Dana-Farber Breast Cancer Course 2026 Slide Intelligence

[Slide 2] Questions Regarding Surgical Management of the Axilla in 2026 - Which patients with invasive breast cancer do not require SLNB? - How do we manage the axilla for HR+/HER2- clinically node positive patients undergoing upfront surgery? - How do we manage positive nodes after neoadjuvant chemotherapy?

[Slide 2] Should we use T-DXd in the Neoadjuvant or the Adjuvant Setting? | Neoadjuvant T-DXd x4 | Adjuvant T-DXd x14 | Improves AEs/tolerability compared to neoadjuvant ddAC-T | Worsens AEs/safety compared to adjuvant T-DM1 EFS will be reported, but secondary endpoint | DFS primary endpoint – statistically significant difference shown What to do with RD post-neoadjuvant T-DXd? | CNS recurrence outcomes look promising in favor of T-DXd • cT2N0 tumors (without ypN+ residual disease) not represented in either neoadjuvant or adjuvant phase 3 T-DXd data • I predict: neoadjuvant THP is sufficient for some pts – await CompassHER2-pCR/HELEN-006/NeoCARHP DFS results • Need biomarkers to help us tailor neoadjuvant + adjuvant regimen selection Adrienne G. Waks, MD | IBC East | 2026 19 --- [Slide 3] ER and HER2 are very good biomarkers for pCR: CompassHER2-pCR: Clinicopathologic factors significantly associated with pCR following neoadjuvant THP x4 (univariable analysis) Slide modified from Nadine Tung MD ASCO 2025 pCR rate table Variable | All pts (n=2141) | ER- HER2+ (n=774) | ER+ HER2+ (n=1367) Age (median, range) | 55 yrs (22-88) | | < 50 years | 43.6% | 63.5% | 34% 50-70 years | 47% | 67.9% | 34.2% >70 years | 31.9% | 48.7% | 21.1% ECOG PS | | | 0 | 44.7% | 65.4% | 32.9% 1 | 37.4% | 51.6% | 29.7% Grade | | | 1 | 26.9% | 60% | 21.1% 2 | 37.2% | 63% | 27.9% 3 | 49.5% | 64% | 37.9% ER (% cells staining) | | | 0% | 63.7% | 63.7% | 1-10% | 62.5% | ---- | 62.5% 11-70% | 51.6% | ---- | 51.6% > 70% | 22.5% | ---- | 22.5% HER2 IHC | | | 3+ | 50.3% | 67.6% | 39.3% 2+ | 11.9% | 26% | 8.0% Taxane^ | | | paclitaxel | 46.5% | 68.5% | 34.2% docetaxel | 39.3% | 55.9% | 29.7% --- [Slide 4] Conclusions • Growing evidence supports omission of carboplatin in the treatment of patients with HER2+ early breast cancer – though we are not yet ready to drop it entirely • T-DXd in the neoadjuvant or the adjuvant setting is the new standard of care for moderate to high risk HER2+ early breast cancer • Biology assessment at baseline and/or on-treatment should be incorporated into the management of HER2+ early breast cancer – HER2DX genomic risk score, ctDNA, breast MRI, PET scans are all contenders Adrienne G. Waks, MD | IBC East | 2026 34

