Margaret Gatti-Mays, MD MPH

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.

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.

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

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

🧐 A 75yo ♀️w/ ER+/HER2- PIK3CA+ mBC is starting 2L therapy with alpelisib + fulvestrant. Baseline A1C is 6.1 and BMI is 33. What steps can limit risk for severe hyperglycemia❓

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.

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

Answer: B. Capivasertib + fulvestrant
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

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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.

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.

Current SOC options for 2L metastatic ER+ breast cancer #OptionsAreGood

18/18 #TumorBoardTuesday
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🔊Take home points 🔊:
✅ Liquid biopsy recommended at progression on 1L to screen for mutations
✅ 2L options have mPFS 5-11 months, some with OS benefit
✅ Optimal sequence unknown at this time, likely depends in part on patient factors

📎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)

2️⃣ TroFuse-011 (NCT06841354)
💊 Sacituzumab tirumotecan vs physician’s choice chemo
💉 Trop-2 directed ADC
👆 Primary endpoints: PFS and OS

17/18 #TumorBoardTuesday
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Ongoing trials in the HR+/HER2- space…

1️⃣ HERTHENA-Breast04 (NCT07060807)
💊 Patritumab deruxtecan (HER3-DXd) vs physician’s choice chemo
💉 ADC of HER3 mAb linked to topoisomerase I payload
👆Primary endpoints: PFS and OS

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 ...

📎Modi et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. NEJM. 2022.

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

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DESTINY-Breast04
👩‍🦳 2L metastatic HER2- low BC
✅ Included both ER+ and ER-; HER2-low breakdown: IHC1+ = 58% and IHC2+ = 42%
💊 Trastuzumab deruxtecan (T-DXd) vs physician’s choice chemo (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel)

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 ...

📎 DESTINY-Breast04. Modi et al. NEJM. 2022

Link to article: www.nejm.org/doi/full/10....

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

15/18 #TumorBoardTuesday
⏭️ Moving on to Case 3…

#TumorBoardTuesday #OncTwitter Case 3
👩‍🦳 67 y.o. postmenopausal female
💉 Metastatic HR+, “HER2 low” BC to bone, liver
💊 Progressed on 1L CDK4/6i + ET within 4 months of starting therapy
🧪 No BRCA mutations

evERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER... TPS1119Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, and...

Link to trial: ascopubs.org/doi/pdf/10.1...
Link to article: www.roche.com/media/releas...

📎 Mayer et al. evERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2– LA/mBC). JCO. 2023.

💊 Giredestrant/Everolimus vs Exemestane/Everolimus
💊 Giredestrant is a novel, nonsteroidal oral SERD 🚫 NOT FDA approved as of today
🥇 Reported that evERA met primary endpoint of PFS in ITT and ESR1 mutated patients
🔊 To be presented at upcoming meeting - #StayTuned

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📰 Breaking news! 🔊 evERA study (#ESMO2025)

🔎 Phase III, randomized trial (NCT05306340)
👩‍🦳 Metastatic HR+/HER2-
✅ Previous tx w/ CDK4/6i + ET
💊 Giredestrant is a novel, nonsteroidal oral SERD 🚫 NOT FDA approved as of today