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Update on Treatment Strategies

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    Posted: Jan 06 2020 at 8:26pm

Update on Strategies to Improve Treatment for Triple Negative Breast Cancer, by Cancer Connect

Neoadjuvant Keytruda, Tecentriq, and Sacituzumab Govitecan (IMMU-132) are promising TNBC treatment advances.

Approximately 12% of all breast cancers are TNBC, meaning that they are estrogen-receptor negative (ER-), progesterone-receptor negative (PR-), and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones estrogen or progesterone, nor through an overactive HER2 pathway.

Unfortunately, many available and effective treatment options for the majority of breast cancers block the growth stimulating effects of ER, PR and/or HER2; therefore, TNBC has had limited therapeutic options.

In addition, TNBC tends to be an aggressive type of cancer, is often diagnosed at a more advanced stage, and proportionately affects younger women more often than other breast cancers. Novel treatment options for TNBC have lagged behind that of other types of breast cancers.

The development of more effective treatment for triple negative breast cancer (TNBC) requires that new and innovative therapies be evaluated in TNBC patients. Areas of active investigation aimed at improving the treatment of TNBC include some of the following:

PD-1 Checkpoint Inhibitors

The cancer immunotherapy strategy known as programmed cell death 1 (PD-1) has generated great excitement for its ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 are called checkpoint inhibitors and may enhance the ability of the immune system to fight cancer.

Keytruda Effective as Neoadjuvant Treatment for TNBC

Keytruda is a fully humanized monoclonal antibody checkpoint inhibitor that binds with high-affinity to the PD-1 receptor. Results in advanced breast cancer have been mixed. In heavily pretreated patients with recurrent or metastatic TNBC positive for PD-1 Keytruda has been reported to produce a response rate of 18.5% (1) however a trial directly comparing single agent Keytruda to chemotherapy in recurrent TNBC found that Keytruda was no better.(2)

Chemotherapy administered before surgery with the goal of reducing the size of the cancer for surgical removal is called neoadjuvant chemotherapy. Use of Keytruda earlier in the adjuvant and neoadjuvant setting may hold more promise. In June 2019 neoadjuvant Keytruda was reported to be significantly more effective than chemotherapy at eradicating cancer confined to the breast prior to surgery. (3) These results are consistent with the ​I-SPY 2 clinical trial which demonstrated that Keytruda in combination with standard therapy as neoadjuvant treatment for patients with locally advanced TNBC increased the pathologic complete response (pCR) nearly threefold in patients with TNBC.(5)

This was confirmed in the KEYNOTE 522 clinical trial which enrolled 1,174 patients with locally advanced TNBC to receive treatment with standard chemotherapy with or without the addition of Keytruda followed by definitive surgery and radiation therapy. After completion of local therapy patients were treated with additional Keytruda.

Analyses revealed that Keytruda treated patents were less likely to have evidence of cancer in their surgically removed breast tissue and more likely to survive without evidence of cancer recurrence. Overall 65% off Keytruda treated patients had a pathologic complete remission compared to only 51 % of women not treated with Keytruda and 91% survived without evidence of cancer compared to 85% at the time of this analyses. PDL-1-positive patients had a higher response to chemotherapy and combination treatment with Keytruda without unexpected side effects. (10)

Tecentriq Improves Survival in Advanced TNBC

Tecentriq (atezolizumb) is another checkpoint inhibitor and when
combined with Abraxane in women with advanced TNBC produced an anti-cancer response in 70.8% of patients.(5) The combination of Tecentriq and Abraxane improved average survival duration from 15.5 months among patients with PD-L1–positive tumors compared to 25 months compared to Abraxane alone, leading to accelerated FDA approval. (8,9)

Treatment combinations consisting of checkpoint inhibitors plus Abraxane and other known active drugs in TNBC like Gemzar (gemcitabine) and Carboplatin are ongoing to determine the optimal way to incorporate this new class of drugs into the overall management of TNBC.(6)

Sacituzumab Govitecan (IMMU-132) is referred to as an antibody-conjugate, and is still in investigative stages. It is comprised of an antibody that attaches to specific receptors called Trop-2 receptors. The antibody is attached to a drug that kills cancer cells, called SN-38.

Trop-2 receptors are often found in large numbers on the surface of cancer cells, but not healthy cells. Once IMMU-132 binds to the Trop-2 receptors, it delivers SN-38 into the cancer cell. This kills the cancer cell, while only affecting a small portion of healthy cells. By targeting Trop-2 receptors, larger amounts of chemotherapy can be delivered to the cancer cells because healthy cells are largely spared from the cancer-killing effects of the treatment.

A recent clinical trial was conducted to further evaluate the effectiveness of IMMU-132 in patients with TNBC. The trial included patients with TNBC that had spread to distant sites in their body, and had received a median of 5 prior therapies. Final results from the trial are awaited to fully determine patient outcomes. Meanwhile, patient enrollment for continuing larger comparative trials with IMMU-132 in TNBC is ongoing.(6)

Strategies To Improve The Treatment of Early Stage TNBC

Adding neoadjuvant carboplatin to pre-surgery chemotherapy improved disease-free survival for patients with TNBC

Previously reported clinical study results have suggested that adding carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy can increase the proportion of patients with TNBC who had attained a pathologic complete response [pCR], from 36.9 percent to 53.2 percent.

In the currently reported study researchers enrolled 315 patients with TNBC to receive 18 weeks of neoadjuvant chemotherapy consisting of paclitaxel, non-pegylated-liposomal doxorubicin, and bevacizumab and were randomly assigned to concurrently receive weekly carboplatin or nothing extra and then directly compared.

After a median follow-up of three years, 85.5 percent of TNBC patients treated with the additional carboplatin survived without evidence of cancer recurrence compared to only 76.1 percent of patients treated with paclitaxel, non-pegylated-liposomal doxorubicin, bevacizumab, and no carboplatin.(7)

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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