[Slide 2] HR+ Early Breast Cancer: The Problem of Prolonged Risk Despite advances in therapy, patients with ER+/HER2- early breast cancer remain at risk of recurrence Methods to augment efficacy of existing therapies: • Adjuvant CDK4/6 inhibitors • Emergence of oral SERDs • Less chemotherapy, more OFS WHO NEEDS LESS? < WHO NEEDS MORE? > HOW CAN WE TAILOR TREATMENT? HR+/HER2– Operable BC Risk of Distant Recurrence Distant Recurrence (%) vs Years (0 to 20) N4–9: 22 (yr5), 36 (yr10), 45 (yr15), 52 (yr20) N1–3: 10 (yr5), 19 (yr10), 25 (yr15), 31 (yr20) N0: 6 (yr5), 11 (yr10), 16 (yr15), 22 (yr20) No. at Risk N4–9: 12,333 | 8,116 | 2165 | 259 | 52 N1–3: 31,936 | 23,576 | 7250 | 949 | 183 N0: 29,925 | 24,081 | 8571 | 1982 | 414 No. of Events — annual rate (%) N4–9: 2568 (4.8) | 969 (4.0) | 121 (3.1) | 13 (2.2) N1–3: 3126 (2.2) | 1421 (1.9) | 241 (1.7) | 39 (1.8) N0: 1646 (1.2) | 835 (1.1) | 272 (1.3) | 68 (1.4) Pan et al, NEJM 2017 Erica L. Mayer MD, MPH | 2026 3 --- [Slide 3] Optima – How to Interpret? • Test-determined treatment selection, using tumor biology rather than clinical features alone, can guide chemo decisions in patients ≥ 40 with ROR scores ≤ 60. • Results were stable in subgroups, including premenopausal and those with ≥ 4 involved nodes. • May help avoid chemotherapy in high anatomic risk/low genomic risk disease, including premenopausal. But Questions • Do we need longer follow-up to feel secure in this data? • What about women < 40? Or patients with multinode positive disease? • Paradigm shift to move away from Oncotype to Prosigna in select situations • Still need to support OFSET trial! Erica L. Mayer MD, MPH | 2026 44 --- [Slide 4] Conclusions: Great Advances in the Management of Early-stage HR+ Disease • Adjuvant CDK4/6 inhibitors are here and growing in use in a broader population • Oral SERDs emerging in adjuvant space ✓ Await future approvals and determination of when/how to use giredestrant ✓ Await results from pending oral SERD trials to understand concurrent use with CDK4/6i and timing of administration • Use of Prosigna may help reduce use of chemotherapy in premenopausal and some higher risk N+ disease Erica L. Mayer MD, MPH | 2026 46

[Slide 2] NEW TREATMENT ALGORITHM FOR mTNBC PD-L1-positive (star) 1L: Sacituzumab govitecan + Pembrolizumab PD-L1-negative (star) 1L: Datopotamab deruxtecan | Sacituzumab govitecan | Olaparib or talazoparib (if BRCAm) 2L: Olaparib or talazoparib (if BRCAm) | Sacituzumab govitecan | T-DXd (if HER2-low) | Chemotherapy (e.g., taxane, platinum) 3L+: Sacituzumab govitecan | T-DXd (if HER2-low) | Olaparib or talazoparib (if BRCAm) | Chemotherapy (e.g., eribulin, capecitabine, gemcitabine, vinorelbine) | Biomarker positive* (TMB-H, MSI-H/dMMR, NTRK fusion, RET fusion) *TMB-H: Pembrolizumab; MSI-H: Pembrolizumab, Dostarlimab; NTRK fusion: Larotrectinib, Entrectinib, Repotrectinib; RET fusion: Selpercatinib Ana C. Garrido-Castro, M.D. | 2026 | 25 --- [Slide 3] TREATMENT OF ADC-REFRACTORY BREAST CANCER WITH DATO-DXd OR T-DXd (TRADE-DXd): DFCI 24-251/TBCRC 064 Primary endpoint (ADC1, ADC2): ORR Secondary endpoints: PFS, OS, CBR, TTOR, DOR Eligibility: - Confirmed unresectable locally advanced or metastatic