Updates on Triple Negative Breast Cancer Research and Practice

Annually, around 1.5 million women are globally diagnosed to have breast cancer. The National Cancer Institute estimates that more than 200,000 Americans are diagnosed with breast cancer every year.

It is the second most leading cause of cancer death among American women, claiming more than 40,000 lives in 2009 alone.

Triple negative breast cancers comprise 10-20% of all breast cancer cases. Women with TNBC tend to present with:

• Higher grade,
• Larger tumors,
• Younger age at diagnosis,
• Higher incidence of metastases and
• Shorter time to recurrence compared to other breast cancer types.

Certain types of proteins can be identified in certain breast cancer cells, those mediate cancerous cell growth; namely Estrogen Receptor (ER), Progesterone Receptor (PR) or Epidermal Growth Factor Receptor 2 (HER2).
Breast cancers can be termed as ER+ve, PR+ve or HER 2+ve according to the receptor protein status; and if, none of the three is present those are classified as triple negative breast cancers (TNBC).
Neo-adjuvant treatment of TNBC with hormonal manipulation is not possible as those lack the receptor proteins.

Until recently, it has been seen that some viruses home in certain tumor cores, best suited for their replication. Those viruses effectively target the tumor tissue and not the normal tissue. So those can be used as vector to deliver drugs precisely in the tumor and achieve tumor cell death.

Many more work in this front is being taken up by the researchers. Some of those are;

1. Researchers from the Memorial Sloan-Kettering Cancer Center in New York City are of the opinion that triple-negative breast cancer (TNBC) might respond to treatment with an oncolytic agent. Their findings were reported in the American College of Surgeons 97th Annual Clinical Congress.

They found that the genetically modified herpes virus, NV1066 may act as an effective oncolytic agent against triple-negative breast cancer.

TNBC uses mitogen-activated protein kinase (MAPK) signaling pathway for its proliferation and survival; and activated (phosphorylated) MAPK signaling has been seen to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.

TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets the cells that over express this protein.

The researchers infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the down regulation of phosphorylated MAPK by 48 hours.

Oncolytic viruses are being studied in head and neck cancers, but this study is the first to show promise in TNBC. If additional animal studies are also positive, human clinical trials are expected.

But, the questioned remains, whether the use of an oncolytic virus can produce an immune response in the host needs to be addressed.

2. Though some medications used in receptor positive cancers have effect on triple negative cancer, still those are not fully responsive.

Scientists have found out that insulin like growth factor receptor (IGF-1R)  over expression is associated with less outside spread of breast cancer, i.e. the more is this protein the better is the outcome for triple negative breast cancer.Less IGF-1R is associated with more spread to lymph nodes.

High expression levels were also linked to longer survival rates among patients younger than 55 years.
The next step forward is perhaps to learn if triple-negative breast cancer patients benefit from targeting IGF-1R.

3. There are drugs like tamoxifen, letrozole and trastuzumab thse can block the receptors in receptor positive breast cancers, but has no action on the receptor negative cases.

There are at least four types of epidermal growth factor receptors, namely: EGFR, HER2, HER3 and HER4.

Researchers from Dublin (Ireland) have found out that TNBC expresses epidermal growth factor receptor (EGFR) in abundance.

They targeted an enzymes called ADAMs (a disintegrin and metalloprotease), those required for activation of EGFR binding proteins during the signaling process.

Gefitinib, a drug that inhibits EGFR was effective as a single drug therapy, but when put to the test along with ADAM17 inhibitor, it did not work well.

Later on the researchers tried another unnamed drug which blocks ADAM10 and ADAM17; and found good response in about 91% of cases.

They also found that the treatment of TNBC cells line with this compound reduced their ability to migrate, a process that is vital for the progression of cancer.

Having found that an ADAM inhibitor can reduce the proliferation of TNBC cell lines, they hope that ADAMs may be a useful therapeutic target.

4. Progesterone is an interesting hormone which prevents endometrial cancer whereas may stimulate breast cancer growth. It has another aspect that after administration it stimulates the breast cells for growth for 24 hours; and then inhibits growth or makes the cells stand still for 3 to 4 days, technically cells remain in the borderline G and S phase.

Dr Rajan Badwe, who is now the director of Tata Memorial Centre, Mumbai started the protocol of four to fourteen days pre-surgical treatment of breast cancer patients with progesterone injection be it a surgical biopsy, lump removal or both.
He is practising this protocol for about a decade now. It cuts down the chances of recurrences by 10% and brings down death rate by 8% as reported in the Tomes of India.
A genomic study over the next year, between the Indian government and the National Cancer Institute of the United States will look at the genomic changes that will establish just how this mechanism works its magic.

Perhaps, the days are not far away when triple negative breast cancers will respond nicely to multimodality approach of treatment; and the outcome can be as good as that is seen in breast cancers positive for ER, PR and HER2.