestern (CRI) provides insight into why this occurs, opening up new targets for treatments that could inhibit the spread of cancer.

The study, published today in Nature, found melanoma cells that pass through the lymph nodes pick up a protective coating, allowing them to survive high levels of oxidative stress in the blood [ferroptosis] and go on to form distant tumors...

They discovered cancer cells from the lymph had higher levels of a monounsaturated fatty acid known as oleic acid, which is the main component of olive oil. They also found this monounsaturated fatty acid was incorporated into the membranes of cancer cells in the lymph. This diluted polyunsaturated fatty acids in the membranes of these cells, inhibiting the chemical reactions that lead to ferroptosis and protecting the cells.

This protective coating of oleic acid from the lymph thus allowed the cancer cells to safely enter the blood, travel to other locations, and form metastatic tumors.

https://medicalxpress.com/news/2020-08-secret-lymph-nodes-cancer-cells.html

Karenfizedbo15

Published today in The Times newspaper, targeted radiotherapy at the same time as surgery can be just as effective as weeks of radiotherapy sessions.
https://www.thetimes.co.uk/article/new-treatment-heralds-breakthrough-for-breast-cancer-patients-c2js2kjjr?shareToken=ba9fca3c89bd9235fc8a5186708869d9

BSandra

Dear Debbew, thanks for the article. The logical question that follows is whether it has something to do with intake of products that contain oleic acid (like olive oil, etc.)? Saulius

moth

Saulius, that would be interesting to know. It's complicated by the fact that the body can make oleic acid and does so but preferentially shuttled it to the brain. We need it in other body systems as welll though...

https://www.sciencedirect.com/science/article/pii/...

"Therefore, the endogenous synthesis in many organs does not compensate for the absence of oleic acid from the food (Bourre et al., 1997b). This fatty acid is therefore partially essential.

There may be several explanations for why the oleic acid concentration in cerebral structures is not altered according to the oleic acid content of the diet. The nervous system may selectively bind oleic acid, perhaps by specific, active transport mechanisms across the blood brain barrier."

beeline

Thanks for this moth, wish there was a like button!

debbew

BSandra,

Adding on to moth's good info, I'll point to the article on olive oil from the food for breast cancer site, which recommends *only* extra virgin olive oil:

"Oleic acid might not account for olive oil's anti-cancer effects. In pure form, oleic acid has been shown to induce migration and proliferation of both hormone receptor positive (ER+/PR+) and triple negative breast cancer cells. These findings imply that the protective effect of olive oil may be due to other components of the oil and not the direct effect of oleic acid. The findings also argue against using highly refined olive oil."

The rest of the article talks about all the potential benefits of EVOO. BTW, I love that site and how they provide handy references to a bunch of relevant research on different foods and, to a lesser degree, supplements.

https://foodforbreastcancer.com/foods/olives-and-olive-oil

BTW, moth, I noticed this link in with their relevant olive oil research references:

Oleic Acid Reduces Brain Injury by Oxidative Stress Induced by Some Anticancer Drugs in Rat Brain

ShetlandPony

This August 2020 paper about the various mutations cancer can develop to resist Ibrance + anti-estrogen looks like it could help us to choose the next line of treatment/trial after Ibrance fail and genomic testing.

https://www.biorxiv.org/content/10.1101/857839v1.full

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

debbew

Long-term TARGIT-A data support single-dose intraoperative breast cancer radiotherapy

The 5-year results of the TARGIT-A trial have demonstrated the noninferiority of risk-adapted, single-dose targeted intraoperative radiotherapy (TARGIT-IORT) delivered during lumpectomy to conventional radiotherapy for the adjuvant treatment of early-stage breast cancer...

In fact, the risk for mortality from causes other than breast cancer was a significant 41% lower for women who received TARGIT-IORT than those given EBRT, a finding consistent with other reports, including a meta-analysis of randomized trials, say the study authors.

https://www.medwirenews.com/oncology/breast-cancer/long-term-data-support-single-dose-targit-iort/18300396

study: https://www.bmj.com/content/370/bmj.m2836

BSandra

Dear Debbew, Moth, thanks for these insights. For sure it should be only "extra virgin" olive oil, as olive oil producing countries only use that one. But everything with moderation. "The middle way" - that is my philosophy... Saulius

BSandra

I start to hate mice:) https://scienmag.com/new-therapy-targets-breast-cancer-metastases-in-brain/ Could not get to the article in Science Translational Medicine Would write to investigators to check when do they plan a clinical trial? Saulius

