San Antonio Breast Cancer Symposium 2015. Dec.8-12

voraciousreader

http://www.prnewswire.com/news-releases/research-p...

voraciousreader

http://www.prnewswire.com/news-releases/tapimmune-...

voraciousreader

http://www.eurekalert.org/pub_releases/2015-12/aaf...

voraciousreader

http://www.prnewswire.com/news-releases/tapimmune-...

voraciousreader

http://money.cnn.com/news/newsfeeds/articles/prnew...

These results should be interesting

cp418

http://www.medpagetoday.com/MeetingCoverage/SABCS/...

JohnSmith

Liquid biopsies (based on analysis from the BOLERO-2 clinical trial) found that D538G and Y537S mutations in the estrogen receptor 1 (ESR1) gene are a prognostic indicator for the advanced ER+ cohort.

http://www.aacr.org/Newsroom/Pages/News-Release-De...

JohnSmith

Resistance of ER-positive Breast Cancer to Tamoxifen Therapy May be Driven by APOBEC3B
Responses to Tamoxifen (Tam) were significantly prolonged by reducing levels of the enzyme APOBEC3B in preclinical models of ER+ breast cancer and significantly shortened by increasing levels of APOBEC3B, suggesting that APOBEC3B drives resistance to Tam.
"Several recent studies have linked elevated levels of the enzyme APOBEC3B in ER+ with poor patient outcomes, but whether APOBEC3B actually drives the poor outcomes has not been determined," said Reuben Harris, PhD, professor in the Department of Biochemistry, Molecular Biology, and Biophysics at the University of Minnesota, Twin Cities.
"We know that APOBEC3B is not required for human life because a large proportion of people in Southeast Asia do not have APOBEC3B as a result of a natural genetic variation," Harris continued. "This, combined with the fact that it is an enzyme, makes APOBEC3B an attractive target for a therapeutic that could stop the development of resistance mutations and substantially extend the length of response to Tam."
* Note: While interesting, this is lab research. Clinical trials would be needed to validate.

For a simpler explanation of this APOBEC3B enzyme at its potential connection to Tam resistance,
watch this 2 minute video by Dr. Reuben Harris.

farmerlucy

Thank you all for the links! My head is spinning from all the info!

JohnSmith

EndoPredict (also called EPclin) is getting a lot of tweets.
It's a multi-gene test that predicts mets risk (beyond 5+ years) in ER+, HER2- patients using algorithm of 8 genes. Like Oncotype, useful when considering chemo.
Developed by German based Sividon Diagnostics & acquired by Myriad Genetics, I think. Not clear if this data is based on large clinical trials.
Will provide link later. Can't keep up with the data dump!!

JohnSmith

In Diagnostics news: Caris Life Sciences' Non-Invasive Liquid Biopsy Platform ADAPT Biotargeting System Demonstrates Potential to Improve Accuracy of Breast Cancer Diagnosis
Study Shows ADAPT Biotargeting System May be an Effective Diagnostic Adjunct to Routine Mammography for Women with Dense Breast Tissue

Caris Life Sciences presented results from the first study using its technology called ADAPT (Adaptive Dynamic Artificial Poly-ligand Targeting) Biotartgeting System to perform multiplexed biomarker discovery in human plasma. The study shows blood plasma contains circulating complexes which contain information that could serve as a diagnostic adjunct to mammography for women with dense breast tissue. Researchers reported results of experiments indicating that ADAPT is equally effective in difficult cases for which imaging technologies are insufficient for characterizing breast tissue as cancerous or non-cancerous.

JohnSmith

Breast-conserving Therapy Yielded Better Outcomes Than Mastectomy for Early-stage Patients
Among patients with early-stage breast cancer, those who received breast- conserving surgery plus Rads had improved overall survival (OS) after 10 years compared with those who received mastectomy without Rads. Several observational studies have provided evidence to suggest that BCT confers better survival than mastectomy; however, these studies have limitations.

