Margaret Gatti-Mays, MD MPH
@drgattimays.bsky.social
Deputy Director Ohio State #MedicalOncology and #BreastCancer Section Chief @OSUCCCjames |#immunotherapy | #Medsky #OncSky #BoyMom | #NIH alumnus | #HoyaSaxa | Posts -My Own
Reference(s)
Andre F, et al. N Engl J Med. 2019 May 16;380(20):1929-1940.
Rodon J, et al. Breast Cancer Res. 2024 Mar 4;26(1):36.
FDA prescribing information, alpelisib. Updated 1/18/2024.
Llombart-Cussac A, et al. EClinicalMedicine. 2024 Apr 11:71:102520.
Andre F, et al. N Engl J Med. 2019 May 16;380(20):1929-1940.
Rodon J, et al. Breast Cancer Res. 2024 Mar 4;26(1):36.
FDA prescribing information, alpelisib. Updated 1/18/2024.
Llombart-Cussac A, et al. EClinicalMedicine. 2024 Apr 11:71:102520.
October 22, 2025 at 1:06 AM
Reference(s)
Andre F, et al. N Engl J Med. 2019 May 16;380(20):1929-1940.
Rodon J, et al. Breast Cancer Res. 2024 Mar 4;26(1):36.
FDA prescribing information, alpelisib. Updated 1/18/2024.
Llombart-Cussac A, et al. EClinicalMedicine. 2024 Apr 11:71:102520.
Andre F, et al. N Engl J Med. 2019 May 16;380(20):1929-1940.
Rodon J, et al. Breast Cancer Res. 2024 Mar 4;26(1):36.
FDA prescribing information, alpelisib. Updated 1/18/2024.
Llombart-Cussac A, et al. EClinicalMedicine. 2024 Apr 11:71:102520.
Metformin prophylaxis can be considered for patients at elevated risk; the METALLICA study4 demonstrated a decreased incidence and severity of alpelisib-related hyperglycemia with metformin, though this was accompanied by increased gastrointestinal AEs (nausea, vomiting, and diarrhea).
October 22, 2025 at 1:06 AM
Metformin prophylaxis can be considered for patients at elevated risk; the METALLICA study4 demonstrated a decreased incidence and severity of alpelisib-related hyperglycemia with metformin, though this was accompanied by increased gastrointestinal AEs (nausea, vomiting, and diarrhea).
The prescribing information for alpelisib3 recommends obtaining FPG and HbA1c at baseline, then monitoring FPG at least weekly for the first 2 weeks and then monthly thereafter; HbA1c should be rechecked every 3 months.
October 22, 2025 at 1:06 AM
The prescribing information for alpelisib3 recommends obtaining FPG and HbA1c at baseline, then monitoring FPG at least weekly for the first 2 weeks and then monthly thereafter; HbA1c should be rechecked every 3 months.
Answer: D. All of the above
Rationale: Hyperglycemia is the most common and clinically significant grade ≥3 adverse event associated with alpelisib, observed in 37% of patients in SOLAR-1.1 This pt has multiple risk factors for severe hyperglycemia: obesity (BMI ≥30 kg/m2), age ≥75, and high HbA1c
Rationale: Hyperglycemia is the most common and clinically significant grade ≥3 adverse event associated with alpelisib, observed in 37% of patients in SOLAR-1.1 This pt has multiple risk factors for severe hyperglycemia: obesity (BMI ≥30 kg/m2), age ≥75, and high HbA1c
October 22, 2025 at 1:06 AM
Answer: D. All of the above
Rationale: Hyperglycemia is the most common and clinically significant grade ≥3 adverse event associated with alpelisib, observed in 37% of patients in SOLAR-1.1 This pt has multiple risk factors for severe hyperglycemia: obesity (BMI ≥30 kg/m2), age ≥75, and high HbA1c
Rationale: Hyperglycemia is the most common and clinically significant grade ≥3 adverse event associated with alpelisib, observed in 37% of patients in SOLAR-1.1 This pt has multiple risk factors for severe hyperglycemia: obesity (BMI ≥30 kg/m2), age ≥75, and high HbA1c