Lumpie

Dual HER2 Blockade Plus an AI in Postmenopausal Women With HER2+/HR+ Metastatic Breast Cancer

Journal of Clinical Oncology August 26, 2020

The authors report updated results from a trial of dual HER2 blockade with trastuzumab plus lapatinib in combination with an aromatase inhibitor (AI) versus trastuzumab and AI in postmenopausal women with HER2+/HR+ metastatic breast cancer. The original publication of this trial was redacted due to statistical errors leading to small changes in the secondary analyses, but these do not impact the overall conclusions of this study, which showed a superior progression-free survival associated with dual HER2 blockade plus AI compared with trastuzumab plus AI.The combination of trastuzumab plus lapatinib plus AI offers an effective treatment alternative to chemotherapy for this population.

Commentary by Lee S. Schwartzberg MD, FACP:

Dual HER2 blockade with chemotherapy has been shown to be of benefit in HER2-positive MBC, as noted in the CLEOPATRA trial for taxane, trastuzumab, and pertuzumab, and the recent HER2CLIMB trial for tucatinib, trastuzumab, and capecitabine. The ALTERNATIVE study evaluated a chemotherapy-free strategy in patients with HR-positive, HER2-positive MBC by utilizing a lapatinib, trastuzumab, and AI combination. They demonstrated improved PFS and a trend toward OS with very good tolerance. Of note, the large majority of these patients had received prior trastuzumab and chemotherapy. For patients with this biomarker profile, an endocrine/HER2–blockade approach makes sense and has the potential for improved quality of life over chemotherapy. It will be interesting to evaluate such a strategy with newer, more effective TKIs (such as neratinib or tucatinib) with trastuzumab and endocrine therapy in this setting.

https://www.practiceupdate.com/C/105438/56?elsca1=emc_enews_topic-alert

https://ascopubs.org/doi/10.1200/JCO.20.01894

DOI: 10.1200/JCO.20.01894 Journal of Clinical Oncology

{Abstract is free; fee for full article.}

Lumpie

BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine

Science Translational Medicine. August 26, 2020

BETting against brain metastases

Brain metastases are a dreaded complication of many cancer types. Even for malignancies that are relatively treatable, such as breast cancer, brain metastases are difficult to reach and often are not susceptible to the same therapies as peripheral tumors. By comparing primary and metastatic breast cancers, Kanojia et al. identified differences in the expression of cytoskeletal protein βIII-tubulin, which was increased in tumors that metastasized to the brain and sensitized them to vinorelbine, a chemotherapy drug. Another drug type, called a BET inhibitor, promoted βIII-tubulin expression and further sensitized breast cancer metastases to vinorelbine in mouse models, demonstrating a promising therapeutic combination.

Abstract

Metastases from primary breast cancer result in poor survival. βIII-tubulin (TUBB3) has been established as a therapeutic target for breast cancer metastases specifically to the brain. In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic xenograft assays using two different breast cancer cell models revealed a reduction in tumor volume with BET inhibition and VRB treatment. In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05). Using in silico analysis and BET inhibition, we found that the transcription factor myeloid zinc finger-1 (MZF-1) protein binds to the TUBB3 promoter. BET inhibition decreases MZF-1 expression and subsequently increases TUBB3 expression. Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy.

https://scienmag.com/new-therapy-targets-breast-cancer-metastases-in-brain/

https://stm.sciencemag.org/content/12/558/eaax2879

DOI: 10.1126/scitranslmed.aax2879

{Abstract is free; fee or membership required to access full article.}

BSandra: this is the article you referenced. Thx for the tip!

Lumpie

Changes in Peripheral and Local Tumor Immunity After Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients With Breast Cancer

Clinical Cancer Research August 27, 2020

The authors completed a genetic evaluation of the tumor microenvironment in patients with residual disease following neoadjuvant chemotherapy to assess the effect of chemotherapy on the tumor microenvironment in correlation with disease outcomes. In ER+/PR+ breast cancer, there was no significant genetic change associated with relapse-free or overall survival. However, there was an increase in gene set expression in triple-negative breast cancer (TNBC), which was associated with improved outcomes. Additionally, increased cytotoxic T-cell signatures in the peripheral blood of TNBC patients suggested that neoadjuvant chemotherapy has potentially immunogenic effects in these patients.While additional studies are needed to clarify this relationship, these data are suggestive that cytotoxic gene signatures in peripheral blood may be an appropriate biomarker for persistent disease activity.

https://www.practiceupdate.com/C/105465/56?elsca1=emc_enews_topic-alert

https://clincancerres.aacrjournals.org/content/early/2020/08/21/1078-0432.CCR-19-3685

DOI: 10.1158/1078-0432.CCR-19-3685

{Abstract is free; log-in or purchase required to access full article.}

Lumpie

FDA approves Foundation Medicine pan-tumor liquid biopsy test

The FDA approved FoundationOne Liquid CDx, a comprehensive pan-tumor liquid biopsy test.

