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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Soroush Seifirad, M.D.[2]

## Overview[edit | edit source]

Medical investigational therapies are a wide range of new generations of targeted therapy, cancer vaccines, oncolytic virotherapy, gene therapy, and immunotherapy. Novel surgical and radiation techniques are also under investigation. A new generation of clinical trials (adaptive trials) are already being used in the war against breast cancer (i.e. I-SPY 2).

## Immunotherapeutic interventions[edit | edit source]

Generally, cancer immunotherapy refers to immune checkpoint inhibitors and cytokines, adoptive cell therapy, and cancer vaccines.

### Immune checkpoint inhibitors[edit | edit source]

#### Programmed cell death protein 1 (PD-1)[edit | edit source]

* Programmed cell death protein 1 (PD-1) is an inhibitory immune checkpoint inhibitor that limits T-cell effector function within tissues, and it is expressed on the surfaces of immune effector cells (T-cells, B cells, NK cells, DCs, and many TILs) and has two known ligands, namely, PD-L1 and PD-L2.[1]

* Anti-PD-1 antibodies (Pembrolizumab, JS001, PDR001, and Nivolumab)[2]
* Anti-PD-L1 antibodies (Atezolizumab and Durvalumab)[3]

#### Anti-CTLA-4 antibodies (Ipilimumab and Tremelimumab)[edit | edit source]

* Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a T-cell inhibitory receptor that is expressed on activated CD8+ T cells and CD4+ regulatory T cells that express CD25 and Foxp3. [4]
* Immune checkpoint inhibitors might be combined with targeted therapy (i.e Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors

### Adoptive cell therapy[edit | edit source]

* Adoptive cell therapy is defined as the induction of anti-tumor immune responses via the isolation of highly active and tumor-specific lymphocytes, such as tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), Th cells, NK and Dendritic cells (DCs).[5]

* Chimeric antigen receptors T-cell-based therapy
* T cell receptors (TCRs)—engineered T cells

### Cancer vaccines[edit | edit source]

* Cancer-testis antigens (CTA) as a vaccine target[6]
* Personalized peptide vaccination (PPV)[7]
* Antigen-presenting cell (APC) and DC-based tumor vaccination[8]

### Antibody–drug conjugates (ADC)[edit | edit source]

* Utilization of monoclonal antibodies that recognize TAAs/TSAs and preferably internalizes when bound to the tumor cells to deliver highly potent cytotoxic agents.[9]

#### Sacituzumab govitecan[edit | edit source]

* It is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.
* Each antibody having on average 6.7 molecules of SN-38 attached.
* SN-38 is too toxic to administer directly to patients, but the linkage to an antibody allows the drug to specifically target cells containing Trop-2.
* In in February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[10]

### Exosomes[edit | edit source]

* Exosomes are mall 30–100 nm sized extracellular vesicles
* They are present in many eukaryotic fluids (normal and malignant)
* Particles that encapsulate contents, such as microRNAs.
* Exosome messaging contributes to:[11]

* TME interactions, including:

* Immune suppression and immune escape,
* Invasive growth, adhesion, angiogenesis,
* Radiation resistance, chemo-resistance
* Genetic intercellular exchange,
* May manipulate tumor progression and metastatic cascade

## Endoxifen[edit | edit source]

* Endoxifen is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group. It is an active metabolite of tamoxifen and has been found to be effective in patients that have failed previous hormonal therapies (tamoxifen, aromatase inhibitors, and fulvestrant).[12][13][14]

## Fenretinide[edit | edit source]

Fenretinide, a retinoid, is also being studied as a way to reduce the risk of breast cancer (retinoids are medications related to vitamin A).