JohnSmith

Targeting copper to treat breast cancer?
Interesting study of a drug called tetrathiomolybdate (TM) that mops up copper. Presented by Dr. Linda Vahdat of Weill Cornell Medical College.
Article is here.
At a median follow-up of nearly five years, 62 other women in the 75 patient TM trial also had no detectable cancer. Among them were 12 of the 15 other women with stage IV triple negative. Interesting, but many challenges to validate in a Phase 3 trial.

more info:

P3-02-02 Targeting the tumor microenvironment: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence
Nackos E, Willis A, Kornhauser N, Ward M, Andreopoulou E, Cigler T, Moore A, Fitzpatrick V, Cobham M, Schneider S, Wiener A, Guillaume-Abraham J, Warren JD, Rubinchik A, Lane M, Mittal V, Linda V. Weill Cornell Medical College, New York, NY; Weill Cornell, New York Presbyterian Hospital, New York, NY; Cornell University, Ithaca, NY.

JohnSmith

Immunotherapy news: [P2-11-09] A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data

Phase 2 trial now open and enrolling ~150 patients for the Immunotherapy drug, Indoximod.
The Phase 1 trial, here, proved to be safe.

JohnSmith

Immunotherapy / Vaccine news: "Robust generation of T-cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine."
TapImmune presents new data showing robust generation of T-Cell Immunity
- Vaccination with TPIV 100 boosts T-cell immunity to HER2 in HER2+ patients
- Provides catalyst to start Phase II studies

JohnSmith

Immunotherapy news:
Seattle Genetics presents Phase 1 data from Novel Antibody-Drug Conjugate SGN-LIV1A
Ongoing phase 1 Trial evaluating SGN-LIV1A, an antibody-drug conjugate (ADC) in development for Stage IV patients.
SGN-LIV1A consists of a humanized anti-LIV-1 monoclonal antibody (mAb) and the microtubule-disrupting agent monomethyl auristatin E (MMAE), utilizing a protease-cleavable linker. ADCs are monoclonal antibodies that are designed to selectively deliver cytotoxic agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemo while enhancing antitumor activity.

JohnSmith

For the AH, LCIS, and DCIS camp:
Chemoprevention with Tamoxifen or Anastrozole significantly reduces the risk of invasive breast malignancies in women with Atypical Hyperplasia (AH), LCIS, and DCIS.
The prospective randomized trial NSABP B-24 randomly assigned 364 women with ER+ DCIS to receive Tamoxifen and 368 to receive placebo, and at a median follow-up of 14.5 years found breast cancer-free survival to be superior among women who received Tamoxifen over placebo.

JohnSmith

Promising phase 1 results lead to phase 2 for ONT-380 in HER2+ breast cancer

Targets HER2+ population and possible game-changer for its specific ability to control brain mets.
Invented by Array Biopharma and now being developed by Oncothyreon, ONT-380 is a small molecule inhibitor of the HER2 growth factor receptor.

Results of this ongoing phase I trial (NCT01983501) support the initiation of a phase II clinical trial (NCT02614794), which Dr. Virginia Borges of the University of Colorado hopes will start accruing patients soon. This study is estimated to be completed in 2019.

JohnSmith

More research on targeting ESR1 mutations. .pdf link not posting properly, so pasting abstract summary.

S3-04. "ESR1 coregulator binding inhibitor (ECBI) as a novel therapeutic to target hormone therapy resistant metastatic breast cancer"
PI: Vadlamudi, Ratna (RK)
The University of Texas Health Science Center at San Antonio