A. Monitor labs QW x 2, then monthly
B. A1C at baseline, then every 3 months
C. Consider metformin premedication
D. All of the above
B. A1C at baseline, then every 3 months
C. Consider metformin premedication
D. All of the above
October 22, 2025 at 1:06 AM
A. Monitor labs QW x 2, then monthly
B. A1C at baseline, then every 3 months
C. Consider metformin premedication
D. All of the above
B. A1C at baseline, then every 3 months
C. Consider metformin premedication
D. All of the above
References
1. Turner NC, et al. N Engl J Med. 2023 Jun 1;388(22):2058-2070.
2. Baselga J, et al. N Engl J Med. 2012 Feb 9;366(6):520-9.
3. Bidard F-C, et al. J Clin Oncol. 2022 Oct 1;40(28):3246-3256.
4. NCCN Guidelines. Breast Cancer. Version 4.2025. Issued 5/17/2025.
1. Turner NC, et al. N Engl J Med. 2023 Jun 1;388(22):2058-2070.
2. Baselga J, et al. N Engl J Med. 2012 Feb 9;366(6):520-9.
3. Bidard F-C, et al. J Clin Oncol. 2022 Oct 1;40(28):3246-3256.
4. NCCN Guidelines. Breast Cancer. Version 4.2025. Issued 5/17/2025.
October 22, 2025 at 1:01 AM
References
1. Turner NC, et al. N Engl J Med. 2023 Jun 1;388(22):2058-2070.
2. Baselga J, et al. N Engl J Med. 2012 Feb 9;366(6):520-9.
3. Bidard F-C, et al. J Clin Oncol. 2022 Oct 1;40(28):3246-3256.
4. NCCN Guidelines. Breast Cancer. Version 4.2025. Issued 5/17/2025.
1. Turner NC, et al. N Engl J Med. 2023 Jun 1;388(22):2058-2070.
2. Baselga J, et al. N Engl J Med. 2012 Feb 9;366(6):520-9.
3. Bidard F-C, et al. J Clin Oncol. 2022 Oct 1;40(28):3246-3256.
4. NCCN Guidelines. Breast Cancer. Version 4.2025. Issued 5/17/2025.
Combining mTOR inhibitor everolimus with fulvestrant offers inferior specificity and efficacy vs AKT inh in AKT-mutant disease (BOLERO-2).2 Elacestrant, an oral SERD, is indicated for ESR1-mut (EMERALD);3 chemotherapy should be reserved for endocrine-refractory in the absence of targetable mut.
October 22, 2025 at 1:01 AM
Combining mTOR inhibitor everolimus with fulvestrant offers inferior specificity and efficacy vs AKT inh in AKT-mutant disease (BOLERO-2).2 Elacestrant, an oral SERD, is indicated for ESR1-mut (EMERALD);3 chemotherapy should be reserved for endocrine-refractory in the absence of targetable mut.
In the CAPItello-291 trial of pts with progression on/after AI + CDK4/6i, addition of the AKT inhibitor capivasertib to fulvestrant sig improved median PFS (7.2 vs 3.6 months overall; HR=0.60, P <.001), with strongest benefit in tumors w/ AKT- alterations (7.3 vs 3.1 months; HR=0.50, P <.001).1
October 22, 2025 at 1:01 AM
In the CAPItello-291 trial of pts with progression on/after AI + CDK4/6i, addition of the AKT inhibitor capivasertib to fulvestrant sig improved median PFS (7.2 vs 3.6 months overall; HR=0.60, P <.001), with strongest benefit in tumors w/ AKT- alterations (7.3 vs 3.1 months; HR=0.50, P <.001).1
Answer: B. Capivasertib + fulvestrant
Rationale: Alterations in the PI3K/AKT/PTEN pathway promote endocrine resistance and tumor proliferation in HR+/HER2– mBC.
Rationale: Alterations in the PI3K/AKT/PTEN pathway promote endocrine resistance and tumor proliferation in HR+/HER2– mBC.
October 22, 2025 at 1:01 AM
Answer: B. Capivasertib + fulvestrant
Rationale: Alterations in the PI3K/AKT/PTEN pathway promote endocrine resistance and tumor proliferation in HR+/HER2– mBC.
Rationale: Alterations in the PI3K/AKT/PTEN pathway promote endocrine resistance and tumor proliferation in HR+/HER2– mBC.