breast cancer - HER2-negative (HER2-low or HER2-0) breast cancer - Prior endocrine therapy and CDK4/6 inhibitor if HR+ - No prior topo-I inhibitor-based therapy - Measurable disease Allocation 1:1 to T-DXd or Dato-DXd as ADC1 ADC1: - T-DXd (0-1 prior lines): HR+ (Arm A) / HR- (Arm B) -> Crossover to ADC2 at progression -> Dato-DXd (1-2 prior lines): HR+ (Arm E) / HR- (Arm F) -> Treat until progression or unacceptable toxicity - Dato-DXd (0-1 prior lines): HR+ (Arm C) / HR- (Arm D) -> Crossover to ADC2 at progression -> T-DXd (1-2 prior lines): HR+ (Arm G) / HR- (Arm H) -> Treat until progression or unacceptable toxicity (star) Tumor assessments + Blood collection q9w Baseline Pre-ADC1 Biopsy; Post-C2 On-ADC1 Biopsy; Baseline Pre-ADC2 Biopsy; Optional Post-ADC2 Biopsy *Patients who received T-DXd/Dato-DXd as ADC1 off-study allowed to enroll on ADC2 cohorts. NCT06533826 / PI: A. Garrido-Castro Ana C. Garrido-Castro, M.D. | 2026 | 46 --- [Slide 4] KEY TAKEAWAYS - Significant improvement in outcomes with TROP2 ADC in 1L mTNBC vs standard chemotherapy - Given the poor prognosis in this setting, with a high proportion of patients who do not survive past 6 months with standard chemotherapy, TROP2 ADC is now considered a preferred 1L regimen - Novel ADC, IO and targeted therapy approaches in development: new targets, payloads, bispecific ADCs, combinations - Understanding the mechanisms that drive response and resistance to ADCs will be key to help inform optimal sequencing, combinations, and duration of therapy Ana C. Garrido-Castro, M.D. | 2026 | 55

[Slide 1] First-Line Therapy: DFCI approach First-Line and Maintenance Therapy Options: - T-DXd-P (Trastuzumab deruxtecan + Pertuzumab) until progression (or toxicity; switch to maintenance to be considered if CR and no BM) -> preferred for patients with high disease burden, recurrent tumors, brain metastases, PIK3CA mutations - Taxane-HP (Trastuzumab/Pertuzumab) x6-8 cycles followed by maintenance therapy -> preferred for patients with de novo presentation, oligometastatic, non-visceral disease, or contraindication to T-DXd Maintenance therapy options after THP: - Palbociclib-HP-ET (Palbociclib + Trastuzumab + Pertuzumab + Endocrine Therapy) -> preferred for patients with ER-positive disease - Tucatinib-HP (Tucatinib + Trastuzumab + Pertuzumab) -> preferred for patients with ER-negative disease and/or brain metastases - HP (Trastuzumab + Pertuzumab) -> to be considered for patients with de novo, ER-negative disease, PIK3CA wild type, no brain metastases and complete response after THP [KM curve, investigator-assessed progression-free survival (%), p<0.0001] Early Progression -> More likely to benefit from escalation to TDXd-P Prolonged Response: Landmark progression-free survival at 8 years 16%, 304 events (76%) Landmark progression-free survival at 8 years 10%, 329 events (81%) -> Could save TDXd as 2L therapy