Summary: Despite initial positive response to Endocrine therapies, most patients develop resistance to these drugs and tumors recur as mets. Resistant tumors retain ESR1-expression, acquire mutations and exhibit alterations in the levels and functions of coregulators that contribute to estrogen independent ESR1-signaling. There is a critical need to develop novel therapeutics that target ligand independent interaction of coregulators with ESR1.
AEs/AIs are ineffectual in disrupting ESR1 protein-protein interactions that occur in therapy-resistant and metastatic cells. Towards this end, we have rationally designed a lead small organic molecule (ESR1 coregulator binding inhibitor, ECBI) that can emulate ESR1 coregulator NR box motif in the structural context critical for ESR1 signaling.
Our preliminary results show that ECBI can function as natural tumor suppressor, and block tumor growth in vivo. ECBI can control multiple pathways, presenting the prospect of one ECBIs blocking numerous protein-protein interactions between critical coregulators with ESR1 in breast cancer, thus has potential to prevent development of resistance to these therapies. ECBI have pharmacologic advantages, associated with fewer systemic side effects and has potential to delay initiation of toxic systemic chemotherapy. Funds from this CPRIT-Bridging the Gap proposal will provide therapeutic utility, biomarker and cGMP-manufactured drug product formulation to enable IND filing and set stage for future initiation of Phase I trials. Successful completion of the proposed studies will lead to the development of first-in-class cancer therapy drugs that addresses the critical need of targeting therapy resistance and metastasis of breast cancer and to commercialize novel drugs that are efficacious against ESR1-coregulator driven breast tumors.
* Note: Sounds great. Need to start Phase 1 trials. Sadly, this is years from the clinic. Ugh...

JohnSmith

Diagnostics / Surgical news:

[OT2-02-03] "Magnetic nano-device for identification of the breast sentinel nodes - A novel method"
This new technique aims to eliminate the use of radioactive tracers that are used in sentinel node biopsy (SNB) procedures.
Clinical trials are underway to compare effectiveness over the standard SNB technique.

JohnSmith

Immunotherapy news for TN cohort:
"Abraxane and immune checkpoint inhibitor show very promising tumor response in TNBC metastatic disease".
Upfront treatment with the PD-L1 inhibitor Atezolizumab (MPDL3280A) plus nab-paclitaxel (Abraxane) showed a confirmed objective response rate (ORR) of 66.7% in patients with metastatic TNBC.

JohnSmith

Two minute video by Dr. Whitworth (Nashville Breast Center) on the importance of additional HER2 Subtyping & adding Perjeta.
Dr. Whitworth keeps refering to Pertuzumab (Brand name: Perjeta) a monoclonal antibody (mAb) for the treatment of HER2+.

The group of patients in the study, when treated with Chemo and Trastuzumab (Herceptin)‎, had a very low complete response rate (CR). However, when Perjeta was added, the CR rate jumped dramatically.
* Note: There was no discussion of the toxicity of taking these three drugs together. Probably worth asking for those considering this route.

JohnSmith

Adjuvant Capecitabine (Brand name: Xeloda) Boosts Survival Rates in HER2-Negative Breast Cancer.

These results come from the Phase III CREATE-X/JBCRG-04 trial, which started in 2007.
This trial originated in Japan, thus didn't appear in clinicaltrials.gov website.
Official title: "A phase III trial of adjuvant capecitabine (Xeloda) with HER2-negative pathologic residual invasive disease after neoadjuvant chemo."

After standard neoadjuvant chemo containing an Anthracycline and/or Taxane, postoperative adjuvant use of Capecitabine improved disease-free survival (DFS). Overall survival (OS) was significantly improved by Capecitabine adjuvant therapy for non-pCR or node-positive patients after neoadjuvant chemo."
A combination of capecitabine and adjuvant therapy dropped the risk of recurrence by 30% and prolonged survival by 40% for patients with residual breast cancer post-neoadjuvant chemotherapy and surgery, according to phase III data.

JohnSmith

Androgen Receptor (AR) news:
"Phase 1 results point to larger trial of enzalutamide and fulvestrant in advanced breast cancer"

Results of a multicenter Phase 1 clinical trial presented today show that the anti-Androgen agent Enzalutamide (Brand name: Xtandi) is active and well-tolerated alone and with Fulvestrant (Brand name: Faslodex) in patients with advanced breast cancer. The study takes another important step toward larger clinical trials targeting Androgen Receptors in breast cancer.

