Episode Notes

About 80% of breast cancers are ER+, meaning that the cancer cells have estrogen receptors, and estrogen is likely to make them grow. Here’s the good news/bad news story for ER+ MBC patients. First, the good news: there are a number of effective medications that either reduce available systemic estrogen or block its ability to stimulate cancer growth. The bad news: over time, ER+ cancers develop resistance to these medications, resulting in cancer progression and signaling the need for a new treatment. For many of us with ER+ MBC, that means a repeating cycle of high stakes scans, biopsies, and blood tests—and the ever present fear that we will run out of treatment options. 

Fortunately, there is more good news: the best minds in cancer research are on the case. In this episode, the Our MBC Life team hears from two dynamic MSK oncologists on treatment strategies and the latest research around the problem of endocrine resistance

 Dr. Pedram Razavi and Dr. Komal Jhaveri will review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance including the molecular tumor board that meets regularly at MSK 

Subjects and Terms Included in This Episode

Novel Therapies Mentioned in the Episode

Clinical Trials

Clinical Trials Investigated by Dr. Jhaveri and Dr. Razavi

• A Phase IA Study of PF-06873600 in Patients with Advanced Breast Cancer

• A Phase II Study of Neratinib in Patients with Solid Tumors Containing Mutated HER2

• A Phase I Study of BDC-1001 Alone or in Combination with Pembrolizumab Immunotherapy in People with Advanced Solid Tumors that Make Too Much HER2

• Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.

• Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer.

• A Phase 1 Study of Letrozole, Palbociclib, and Onapristone ER in People With Metastatic Breast Cancer

Clinical Trials Investigated by Dr. Ezra Rosen

• A Phase I Study of ERAS-601 Alone or with a MEK inhibitor for People with Advanced or Metastatic Solid Tumors

• A Phase IB/IIA Study of Mirdametinib on Its Own or in Combination with Fulvestrant in People with Advanced Breast Cancer and Other Solid Tumors with Certain Genetic Changes

  
  

Research and Publications

The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.

Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N, Cai Y, Bielski CM, Donoghue MTA, Jonsson P, Penson A, Shen R, Pareja F, Kundra R, Middha S, Cheng ML, Zehir A, Kandoth C, Patel R, Huberman K, Smyth LM, Jhaveri K, Modi S, Traina TA, Dang C, Zhang W, Weigelt B, Li BT, Ladanyi M, Hyman DM, Schultz N, Robson ME, Hudis C, Brogi E, Viale A, Norton L, Dickler MN, Berger MF, Iacobuzio-Donahue CA, Chandarlapaty S, Scaltriti M, Reis-Filho JS, Solit DB, Taylor BS, Baselga J.Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016

Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.

Vasan N, Razavi P, Johnson JL, Shao H, Shah H, Antoine A, Ladewig E, Gorelick A, Lin TY, Toska E, Xu G, Kazmi A, Chang MT, Taylor BS, Dickler MN, Jhaveri K, Chandarlapaty S, Rabadan R, Reznik E, Smith ML, Sebra R, Schimmoller F, Wilson TR, Friedman LS, Cantley LC, Scaltriti M, Baselga J.Science. 2019 Nov 8;366(6466):714-723. doi: 10.1126/science.aaw9032.

Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors.

Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, Li BT, Shen R, Vasan N, Modi S, Jhaveri K, Caravella BA, Patil S, Selenica P, Zamora S, Cowan AM, Comen E, Singh A, Covey A, Berger MF, Hudis CA, Norton L, Nagy RJ, Odegaard JI, Lanman RB, Solit DB, Robson ME, Lacouture ME, Brogi E, Reis-Filho JS, Moynahan ME, Scaltriti M, Chandarlapaty S.

Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.Smyth LM, Batist G, Meric-Bernstam F, Kabos P, Spanggaard I, Lluch A, Jhaveri K, Varga A, Wong A, Schram AM, Ambrose H, Carr TH, de Bruin EC, Salinas-Souza C, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Nikolaou M, Schiavon G, Razavi P, Banerji U, Baselga J, Hyman DM, Chandarlapaty S.

A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer.

Hamilton EP, Patel MR, Armstrong AC, Baird RD, Jhaveri K, Hoch M, Klinowska T, Lindemann JPO, Morgan SR, Schiavon G, Weir HM, Im SA.

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann J, Marshall G, Morgan S, Patel P, Rowlands V, Sathiyayogan N, Aung K, Hamilton E, Patel M, Armstrong A, Jhaveri K, Im SA, Iqbal N, Butt F, Dive C, Harrington EA, Barrett JC, Baird R, Hayes DF.

Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists.Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, Smith A, Wilson J, Morrow C, Wong WL, De Stanchina E, Carlson KE, Martin TS, Uddin S, Li Z, Fanning S, Katzenellenbogen JA, Greene G, Baselga J, Chandarlapaty S.

Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS.

Rose Brannon A, Jayakumaran G, Diosdado M, Patel J, Razumova A, Hu Y, Meng F, Haque M, Sadowska J, Murphy BJ, Baldi T, Johnson I, Ptashkin R, Hasan M, Srinivasan P, Rema AB, Rijo I, Agarunov A, Won H, Perera D, Brown DN, Samoila A, Jing X, Gedvilaite E, Yang JL, Stephens DP, Dix JM, DeGroat N, Nafa K, Syed A, Li A, Lebow ES, Bowman AS, Ferguson DC, Liu Y, Mata DA, Sharma R, Yang SR, Bale T, Benhamida JK, Chang JC, Dogan S, Hameed MR, Hechtman JF, Moung C, Ross DS, Vakiani E, Vanderbilt CM, Yao J, Razavi P, Smyth LM, Chandarlapaty S, Iyer G, Abida W, Harding JJ, Krantz B, O'Reilly E, Yu HA, Li BT, Rudin CM, Diaz L, Solit DB, Arcila ME, Ladanyi M, Loomis B, Tsui D, Berger MF, Zehir A, Benayed R.Nat Commun. 2021 Jun 18;12(1):3770. doi: 10.1038/s41467-021-24109-5.

Large Study Pinpoints Genetic Changes Underlying Drug Resistance in the Most Common Type of Breast Cancer

Scientists are learning how estrogen receptor-positive breast cancer evolves to thwart hormonal therapies and are developing ways to stop it. (65 kB)

https://www.mskcc.org/news/large-study-pinpoints-genetic-changes-underlying-drug-resistance-most-common-type-breast

Want more?

Enhertu granted Breakthrough Therapy Designation in the US for patients with HER2-low metastatic breast cancer

For an introduction to resistance and progression, we suggest that you listen to this episode with Dr. Stephanie Graff, Director of the Breast Oncology Program at Lifespan Cancer Institute and co-leader of the Breast Cancer Translational Research Disease Group at Brown University in Rhode Island.

Meet the Guests of this Episode