BRCA1/2 are DNA repair enzymes that are the essential components of homologous repair (HR), which is invoked when DNA doubles strand breaks are encountered. HR works via consultation of sister chromatids during late S to early G2 of the cell cycle – without repair of double strand breaks, mitotic catastrophe ensues: Continue reading
Augmenting the responses to checkpoint inhibitors, which remove the “breaks” from the immune response, is a very popular area of research. The general concept is to turn immunologically cold tumors hot. For example, triple negative breast cancer (TNBC) is considered an immunologically cold tumor – anti-PD(L)1 therapy has shown responses of just 5-10%. Continue reading
Immune checkpoint inhibitors are simply cancer wonder drugs about which we are learning more each day. Because they don’t work optimally in many patients and some even hyper-progress, the goal is to determine ways to expand their effectiveness to more patients. As such, the number of clinical studies with checkpoints and checkpoint combinations continues to grow.
Immune checkpoint inhibitors act by blocking the abrogating phase of the immune response that is necessary to prevent autoimmune disease – by prolonging the immune response against cancer, a more robust and prolonged immune response, which is required for effective cancer therapy, is achieved with checkpoint therapy. Continue reading
Olaparib (Lynparza) is a PARP (poly-ADP ribose polymerase) inhibitor that was approved by the FDA in 2014 for the treatment of patients with advanced ovarian cancer who have mutated BRCA1,2 gene. Recently, the drug showed a 70% reduction in risk of progression in patients with less-advanced disease in the maintenance therapy setting:
The Phase III SOLO-2 trial demonstrated a significant improvement in progression-free survival (PFS) in germline BRCA-mutated (gBRCA), platinum-sensitive, relapsed ovarian cancer patients treated with Lynparza (olaparib) tablets (300mg twice daily) compared with placebo in the maintenance setting. The trial met its primary endpoint of investigator assessed PFS (HR 0.30; 95% CI 0.22 to 0.41; P<0.0001; median 19.1 months vs 5.5 months).
PARP inhibitors act in a counter-intuitive manner – by blocking PARP in the context of mutated BRCA1, the cell becomes overwhelmed with double strand breaks, leading to crisis and cell death. BRCA1 mutations, alone, predispose the cell to the accumulation of mutations in protooncogenes and tumor suppressor genes – a few double strand breaks are tumorigenic, whereas a massive number of double strand breaks, as occurs in the context of PARP inhibition, leads to apoptosis.
The use of PARP inhibitors for breast cancer makes great sense, However, in a Phase 3 trial of velparib, an experimental PARP inhibitor, failed to achieve better rates of complete pathogenic response in patients with triple negative breast cancer (TNBC – lack of HER-2, estrogen, and progesterone receptor up-regulation) versus chemotherapy, alone.
At the ASCO conference last week, AstraZeneca presented data on the use of olaparib in 302 patients with BRCA1,2 mutated breast cancer from its OlympiAD trial that compares olaparib against physician’s choice of chemotherapy (capecitabine 2500 mg/m2 d1-14 q 21, or vinorelbine 30 mg/m2 d1,8 q 21, or eribulin 1.4 mg/m2 d1,8 q 21):
OlympiAD Inclusion Criteria:
- Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious.
- Histologically or cytologically confirmed breast cancer with evidence of metastatic disease.
- Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting.
- Prior platinum allowed as long as no breast cancer progression occurred on treatment or if given in adjuvant/neoadjuvant setting at least 12 months from last dose to study entry elapsed.
- ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy.
- ECOG performance status 0-1.
- Adequate bone marrow, kidney and liver function.
OlympiAD Exclusion Criteria:
- Prior treatment with PARP inhibitor.
- Patients with HER2 positive disease.
- More than 2 prior lines of chemotherapy for metastatic breast cancer.
- Untreated and/or uncontrolled brain metastases.
Results were quite impressive – this was the first study that demonstrated PARP inhibition is effective in breast cancer:
- About 60% of patients saw their tumors shrink, a hair more than double the 29% objective response rate seen in those patients on chemotherapy.
- Lynparza showed efficacy in patients with TNBC, which is more difficult to treat. AbbVie, which is developing its own PARP inhibitor called veliparib, recentlyannounced a study specifically geared to look at veliparib’s activity in triple negative breast cancer failed to show a benefit when added to chemo.
- Additionally, treatment with Lynparza improved the time to second progression or death compared to chemo,suggesting patients who relapsed after Lynparza experienced a less aggressive return of their cancers.
Astrazeneca is studying olaparib with many combinations, including a study in TNBC with PD-L1 inhibitor durvalumab and CTLA-4 inhibitor tremelimumab.
Antibody drug conjugate Glembatumumab vedotin (GV) is in late phase 2 trials for patients with triple negative breast cancer (TNBC) – those whose tumors do not express estrogen, progesterone, or HER-2. Approximately 15% of breast cancer patients have TNBC; it is an important area of research for both researchers and clinicians alike because: Continue reading
The FDA granted Breakthrough Therapy Designation to Sacituzumab govetican (IMMU-132) for treatment of triple-negative breast cancer (TNBC). A diagnosis of triple negative breast cancer means that the three most common types of receptors known to fuel most breast cancer growth–estrogen, progesterone, and the HER-2/neu gene– are not present in the cancer tumor. This means that the breast cancer cells have tested negative for hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR). Since the tumor cells lack the necessary receptors, common treatments likehormone therapy and drugs that target estrogen, progesterone, and HER-2 are ineffective.
Autophagy is a process by which cells that are under stress and deprived of nutrients pause to recycle themselves in order to maintain viability. Autophagosomes comprised of cellular organelles are formed, followed by Lysosomal destruction; the cell then uses the substrates for synthesis and reconstitution. Cells in autophagy do not replicate… Continue reading