This human data follows extremely promising preclinical data (much of which was reported at last years SABCS supporting the Androgen Receptor as a target in breast cancer. Enzalutamide is also being evaluated in a Phase 2 clinical trial in combination with the AI, Exemestane (NCT02007512) and demonstrated promising results in another Phase 2 trial against advanced Triple Negative disease (NCT01889238).

voraciousreader

yay! John!!

JohnSmith

CYP2D6 Testing still not clinically relevant.

"Why does tamoxifen work better in some women?"
Studies challenge CYP2D6 as marker, point to need for validation
"At this point we still have a hypothetical association between genotype and efficacy that has not been validated. For now, there is no clinical benefit to using CYP2D6 to inform Tamoxifen treatment decisions. We need to validate these hypotheses."

Oh my!

Hopeful82014

"yay! John!!"

Ditto!!

JohnSmith

News about HER2- Biomarkers / using Veliparib (ABT-888) acting as a PARP inhibitor:

[P3-07-48] "Prediction of complete pathologic response to veliparib/carboplatin plus standard neoadjuvant therapy in HER2- | Exploratory protein pathway marker results from the I-SPY 2 trial"

In the I-SPY 2 Trial, HER2- patients were randomized to receive standard chemotherapy or chemotherapy plus the oral PARP inhibitor veliparib in combination with carboplatin (V+C), which graduated in the HR-/HER2- arm. Exploratory analysis of protein signaling was performed to identify biomarker candidates that correlated with pCR in the HER2- population.

Conclusion: Our sample size (115 patients) is too small to draw definitive conclusions and the results are exploratory. Coordinated RTK-mTOR pathway activation appears to be a hallmark signature of lack of response to veliparib in HER2- tumors. We also found that HER2 levels were correlated paradoxically with lack of response in this HER2- population, suggesting potential added clinical value of quantitative HER2 measurement techniques. Such exploratory results merit evaluation in larger trials with HER2- breast cancer patients.

JohnSmith

Immunotherapy news using cyclophosphamide with Aromasin:

[P2-11-11] Phase II trial of Exemestane (Aromasin) with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile

Background: Resistance to endocrine therapies in HR+ is a significant challenge. The AI Exemestane (EXE) has demonstrated short-term efficacy in metastatic HR+ HER2- (mHR+BC) that has progressed during treatment with a non-steroidal AI. Combination strategies have not shown a survival benefit. Immunotherapy represents a promising approach as it may increase durability of responses. Low dose cyclophosphamide (CTX) has demonstrated efficacy in combination with neoadjuvant Letrozole in HR+, conceivably by enhancing anti-tumor immune responses. Here we investigated whether EXE combined with immunomodulatory CTX could provide durable responses in heavily pretreated patients and assessed immunological profiles (NCT01963481).

Conclusion: EXE and CTX had a favorable safety profile with evidence of clinical activity in patients with heavily pretreated mHR+BC, including durable responses in liver and bone. Correlative studies are ongoing to identify potential biomarkers of response or resistance to therapy.

JohnSmith

Immunotherapy / Vaccine news:
[P2-11-01] Final pre-specified analysis of the Phase II trial of the GP2+GM-CSF peptide vaccine in high risk breast cancer patients to prevent recurrence.

Conclusions: The final pre-specified analysis of this randomized phase II trial of the GP2+GM-CSF adjuvant breast cancer vaccine shows no statistical differences between treatment arms. However, it does identify a particular patient population where the vaccine may have efficacy; HER2 3+ patients appear to derive the greatest clinical benefit from GP2 vaccination after trastuzumab treatment with the PT analysis nearing statistical significance. Further studies are required to confirm these findings and investigate the potential link between hormone receptor status and the induction of clinically beneficial anti-tumor immunity with this vaccine.