Morganti et al., under review --- [Slide 2] First-Line Therapy NCCN Guidelines (June 2026) Setting: First Line Regimen: - Docetaxel + Trastuzumab + Pertuzumab (category 1, preferred) with maintenance Pertuzumab + Trastuzumab. If HR-positive: Endocrine therapy (Aromatase inhibitor +/- Palbociclib) + Trastuzumab +/- Pertuzumab - Paclitaxel + Trastuzumab + Pertuzumab (preferred) with maintenance Pertuzumab + Trastuzumab. If HR-positive: Endocrine therapy (Aromatase inhibitor +/- Palbociclib) + Trastuzumab +/- Pertuzumab - Fam-trastuzumab deruxtecan-nxki(o) + Pertuzumab (other recommended) CLEOPATRA: - Centrally confirmed HER2-positive metastatic breast cancer - No previous treatment for metastatic disease (one previous hormonal treatment permitted) - N = 808 1:1 - n = 406: Placebo + trastuzumab; Docetaxel >=6 cycles -> PD - n = 402: Pertuzumab + trastuzumab; Docetaxel >=6 cycles -> PD DESTINY-Breast09: Eligibility criteria: - HER2+ a/mBC - Asymptomatic/inactive brain mets allowed - DFI >6 mo from last chemotherapy or HER2-targeted therapy in neoadjuvant/adjuvant setting - One prior line of ET for mBC permitted - No other prior systemic treatment for mBC(dagger) R 1:1:1 - n=387: T-DXd(double-dagger) + placebo - n=383: T-DXd(double-dagger) + pertuzumab(section) - n=387: THP — Taxane (paclitaxel or docetaxel(paragraph)) + trastuzumab(paragraph) + pertuzumab(section) Baselga et al, NEJM 2012; Tolaney, ASCO 2025 --- [Slide 3] Induction followed by Maintenance versus Continuous Strategy? CLEOPATRA: Table 4. Stratified time-dependent Cox regression analysis of PFS and OS(a) Comparison | Hazard ratio | 95% confidence interval | P-value PFS Study treatment (pertuzumab versus placebo) | 0.61 | 0.51-0.74 | <0.0001 D cumulative cycles (>6D versus 6D) | 0.80 | 0.63-1.01 | 0.0640 D cumulative cycles (<6D versus 6D) | 1.72 | 1.13-2.60 | 0.0106 OS Study treatment (pertuzumab versus placebo) | 0.60 | 0.49-0.74 | <0.0001 D cumulative cycles (>6D versus 6D) | 0.88 | 0.69-1.12 | 0.3073 D cumulative cycles (<6D versus 6D) | 2.49 | 1.79-3.48 | <0.0001 (a)Stratification factors for PFS and OS include prior treatment status and region. OS, overall survival; PFS, progression-free survival. More than 6 cycles of docetaxel NOT associated with PFS or OS improvement DESTINY-Breast09: | CR (n=58) | Deep PR(a) (n=141) | PR (<80%) (n=127) | SD/PD (n=51) Time to best response (median, mo) [95% CI] | 8.4 [5.6, 11.1] | 9.6 [6.8, 11.0] | 1.5 [1.4, 2.0] | NA Duration of best response (median, mo) [95% CI] | NC [35.1, NC] | 39.2 [35.3, NC] | 34.8 [22.8, NC] | NA Patients remaining in best response, % [95% CI] 12 mo | 94.8 [84.8, 98.3] | 91.3 [85.1, 95.0] | 78.9 [70.1, 85.3] | NA 24 mo | 85.0 [72.1, 92.3] | 78.9 [70.4, 85.2] | 60.4 [50.0, 69.3] | NA Total treatment duration (median, mo) [range](b) | 28.0 [4.8-44.5] | 25.4 [3.4-42.7] | 20.6 [2.8-41.8] | 4.4 [0.3-37.2] PFS at 24 mo, % [95% CI] | 85.1 [72.2, 