Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial NatureMedicine Everolimus with or without Hydroxychloroquin
Interesting Phase 2 study showing on a series of tests, -51 people who had previously had breast cancer and were confirmed to have DTCs. Individually, the drugs cleared up to 80 percent of the DTCs, but together they were even more effective, wiping out 87 percent of the dormant cells.
In the group that took both hydroxychloroquine and everolimus, all of the participants [remained cancer-free after three years. For those who took either drug on its own, the survival rate was still an impressive 92-93 percent.
Patients with confirmed DCT’s make up a large component of the 30% recurrence of breast cancer.
-This study shows that drugs that don’t work against actively growing cancers can be very effective against these sleeper cells. - and possibly one of the reasons rapa/everolimus provide longevity.
-It will be interesting to see if this holds for other epithelial tumours like prostate and liver.
These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial.
In research and clinical studies, what types of cancer (breast, lung, etc.), or cancer cell types, have mTOR inhibitors like sirolimus (rapamycin) and Everolimus been most effective in terms of preventing, targeting, eliminating, clearing or suppressing?
CGPT5 response:
Here’s a crisp, evidence-first map of where rapalogs (sirolimus/rapamycin and everolimus) have been most effective at actually shrinking tumors vs. mainly suppressing/stabilizing them, plus the best-documented prevention niche.
Tumors with high, reproducible shrinkage responses
Malignant PEComa (perivascular epithelioid cell tumor) — nab-sirolimus (Fyarro) shows one of the clearest response stories in solid tumors: ORR ~39% with durable responses in the phase-2 AMPECT program and its long-term update. (ASCOPubs)
TSC-related brain & kidney tumors
SEGA (subependymal giant cell astrocytoma) — everolimus causes robust and sustained tumor shrinkage (EXIST-1 RCT + long-term extension). (PubMed)
Renal angiomyolipoma (AML) — everolimus: 42% response vs 0% placebo in EXIST-2; sirolimus also shrinks AMLs in phase-2/open-label cohorts. (PubMed)
Post-transplant Kaposi’s sarcoma (KS) — Switching calcineurin inhibitors to sirolimus often triggers partial/complete remissions in series and multicenter cohorts. (Clinical niche; not a randomized tumor-therapy trial.) (PubMed)
Cancers where benefit is mostly suppression/stabilization (PFS gains)
Neuroendocrine tumors (NETs)
Pancreatic NETs — everolimus (RADIANT-3): PFS 11.0 vs 4.6 mo (HR 0.35); responses are uncommon but disease control is consistent. (New England Journal of Medicine)
Non-functional GI & lung NETs — everolimus (RADIANT-4): PFS benefit ~7 months; HR ~0.48–0.50, including a specific lung-NET subgroup analysis. (PMC)
HR+/HER2- advanced breast cancer (after aromatase inhibitor) — everolimus + exemestane (BOLERO-2): PFS ~6.9 vs 2.8 mo by local review; ~10.6 vs 4.1 mo by central. (Disease control > objective shrinkage.) (New England Journal of Medicine)
Metastatic renal cell carcinoma (post-VEGF-TKI) — everolimus (RECORD-1): PFS 4.9 vs 1.9 mo (HR 0.33); low ORR (mainly stabilization). (ScienceDirect)
Other signals (select)
Recurrent endometrioid endometrial cancer — everolimus + letrozole (phase-2): ORR 32% (many complete responses); histology matters (endometrioid ≫ serous). (Not an approved standard, but noteworthy). (PMC)
Prevention / chemoprevention niche (strongest in skin)
In kidney-transplant recipients with prior non-melanoma skin cancer, converting to sirolimushalved subsequent cutaneous SCC risk vs. staying on calcineurin inhibitors in randomized trials; benefit persists on 5-year follow-up of TUMORAPA. (New England Journal of Medicine)
Places where mTOR inhibitors did not show clear benefit (context)
Advanced hepatocellular carcinoma (post-sorafenib) — everolimusfailed to improve OS in the phase-3 EVOLVE-1 trial. (JAMA Network)
Unselected NSCLC and several other solid tumors — studies have generally been negative or modest at best outside of biomarker-driven subsets. (ASCO)
Durable suppression (PFS):pNETs; GI/lung NETs; HR+/HER2- breast (with exemestane); RCC — mostly disease control rather than high ORR. (New England Journal of Medicine)
Prevention:Cutaneous SCC/NMSC risk reduction in transplant patients after sirolimus conversion. (New England Journal of Medicine)