FoundationOne Liquid CDx (Foundation Medicine) is a qualitative next-generation sequencing-based in vitro diagnostic test that analyzes 324 genes and genomic signatures to help guide treatment decisions for patients with solid tumors.

The FDA based the approval on results of clinical and analytical validation studies that included more than 7,500 samples and 30,000 unique variants representing more than 30 cancer types. Results showed high sensitivity and specificity, including at low allele frequencies, according to Foundation Medicine.

"Liquid biopsies are becoming an increasingly important option to inform personalized treatment decisions for physicians treating certain [patients with advanced cancer] who require minimally invasive solutions to genomic testing,"... "This approval helps expand access to important genomic information needed for physicians to make more informed decisions about targeted treatment approaches for their patients, and is another important step toward making comprehensive genomic testing a part of routine clinical cancer care."

https://www.healio.com/news/hematology-oncology/20200827/fda-approves-foundation-medicine-pantumor-liquid-biopsy-test?utm_source=selligent&utm_medium=email&utm_campaign=news&m_bt=6155829948217

Older and longer, more detailed article on similar topic here:

https://www.healio.com/news/hematology-oncology/20200116/oncologists-must-be-very-cautious-as-liquid-biopsy-use-expands

Lumpie

Study Finds Dairy (Not Soy) Skyrockets Breast Cancer Risk

Int J Epidemiol 2020 Feb 25

A new study claims that women who drink cows' milk could increase their risk of developing breast cancer by up to 80 percent compared to women who drink soy milk. Unbiased by either soy or dairy industry funding, this research was commissioned by the National Cancer Institute at the National Institutes of Health and the World Cancer Research Fund.

the researchers found a dramatic increase in risk with as little as a ¼-⅓ cup margin. Women who reported drinking just eight ounces a day increased their risk of breast cancer by 50 percent, and those who consumed two to three glasses of cows' milk escalated their risk by up to 80 percent (in comparison to the women who did not drink any cows' milk). To clarify, drinking one cup of cows' milk per day does not guarantee a woman is 50 percent more likely to get breast cancer. It does, however, suggest that her individual risk increases by 50 percent. So, if a person has an inherent 12 percent risk (the average), she can increase that risk by half simply by sipping one cows' milk latte or dairy-based smoothie a day. In contrast, participants who completely avoided cows' milk but consumed soy milk did not show an increased risk of cancer.

While this study does not prove cows' milk causes cancer, it opens up the field of study and provides a strong indicator of the harmful effects of dairy in comparison to benign foods. Researchers also suggested that the greatest benefits of soy milk in relation to breast cancer may not be in soy itself, but in the exclusion of dairy.

Conclusions: Higher intakes of dairy milk were associated with greater risk of breast cancer, when adjusted for soy intake. Current guidelines for dairy milk consumption could be viewed with some caution.

https://nutritionstudies.org/study-finds-dairy-not-soy-skyrockets-breast-cancer-risk/?fbclid=IwAR3SYgJN3s-zwytFJ0ccw-D3HVTSGhVGLJYg4DbkDbXFRuZEXvVdQw4MO3w

https://pubmed.ncbi.nlm.nih.gov/32095830/

doi: 10.1093/ije/dyaa007

{As the daughter of several generation of dairy farmers (with no history of breast cancer), it pains me to post this.... but there it is...}

NorCalS

Lumpie,

Thanks for posting the information on liquid biopsies. I really appreciate all the information you have been providing the group. It is so helpful. I’ll have to pester MO about this

Lumpie

My pleasure NorCalS. My MO has not wanted to use liquid biopsy either. I really hope she may change her mind if they become more standard practice. I have a resistant tumor. Biopsy showed it to be same old type as before, but I wonder if part of it has morphed. A liquid biopsy could be really helpful in such a sitaution.