The first 60 days: HR-positive metastatic breast cancer after CDK4/6 inhibitors

Staging tests establish exactly what and where the cancer is. Everything else follows from the answers.

These specialties appear in the standard of care for this cancer. In most centres they meet weekly as a tumour board to agree each plan; you can ask when yours was discussed and what was decided.

• PathologistNamed in the standard of care for: ESR1-mutant disease after a CDK4/6 inhibitor.
• Medical oncologistNamed in the standard of care for: ESR1-mutant disease after a CDK4/6 inhibitor, PIK3CA, AKT1 or PTEN alteration, No targetable alteration, Endocrine-refractory, HER2-low or ultralow and 1 more.

A second opinion from a centre that treats many similar cases is normal, not rude; the standard of care tells you what to compare it against.

Each row is a setting from the standard of care, in the order it usually arises. Not all will apply to you; your stage and biomarkers decide which do. The guideline grade, where recorded, says how strong the evidence is.

1. 1.ESR1-mutant disease after a CDK4/6 inhibitor

   Elacestrant (EMERALD), imlunestrant (EMBER-3) or vepdegestrant; where available, a switch to camizestrant at the moment ESR1 appears in plasma while continuing the CDK4/6 inhibitor (SERENA-6).

   ElacestrantEMERALDImlunestrantEMBER-3CamizestrantSERENA-6VepdegestrantLiquid biopsy (ctDNA)
2. 2.PIK3CA, AKT1 or PTEN alteration

   Capivasertib with fulvestrant (CAPItello-291); alpelisib with fulvestrant for PIK3CA (SOLAR-1); inavolisib with palbociclib and fulvestrant for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy (INAVO120).

   CapivasertibCAPItello-291AlpelisibSOLAR-1InavolisibINAVO120Fulvestrant
3. 3.No targetable alteration

   Fulvestrant with abemaciclib (postMONARCH), everolimus with exemestane, or another endocrine agent; giredestrant with everolimus is emerging (evERA).

   AbemaciclibpostMONARCHEverolimusExemestaneevERA
4. 4.Germline BRCA carriers

   Olaparib (OlympiAD) or talazoparib (EMBRACA) in place of chemotherapy.

   OlaparibOlympiADTalazoparibEMBRACAGermline BRCA mutation (gBRCA)
5. 5.Endocrine-refractory, HER2-low or ultralow

   Trastuzumab deruxtecan before chemotherapy (DESTINY-Breast06), then sacituzumab govitecan (TROPiCS-02) or datopotamab deruxtecan (TROPION-Breast01) after chemotherapy.

   Trastuzumab deruxtecanDESTINY-Breast06Sacituzumab govitecanTROPiCS-02Datopotamab deruxtecanTROPION-Breast01HER2-low and HER2-ultralow

Generated from this cancer's standard of care, biomarkers and open problems. Take the group that matches where you are. To tick, add your own and print, open the one-page appointment sheet.

Trials open now for this cancer in OnCo, largest phase first. Joining a trial is a decision like any other: ask what the comparison arm is, whether a placebo is used, and what happens if you leave. The cancer page searches ClinicalTrials.gov live for more.

• A Randomised, Open-label, Multicentre Phase III Clinical Study to Evaluate the Efficacy and Safety of JS105 Combined With Dalpiciclib and Fulvestrant Compared With Dalpiciclib and Fulvestrant in Patients With PIK3CA-mutated, HR-positive, HER2-negative Recurrent or Metastatic Breast CancerPhase 3 · recruiting · NCT07207070A Randomised, Open-label, Multicentre Phase III Clinical Study to Evaluate the Efficacy and Safety of JS105 Combined With Dalpiciclib and Fulvestrant Compared With Dalpiciclib and Fulvestrant in Patients With PIK3CA-mutated, HR-positive, HER2-negative Recurrent or Metastatic Breast Cancer
• A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination TherapyPhase 3 · recruiting · NCT05646862A Phase III, Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Versus Alpelisib Plus Fulvestrant in Patients With Hormone Receptor-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Who Progressed During or After CDK4/6 Inhibitor and Endocrine Combination Therapy
• A Study of SIM0270 Combined With Everolimus vs. Treatment of Physician's Choice in Patients With ER+/HER2- Advanced Breast Cancer (SIMRISE)Phase 3 · active · NCT06680921A Randomized, Open-label, Phase III Study of SIM0270 Combined With Everolimus Versus Treatment of Physician's Choice in Patients With CDK4/6 Inhibitors Previously Treated, ER+/HER2- Locally Advanced or Metastatic Breast Cancer
• A Study of Tersolisib (LY4064809/STX-478) With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA)Phase 3 · recruiting · NCT07174336A Phase 2, Randomized, Open-Label Dose Optimization and Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY4064809 Combined With a CDK4/6 Inhibitor and Endocrine Therapy in Adults With HR+, HER2-Advanced Breast Cancer With a PIK3CA Mutation Who Received No Prior Treatment for Advanced Breast Cancer (PIKALO-2)
• A Study to Learn About the Study Medicine Called PF-07248144 in Combination With Fulvestrant in People With HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Progressed After a Prior Line of TreatmentPhase 3 · recruiting · NCT07062965An Interventional, Open-Label, Randomized, Multicenter, Phase 3 Study of PF-07248144 Plus Fulvestrant Compared to Investigator's Choice of Therapy in Adult Participants With Hormone Receptor-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Whose Disease Progressed After Prior CDK4/6 Inhibitor-based Therapy

Much of what helps in the first weeks is free if you know to ask: testing, helplines, rides and lodging, second opinions, trial travel.

• Free in oncologyFree testing, helplines, rides and lodging, second opinions and trial travel help, with who is eligible.
• Financial helpManufacturer programmes, national schemes and charities by country and product.
• Second opinionExpert centres for this cancer in your country and how referral works.

• HR-positive metastatic breast cancer after CDK4/6 inhibitors: the full pageWhen hormone-positive breast cancer grows through a CDK4/6 inhibitor, a blood test picks the next drug. Tumours with an acquired ESR1 mutation respond to the oral degraders elacestrant, camizestrant and imlunestrant; tumours with PIK3CA, AKT1 or PTEN changes to capivasertib, inavolisib or alpelisib; and once endocrine options run out, antibody-drug conjugates come before chemotherapy.
• One-page appointment sheetYour questions, the words you may hear, what to bring, and space for the answers. Print it.
• Treatment sequencingWhich treatment tends to follow which, line by line.
• NavigatorStandard of care for your stage, what you have tried, and trials near you.