92.3] | 80.0 [71.7, 86.1] | 64.3 [54.3, 72.8] | 35.5 [21.1, 50.2] Median time to maximum tumor reduction (nadir) in the overall population (n=383): ~11 months 60% discontinued TDXd (21% PD, 21% AEs, 11% pt decision, 9% transitioned to maintenance T, 6% other, 4% death) Miles et al, Ann Onc 2017; Park, ASCO 2026 --- [Slide 4] Induction followed by Maintenance versus Continuous Strategy? Maintenance after THP: Median PFS (months), 1L: - PATINA (HR+ only): HP + ET + palbo: 44.3 (vs 29.1) - HER2CLIMB-05: HP + tuc +/- ET: 24.9 (vs 16.3); 24.9 in HR- (vs 12.6) and 25 in HR+ (vs 18.1) - CLEOPATRA: HP: 18.5 ongoing: - INAVO 122 (PIK3CAm): HP + inavolisib - heredERA (HR+ only): HP + giredestrant PATINA: - 97% had pertuzumab - CR/PR to taxane 69%; rapid progressors not included H2C-05: - prior pertuzumab mandatory - CR/PR to taxane 69%; rapid progressors not included - Concurrent ET allowed for HR+, but only 45% received it [PATINA KM curve — Progression-free Survival; Palbociclib+HER2+ET vs HER2+ET] No. at Risk: Palbociclib+HER2+ET: 261 230 202 166 144 130 111 92 76 54 33 15 5 HER2+ET: 257 197 157 135 115 101 88 68 52 30 15 6 1 (Months: 0 6 12 18 24 30 36 42 48 54 60 66 72) [HER2CLIMB-05 KM curves — PFS Probability (%)] Left panel: TUC + TRAS + PERT (n=158) vs PBO + TRAS + PERT (n=152) Events 68 | 92; Median (months) 24.9 | 12.6; (95% CI) (19.4 to -) | (9.4 to 16.8); HR (95% CI) 0.554 (0.403 to 0.761) Right panel: TUC + TRAS + PERT (n=168) vs PBO + TRAS + PERT (n=176) Events 73 | 98; Median (months) 25.0 | 18.1; (95% CI) (16.5 to -) | (13.0 to 20.8); HR (95% CI) 0.725 (0.535 to 0.983) --- [Slide 5] Induction followed by Maintenance versus Continuous Strategy? Maintenance after THP: Median PFS (months), 1L: - PATINA (HR+ only): HP + ET + palbo: 44.3 (vs 29.1) - HER2CLIMB-05: HP + tuc +/- ET: 24.9 (vs 16.3); 24.9 in HR- (vs 12.6) and 25 in HR- (vs 18.1) - CLEOPATRA: HP: 18.5 ongoing: - INAVO 122 (PIK3CAm): HP + inavolisib - heredERA (HR+ only): HP + giredestrant PATINA: - 97% had pertuzumab - CR/PR to taxane 69%; rapid progressors not included H2C-05: - prior pertuzumab mandatory - CR/PR to taxane 69%; rapid progressors not included - Concurrent ET allowed for HR+, but only 45% received it DESTINY-Breast09: DEMETHER: Phase II study of 1L T-DXd induction followed by maintenance PH FDC SC(1) HER2+ mBC - No prior systemic therapy for advanced disease (one prior line of ET for aBC allowed) N = 165 Induction therapy: T-DXd (6 cycles) -> Maintenance therapy: PH FDC SC +/- ET -> Follow-up ctDNA monitoring Primary endpoints: 1-year PFS, 3-year OS - Do all patients need 1L TDXd? - What is the optimal duration of TDXd induction? - How do we integrate maintenance studies into 1L TDXd?