## Adaptive clinical trials such as I-SPY 2[edit | edit source]

* I-SPY 2 is an adaptive clinical trial of multiple Phase 2 treatment regimens combined with standard chemotherapy.[15] [16]
* I-SPY 2 linked 19 academic cancer centers, two community centers, the FDA, the NCI, pharmaceutical and biotech companies, patient advocates and philanthropic partners.
* The trial is sponsored by the Biomarker Consortium of the Foundation for the NIH (FNIH) and is co-managed by the FNIH and QuantumLeap Healthcare Collaborative.
* I-SPY 2 was designed to explore the hypothesis that different combinations of cancer therapies have varying degrees of success for different patients.
* Conventional clinical trials that evaluate post-surgical tumor response require a separate trial with long intervals and large populations to test each combination. Instead, I-SPY 2 is organized as a continuous process. It efficiently evaluates multiple therapy regimes by relying on the predictors developed in I-SPY 1 that help quickly determine whether patients with a particular genetic signature will respond to a given treatment regime.
* The trial is adaptive in that the investigators learn as they go, and do not continue treatments that appear to be ineffective.
* All patients are categorized based on tissue and imaging markers collected early and iteratively (a patient's markers may change over time) throughout the trial so that early insights can guide treatments for later patients.
* Treatments that show positive effects for a patient group can be ushered to confirmatory clinical trials, while those that do not can be rapidly sidelined.
* Importantly, confirmatory trials can serve as a pathway for FDA Accelerated Approval.
* I-SPY 2 can simultaneously evaluate candidates developed by multiple companies, escalating or eliminating drugs based on immediate results. Using a single standard arm for comparison for all candidates in the trial saves significant costs over individual Phase 3 trials.
* All data are shared across the industry.
* As of January 2016, I-SPY 2 is comparing 11 new treatments against 'standard therapy' and is estimated to complete in Sept 2017. By mid-2016 several treatments had been selected for later stage trials. (Clinical trials website: https://www.clinicaltrials.gov/ct2/show/NCT01042379)[16]

[17][18]

## Transcription factors[edit | edit source]

* NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation.[19]
* Indeed, NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma and NFAT3 (NFATc4) is an inhibitor of cell motility.
* NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin-2 to increase breast cancer cell invasion and NFAT3 inhibits Lipocalin-2 expression to blunt the cell invasion.[20]
* NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2.[21]

## Cryoablation[edit | edit source]

* As of 2014 cryoablation is being studied to see if it could be a substitute for a lumpectomy in small cancers.
* There is tentative evidence in those with tumors less than 2 centimeters.
* It may also be used in those in who surgery is not possible.
* Another review states that cryoablation looks promising for early breast cancer of small size.
* New research also demonstrated promising results for the combination of cryotherapy and immune modulation as it may help prevent tumor recurrence.[22][23][24]

