QuoteReplyTopic: Update on Treatment Strategies 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)
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