[Slide 1] HER2 targeted agents changed the history of HER2+ MBC 2001 [KM curve, Survival (%) vs Months After Enrollment 0-50]: Chemotherapy plus trastuzumab (upper curve) Chemotherapy alone (lower curve) Median OS 20.3 months with CT alone 2025 [KM curve, Survival (%) vs Months After Enrollment 0-45]: T-DXd plus pertuzumab (upper curve) Taxane-trastuzumab-pertuzumab (lower curve) Median OS NR, ~80% alive at 3 years (16% maturity) Slamon et al, NEJM 2001; Tolaney, ASCO 2025 --- [Slide 2] Multiple effective agents led to incremental outcomes improvement STUDY | LINE OF THERAPY | TREATMENT ARMS | MEDIAN PFS | MEDIAN OS Pivotal Trastuzumab Trial | 1L | AC/EC or paclitaxel +/- trastuzumab | 4.6 mo vs 7.4 mo | 20.3 mo vs 25.1 mo CLEOPATRA | 1L | Docetaxel/trastuzumab +/- pertuzumab | 12.4 mo vs 18.7 mo | 40.8 mo vs 57.1 mo EMILIA | 2L | Lapatinib/capecitabine vs TDM1 | 6.4 mo vs 9.6 mo | 25.9 mo vs 29.9 mo HER2CLIMB | 3L | Trastuzumab/capecitabine +/- tucatinib | 4.9 mo vs 7.6 mo | 19.2 mo vs 24.7 mo HER2CLIMB-02 | 2L | TDM1 +/- tucatinib | 7.4 mo vs 9.5 mo | Immature DESTINY-Breast03 | 2L | TDM1 vs TDXd | 7.2 mo vs 29.0 mo | 42.7 mo vs 52.6 mo DESTINY-Breast09 | 1L | THP vs TDXd + pertuzumab | 26.9 mo vs 40.7 mo | Immature PATINA | 1L maintenance | H(P)/ET +/- palbociclib | 29.1 mo vs 44.3 mo | Immature Courtesy of Nancy Lin --- [Slide 3] What's Next? Future therapies for HER2+ MBC TRIAL | AGENT | PRELIMINARY DATA ADCs: SATEEN | SG + trastuzumab | ORR 3%, 18-week CBR 14.8% in TDXd-pretreated patients Phase I/Ib | SMP-656 (eribulin payload) | ORR 20% and DCR 100% in ADC-pretreated BC patients *HERTHENA-Breast-01 | HER3-DXd + H / HER3-DXd + HP / HER3-DXd + tucatinib | J101 FIH study: ORR 42.9%, median DOR 8.3 months, median PFS 11.0 months in HER2+ *IKS014-01 | IKS014 (MMAF payload) | ORR 100% (3/4 patients pretreated with TDXd) TKIs: *Beamion BCGC-1 | Zongertinib + TDXd / Zongertinib + TDM1 | Data in NSCLC (76% ORR in 1L for ERBB2m NSCLC) *BREnnA | RO7771950 (ZN-1041) + cape + H vs HER2CLIMB | ZN-1041 + cape + H: ORR 73% (no prior TDXd); ZN-1041 + TDXd: ORR 65-76%, DCR 90-95% (no prior TDXd); ZN-1041 + HP (maintenance): ORR 30%, DCR 100% (no prior TDXd) *IAM1363-01 | IAM1363 | ORR 28% across HER2+ solid tumors bispecifics: *EmpowHER 303 | Zanidatamab + CT | ORR 91% in first-line (+Docetaxel); ORR 43% in late-line setting (+CT) Zhang, ESMO Asia 2025; Tarantino, ESMO breast 2026; Krop et al., JCO 2023; Ameratunga, ESMO 2025; Lin, ASCO 2026; Ma, SABCS 2024 --- [Slide 4] Key Takeaways 1. HER2 targeted therapies revolutionized the history of HER2+ MBC, with most patients alive many years after diagnosis. 2. Efforts are needed to understand how to best treat each individual patient, to avoid undertreatment and overtreatment - How to best sequence HER2 targeted agents? - Do all patients need first-line TDXd-pertuzumab? - Can an induction-maintenance strategy be used for 1L TDXd? - Can HER2 targeted therapy be safely stopped in exceptional responders? - Can HER2+ MBC be approached with curative intent? - What biomarkers can be used to guide individual approaches?