🤔What 2L Tx would you offer a 45yo♀️w/ ER+/HER2- mBC and an AKT mutation on 🧪liquid biopsy after progression at cycle 47 of ribociclib ➕ AI/OFS❓
Capecitabine monotherapy
Capivasertib + fulvestrant
Elacestrant monotherapy
Everolimus + fulvestrant
Capecitabine monotherapy
Capivasertib + fulvestrant
Elacestrant monotherapy
Everolimus + fulvestrant
October 22, 2025 at 12:58 AM
🤔What 2L Tx would you offer a 45yo♀️w/ ER+/HER2- mBC and an AKT mutation on 🧪liquid biopsy after progression at cycle 47 of ribociclib ➕ AI/OFS❓
Capecitabine monotherapy
Capivasertib + fulvestrant
Elacestrant monotherapy
Everolimus + fulvestrant
Capecitabine monotherapy
Capivasertib + fulvestrant
Elacestrant monotherapy
Everolimus + fulvestrant
OlympiAD. Robson et al. NEJM. 2017
DESTINY-Breast04. Modi et al. NEJM. 2022.
TROPiCS-02. Rugo et al. JCO. 2022.
TROPION-Breast01. Bardia et al. JCO. 2024.
DESTINY-Breast04. Modi et al. NEJM. 2022.
TROPiCS-02. Rugo et al. JCO. 2022.
TROPION-Breast01. Bardia et al. JCO. 2024.
October 22, 2025 at 12:56 AM
OlympiAD. Robson et al. NEJM. 2017
DESTINY-Breast04. Modi et al. NEJM. 2022.
TROPiCS-02. Rugo et al. JCO. 2022.
TROPION-Breast01. Bardia et al. JCO. 2024.
DESTINY-Breast04. Modi et al. NEJM. 2022.
TROPiCS-02. Rugo et al. JCO. 2022.
TROPION-Breast01. Bardia et al. JCO. 2024.
References (in order from top to bottom):
CAPItello-291. Turner et al. NEJM. 2023.
SOLAR-1. Andre et al. NEJM. 2019.
EMERALD. Bidard et al. JCO. 2022.
EMBER-3. Jhavari et al. NEJM. 2025
PrE0102. Kornblum et al. JCO. 2018
BOLERO-2. Baselga et al. NEJM. 2012.
MAINTAIN. Kalinsky et al. JCO. 2023.
CAPItello-291. Turner et al. NEJM. 2023.
SOLAR-1. Andre et al. NEJM. 2019.
EMERALD. Bidard et al. JCO. 2022.
EMBER-3. Jhavari et al. NEJM. 2025
PrE0102. Kornblum et al. JCO. 2018
BOLERO-2. Baselga et al. NEJM. 2012.
MAINTAIN. Kalinsky et al. JCO. 2023.
October 22, 2025 at 12:56 AM
References (in order from top to bottom):
CAPItello-291. Turner et al. NEJM. 2023.
SOLAR-1. Andre et al. NEJM. 2019.
EMERALD. Bidard et al. JCO. 2022.
EMBER-3. Jhavari et al. NEJM. 2025
PrE0102. Kornblum et al. JCO. 2018
BOLERO-2. Baselga et al. NEJM. 2012.
MAINTAIN. Kalinsky et al. JCO. 2023.
CAPItello-291. Turner et al. NEJM. 2023.
SOLAR-1. Andre et al. NEJM. 2019.
EMERALD. Bidard et al. JCO. 2022.
EMBER-3. Jhavari et al. NEJM. 2025
PrE0102. Kornblum et al. JCO. 2018
BOLERO-2. Baselga et al. NEJM. 2012.
MAINTAIN. Kalinsky et al. JCO. 2023.
Current SOC options for 2L metastatic ER+ breast cancer #OptionsAreGood
October 22, 2025 at 12:56 AM
Current SOC options for 2L metastatic ER+ breast cancer #OptionsAreGood
📎A Phase 3, Randomized, Open-label Study Comparing Efficacy and Safety of Sacituzumab Tirumotecan (Sac-TMT, MK-2870) as a Monotherapy and in Combination With Pembro (MK-3475) Vs Physician's Choice in Previously Untreated Locally Recurrent Unresectable or Metastatic TNBC, PD-L1 CPS <10 (TroFuse-011)
October 22, 2025 at 12:48 AM
📎A Phase 3, Randomized, Open-label Study Comparing Efficacy and Safety of Sacituzumab Tirumotecan (Sac-TMT, MK-2870) as a Monotherapy and in Combination With Pembro (MK-3475) Vs Physician's Choice in Previously Untreated Locally Recurrent Unresectable or Metastatic TNBC, PD-L1 CPS <10 (TroFuse-011)
📎An Open-label, Randomized, Phase 3 Study to Evaluate Patritumab Deruxtecan Monotherapy Versus Treatment of Physician's Choice in Hormone Receptor-positive, HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer (HERTHENA-Breast04)
ClinicalTrials.gov
clinicaltrials.gov
October 22, 2025 at 12:48 AM
📎An Open-label, Randomized, Phase 3 Study to Evaluate Patritumab Deruxtecan Monotherapy Versus Treatment of Physician's Choice in Hormone Receptor-positive, HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer (HERTHENA-Breast04)
2️⃣ TroFuse-011 (NCT06841354)
💊 Sacituzumab tirumotecan vs physician’s choice chemo
💉 Trop-2 directed ADC
👆 Primary endpoints: PFS and OS
💊 Sacituzumab tirumotecan vs physician’s choice chemo
💉 Trop-2 directed ADC
👆 Primary endpoints: PFS and OS
October 22, 2025 at 12:48 AM
2️⃣ TroFuse-011 (NCT06841354)
💊 Sacituzumab tirumotecan vs physician’s choice chemo
💉 Trop-2 directed ADC
👆 Primary endpoints: PFS and OS
💊 Sacituzumab tirumotecan vs physician’s choice chemo
💉 Trop-2 directed ADC
👆 Primary endpoints: PFS and OS
📎Modi et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. NEJM. 2022.
