29/01/2024
Precision Oncology and Combinatorial Approach:
We have a fit, 51 year old, Left Breast, IDC, Triple Negative Breast Cancers (TNBC), Grade III, with a high Ki67 (80%). She was oligometastatic at presentation with biopsy proven liver metastasis. Her germline panel (with MLPA) was suggestive of RAD54B VUS. She was micro-satellite stable with Negative PD-L1 CPS (DAKO 22C3).
She was started on weekly Taxane / Platinum, and a progressive elevation of transaminases was noted. Review liver sonogram after 4 weekly doses done to evaluate transaminitis was suggestive of disease progression in liver with increase in number as well as size of lesions. Startled at the aggressiveness, we started her on Anathracyclines along with Bevacizumab while exploring the option of Trodelvy, on which she further progressed within 3 weeks.
Her somatic Foundation CGP (below), suggested a classical Basal like TNBC signatures including Low TMB, TP53, RB1 loss, and a classical PIK3CA. Besides that there were RAD21, EGFR, and FGFR1 amplification among others. Puzzled at what was driving the tumour so rapidly (locally as well as liver), the choice was now to move on to ADC (Trodelvy) vs try n-of-1 kind combinatorial approach. After discussions with Dr Arun Kumar and Dr Aparna Dhar, the brilliant molecular oncologists at Foundation Medicine and Max Healthcare, a consensus emerged that tumour was being driven by the multiple amplifications she harbours, especially FGFR1.
Considering her genomic profile, and keeping our fingers crossed, we considered her for combinatorial approach with Gemcitabine/Cisplatin along with Lenvatinib and Keytruda and for the first time she started to respond with her liver functions improving and tumour markers (CA 15.3) reducing.
Take Home:
Combinatorial approach is tricky, it can be simple and yet can get complex. One of the important component of practicing combinatorial approach is Molecular Tumour Board.
Treating newly diagnosed, treatment-naïve cancer patients with an N-of-1 approach over standard of care requires a strong understanding of molecular results & molecularly guided therapies. Better to begin with previously treated patient before considering the approach in treatment naïve patients
Drug Dosage can be started at lower doses and increased from there, certain basic guiding principles can be:
70% of each drug if there is no overlap in targets or class and no mTor inhibitor in the regimen
30% of each drug with overlap of class and/or target or inclusion of a mTor inhibitor
If one drug is held at 100% of full dose, the lowest safe starting dose of the second drug is about 25%, and especially in case of overlapping drug class/target.