## References[edit | edit source]

1. ↑ Rosato RR, Dávila-González D, Choi DS, Qian W, Chen W, Kozielski AJ et al. (2018) Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models. Breast Cancer Res 20 (1):108. DOI:10.1186/s13058-018-1037-4 PMID: 30185216
2. ↑ Swoboda A, Nanda R (2018) Immune Checkpoint Blockade for Breast Cancer. Cancer Treat Res 173 ():155-165. DOI:10.1007/978-3-319-70197-4_10 PMID: 29349763
3. ↑ Wu B, Sun X, Gupta HB, Yuan B, Li J, Ge F et al. (2018) Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer. Oncoimmunology 7 (11):e1500107. DOI:10.1080/2162402X.2018.1500107 PMID: 30393583
4. ↑ Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271 (5256):1734-6. PMID: 8596936
5. ↑ June CH (2007) Adoptive T cell therapy for cancer in the clinic. J Clin Invest 117 (6):1466-76. DOI:10.1172/JCI32446 PMID: 17549249
6. ↑ Mirandola L, Pedretti E, Figueroa JA, Chiaramonte R, Colombo M, Chapman C et al. (2017) Cancer testis antigen Sperm Protein 17 as a new target for triple negative breast cancer immunotherapy. Oncotarget 8 (43):74378-74390. DOI:10.18632/oncotarget.20102 PMID: 29088794
7. ↑ Takahashi R, Toh U, Iwakuma N, Takenaka M, Otsuka H, Furukawa M et al. (2014) Feasibility study of personalized peptide vaccination for metastatic recurrent triple-negative breast cancer patients. Breast Cancer Res 16 (4):R70. DOI:10.1186/bcr3685 PMID: 24992895
8. ↑ Zhang P, Yi S, Li X, Liu R, Jiang H, Huang Z et al. (2014) Preparation of triple-negative breast cancer vaccine through electrofusion with day-3 dendritic cells. PLoS One 9 (7):e102197. DOI:10.1371/journal.pone.0102197 PMID: 25036145
9. ↑ Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR (2014) Site-specific antibody-drug conjugates for cancer therapy. MAbs 6 (1):34-45. DOI:10.4161/mabs.27022 PMID: 24423619
10. ↑ Dizon DS, Krilov L, Cohen E, Gangadhar T, Ganz PA, Hensing TA et al. (2016) Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol 34 (9):987-1011. DOI:10.1200/JCO.2015.65.8427 PMID: 26846975
11. ↑ Dioufa N, Clark AM, Ma B, Beckwitt CH, Wells A (2017) Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells. Mol Cancer 16 (1):172. DOI:10.1186/s12943-017-0740-6 PMID: 29137633
12. ↑ Hawse JR, Subramaniam M, Cicek M, Wu X, Gingery A, Grygo SB et al. (2013) Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens. PLoS One 8 (1):e54613. DOI:10.1371/journal.pone.0054613 PMID: 23382923
13. ↑ Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 69 (5):1722-7. DOI:10.1158/0008-5472.CAN-08-3933 PMID: 19244106
14. ↑ Gingery A, Subramaniam M, Pitel KS, Reese JM, Cicek M, Lindenmaier LB et al. (2014) The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton. PLoS One 9 (5):e98219. DOI:10.1371/journal.pone.0098219 PMID: 24853369
15. ↑ Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 86 (1):97-100. DOI:10.1038/clpt.2009.68 PMID: 19440188
16. ↑ 16.0 16.1 Das S, Lo AW (2017) Re-inventing drug development: A case study of the I-SPY 2 breast cancer clinical trials program. Contemp Clin Trials 62 ():168-174. DOI:10.1016/j.cct.2017.09.002 PMID: 28899813
17. ↑ (2014) Positive results for drug combo in I-SPY 2 trial. Cancer Discov 4 (2):OF2. DOI:10.1158/2159-8290.CD-NB2013-182 PMID: 24501314
18. ↑ Bartsch R, de Azambuja E (2016) I-SPY 2: optimising cancer drug development in the 21st century. ESMO Open 1 (5):e000113. DOI:10.1136/esmoopen-2016-000113 PMID: 27900209
19. ↑ Quang CT, Leboucher S, Passaro D, Fuhrmann L, Nourieh M, Vincent-Salomon A et al. (2015) The calcineurin/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells. Cell Death Dis 6 ():e1658. DOI:10.1038/cddis.2015.14 PMID: 25719243
20. ↑ Gaudineau B, Fougère M, Guaddachi F, Lemoine F, de la Grange P, Jauliac S (2012) Lipocalin 2, the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion. J Cell Sci 125 (Pt 19):4475-86. DOI:10.1242/jcs.099879 PMID: 22767506
21. ↑ Yiu GK, Toker A (2006) NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 281 (18):12210-7. DOI:10.1074/jbc.M600184200 PMID: 16505480
22. ↑ Swintelski C, Plaza M (2018) Successful cryoablation of breast cancer. Breast J 24 (4):704-706. DOI:10.1111/tbj.12996 PMID: 29411921
23. ↑ Pusceddu C, Melis L, Ballicu N, Meloni P, Sanna V, Porcu A et al. (2017) Cryoablation of Primary Breast Cancer in Patients with Metastatic Disease: Considerations Arising from a Single-Centre Data Analysis. Biomed Res Int 2017 ():3839012. DOI:10.1155/2017/3839012 PMID: 29201903
24. ↑ Tarkowski R, Rzaca M (2014) Cryosurgery in the treatment of women with breast cancer-a review. Gland Surg 3 (2):88-93. DOI:10.3978/j.issn.2227-684X.2014.03.04 PMID: 25083502