Link to trial: www.nejm.org/doi/full/10....
Link to trial: www.nejm.org/doi/full/10....
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer | NEJM
Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently ...
www.nejm.org
October 22, 2025 at 12:46 AM
📎Modi et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. NEJM. 2022.
Link to trial: www.nejm.org/doi/full/10....
Link to trial: www.nejm.org/doi/full/10....
DB-04 Con't
💊 T-DXd: antibody-drug conjugate (ADC) of humanized anti-HER2 mAb linked to topoisomerase I inhibitor
⬆️ mPFS 10.1 months in ER+/HER-low with T-DXd vs mPFS 5.4 doc’s choice
⬆️ mOS 23.9mon in ER+/HER2-low vs mOS 17.5 doc’s choice
💊 T-DXd: antibody-drug conjugate (ADC) of humanized anti-HER2 mAb linked to topoisomerase I inhibitor
⬆️ mPFS 10.1 months in ER+/HER-low with T-DXd vs mPFS 5.4 doc’s choice
⬆️ mOS 23.9mon in ER+/HER2-low vs mOS 17.5 doc’s choice
October 22, 2025 at 12:46 AM
DB-04 Con't
💊 T-DXd: antibody-drug conjugate (ADC) of humanized anti-HER2 mAb linked to topoisomerase I inhibitor
⬆️ mPFS 10.1 months in ER+/HER-low with T-DXd vs mPFS 5.4 doc’s choice
⬆️ mOS 23.9mon in ER+/HER2-low vs mOS 17.5 doc’s choice
💊 T-DXd: antibody-drug conjugate (ADC) of humanized anti-HER2 mAb linked to topoisomerase I inhibitor
⬆️ mPFS 10.1 months in ER+/HER-low with T-DXd vs mPFS 5.4 doc’s choice
⬆️ mOS 23.9mon in ER+/HER2-low vs mOS 17.5 doc’s choice
What is HER2 low breast cancer?
👉 HER2 IHC 1+ or IHC 2+ with neg FISH
🔬Recent review showed that among all patients 35.2% are HER2-low
🔎HR+ patients, 39.8% are HER2-low expressing
🔎HR- patients, 22.5% are HER2-low expressing
🚫Clinical data - probably not a separate subtype but data is immature
👉 HER2 IHC 1+ or IHC 2+ with neg FISH
🔬Recent review showed that among all patients 35.2% are HER2-low
🔎HR+ patients, 39.8% are HER2-low expressing
🔎HR- patients, 22.5% are HER2-low expressing
🚫Clinical data - probably not a separate subtype but data is immature
October 22, 2025 at 12:44 AM
What is HER2 low breast cancer?
👉 HER2 IHC 1+ or IHC 2+ with neg FISH
🔬Recent review showed that among all patients 35.2% are HER2-low
🔎HR+ patients, 39.8% are HER2-low expressing
🔎HR- patients, 22.5% are HER2-low expressing
🚫Clinical data - probably not a separate subtype but data is immature
👉 HER2 IHC 1+ or IHC 2+ with neg FISH
🔬Recent review showed that among all patients 35.2% are HER2-low
🔎HR+ patients, 39.8% are HER2-low expressing
🔎HR- patients, 22.5% are HER2-low expressing
🚫Clinical data - probably not a separate subtype but data is immature