Key advancements continue to drive more effective and potent cancer treatments across tumor types. One such development includes the ringing in of PARP inhibitors (PARPi). Progress in this particular arena has recently led to the first US Food and Drug Administration-approved PARPi treatments for germline BRCA-mutated metastatic breast cancer, olaparib and talazoparib.
While such progress must quite rightly be celebrated, the inevitable challenge remains when some patients either cease to respond to PARPi therapy through acquired resistance, or their respective tumors do not unfortunately respond to treatment.
Seeking out new therapeutic avenues and novel approaches through which to both reverse resistance and halt cancer cell spread must consequently remain at the top of the research agenda.
In determined pursuit of essential new strategies that target vulnerabilities in BRCA-associated breast cancer, research led by VHIO and published last month in The Journal of Clinical Oncology*, proposes lurbinectedin — a novel anti-cancer drug that blocks transcription and induces DNA double-strand breaks, leading to apoptosis – as therapy against BRCA-mutated advanced breast cancer.
Approximately 3-5% of metastatic breast cancer (MBC) patients harbor germline mutations in the BRCA1 or BRCA2 genes, many of whom have already been heavily been pretreated with other agents and have subsequently developed resistance to standard anti-cancer medicines.
BRCA1 and BRCA2 genes encode for proteins of homology recombination repair (HRR) machinery – a vital process in fixing DNA double-strand breaks.
Considering lurbinectedin’s capacity to stall the elongating RNA polymerase II on DNA and subsequent accumulation of double strand-breaks (DSB) and apoptosis, the researchers of this present study* assessed whether this novel agent might more effectively and safely deliver its anti-cancer blows in the treatment of BRCA1/2 mutated advanced breast cancer.
Findings from this phase II collaborative USA-Spanish multicenter trial, co-senior authored by Judith Balmaña, Principal Investigator of VHIO’s High Risk & Cancer Prevention Group, and Steven J. Isakoff at the Massachusetts General Hospital Cancer Center (Boston, USA), show that treatment with lurbinectedin might benefit patients with BCRA1 or BRCA2-mutated metastatic breast cancer, and thus provide much needed and more potent anti-cancer armory.
Co-first authored by VHIO’s Cristina Cruz and Alba Llop-Guevara, Medical Oncologist and Post-Doctoral Fellow of our Experimental Therapeutics Group directed by Principal Investigator and co-author Violeta Serra, respectively, the study team enrolled 84 patients with metastatic breast cancer and divided them into two groups according to germline BRCA1/2 status. Arm A of the study included 54 patients with BRCA1/2 mutated breast cancer, and arm B, patients with unselected (either wild-type or unknown) disease, totaling at 35.
The overall response rate (ORR) was 41% in arm A and 9% in arm B. In arm A, results confirmed tumor reduction and median progression-free survival was 4.6 months and median overall survival was 20 months. Anti-tumor activity was most notable in patients with BRCA2 mutations who showed an ORR of 61% and median progression-free survival increasing to 5.9 months with median overall survival of 26.6 months.
Talking to VHIO Communications, co-senior author Judith Balmaña observed, “In our dedicated efforts aimed at potentiating therapies against advanced breast cancer towards ultimately halting disease progression, this present study could be an important next step. While the further testing of lurbinectedin in this subset of patients is certainly warranted, our findings show promise in more effectively treating patients with BRCA1/2 mutations, especially those with BRCA2 mutated breast cancer.”
As further reflection of the potential relevance of the study, The Lancet Oncology covered the paper in this month’s issue as a News**, and invited both Judith and fellow renowned expert, Karen Gelmon, Clinical Professor and Medical Oncologist at the Vancouver Coastal Health Research Institute (BC, Canada), for comment.
Commenting for VHIO Communications Judith concluded, “In our collective quest to develop and potentiate anti-cancer therapies, we must continue to center our efforts on upholding the proven as opposed to promising. As importantly we must also figure how to be, and remain, one step ahead of cancer. For this very reason, our research included a unicenter translational substudy assessing potential mechanisms of resistance to this novel inhibitor.”
For over a decade VHIO’s High Risk and Cancer Prevention Group led by Judith, Breast Cancer Group and the Vall d´Hebron University Hospital’s Breast Cancer Unit, directed by Cristina Saura, and our Institute’s Experimental Therapeutics Group headed by Violeta Serra, have been deeply committed to identifying and counteracting mechanisms of resistance to current as well as novel therapies.
In addition to spearheading pioneering research aimed at establishing mechanisms of resistance to PARPi, their collective expertise also continues to drive approaches aimed at more precisely selecting patients who would most likely benefit from novel anti-cancer treatments and drug-drug combinations tested preclinically in patient-derived xenografts (PDX).
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References:
*Cruz C, Llop-Guevara A, Garber JE, Arun BK, Pérez Fidalgo JA, Lluch A, Telli ML, Fernández C, Kahatt C, Galmarini CM, Soto-Matos A, Alfaro V, Pérez de la Haza A, Domchek SM, Antolin S, Vahdat L, Tung NM, Lopez R, Arribas J, Vivancos A, Baselga J, Serra V, Balmaña J, Isakoff SJ. Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected MetastaticAdvanced Breast Cancer and Biomarker Assessment Substudy. J Clin Oncol. 2018 Sep 21:JCO2018786558. doi: 10.1200/JCO.2018.78.6558. [Epub ahead of print].
**Gourd E. Lurbinectedin for BRCA-mutated advanced breast cancer. Lancet Oncol. 2018 Sep 27. pii: S1470-2045(18)30737-X. doi: 10.1016/S1470-2045(18)30737-X. [Epub ahead of print].