[Slide 2] Should Oral SERDs be Used in the First-Line Setting? Columns: Trial | Oral SERD | Line of Therapy | Trial Population | Therapy Partner persevERA | Giredestrant | 1L | Endocrine sensitive | + Palbociclib pionERA | Giredestrant | 1L | Endocrine resistant | + CDK4/6i SERENA-4 | Camizestrant | 1L | Endocrine sensitive | + Palbociclib SERENA-6 | Camizestrant | 1.5L | Patients currently receiving AI + CDK4/6i with emergence of ESR1mut | + CDK4/6i OPERA-02 | Palazestrant | 1L | Endocrine sensitive | + Ribociclib 22 --- [Slide 3] Non-chemo Regimens Beyond 1L for HR+/HER2- MBC 1L: AI or fulvestrant + CDK4/6i | Fulvestrant + palbociclib + inavolisib (if PIK3CA mut and relapse during w/in 12 months adjuvant ET) 1.5L: ?? Screen for ESR1m -> Camizestrant + CDK4/6i* 2L+: ESR1 wt/PAM not altered - Fulvestrant/Abema - Imlunestrant/Abema (Elacestrant/Abema) - AI or Fulvestrant + Everolimus - Gedatolisib/Fulvestrant +/-Palbo (PIK3Awt) ESR1 mut/PAM not altered Endocrine sensitive: >= 12 mo on prior ET+CDK4/6i - Elacestrant, Imlunestrant, Vepdegestrant For ET Sensitive or Resistant: - Imlunestrant/Abema (Elacestrant/Abema) - Gedatolisib/Fulvestrant +/-Palbo (PIK3Awt) - Giradestrant/Everolimus* PAM altered/ESR1wt - AI or Fulvestrant w/Alpelisib (PIK3Amut) - Fulvestrant/Capivasertib (AKT pathway altered) - Gedatolisib/Fulvestrant +/-Palbo* (PIK3Amut) - AI or Fulvestrant + Everolimus - Imlunestrant/Abema, Fulvestrant/Abema (Elacestrant/Abema) PAM altered/ESR1mut - Fulvestrant/Alpelisib (PIK3Amut) - Fulvestrant/Capivasertib (AKT pathway altered) - Gedatolisib/Fulvestrant +/-Palbo* (PIK3Amut) - Giradestrant/Everolimus* - Imlunestrant/Abema (Elacestrant/Abema) Other Biomarker positive (gBRCA1/2, gPALB2, sBRCA1/2, TMB-H, ERBB2 mut, MSI-H/dMMR, NTRK fusion, RET fusion) *If FDA approved --- [Slide 4] Conclusions and Questions ET + CDK4/6i remains 1L standard of care - Potential role of ESR1 monitoring for early switch to camizestrant + CDK4/6i if approved - in whom and how often and how long to monitor? Multiple options available after progression on CDK4/6 inhibitor - For most patients, combination therapy is preferred - For those with both ESR1m and PAM pathway altered disease - optimal sequence is not yet defined - Is there a preferred PAM inhibitor? - Exciting agents in development - Tolerability and ability to combine may be key Can we overcome resistance? - Is there a role for oral SERD after oral SERD, especially when switching out the targeted partner? - Can PAM pathway inhibitors work in sequence? 53

[Slide 2] Outcomes of Endocrine Therapy by Line of Treatment 1L: Most patients with ER+ MBC tend to do quite well upon 1L treatment, with mPFS of ~2 years and relatively good QoL [KM curve - Ribociclib + Letrozole vs Placebo + Letrozole. Number of events, n (%): 140 (41.9) n=334 | 205 (61.4) n=334. Median PFS, months (95% CI): 25.3 (23.0-30.3) | 16.0 (13.4-18.2). Hazard ratio (95% CI): 0.568 (0.457-0.704). P value: 9.63x10^-8] 2L: Outcomes with 2L ET-based treatments are less favorable, yet novel combinations are demonstrating promising mPFS of ~10 months [KM curve - Imlunestrant-Abemaciclib vs Imlunestrant Alone. No. of Patients: 213 | 213. No. of Events: 114 | 149. Median Progression-free Survival (95% CI): 9.4 (7.5-11.9) | 5.5 (3.8-5.6). Hazard ratio for disease progression or death, 0.57 (95% CI, 0.44-0.73); P<0.001] 3L+: More limited benefit is seen with ET in highly pretreated patients, warranting cautious patient selection and consideration of chemo-based strategies [KM curve - Elacestrant (n=239) vs SOC (n=238). Events, No. (%): 144 (60.3) | 156 (65.5). HR (95% CI): 0.70 (0.55 to 0.88). P: .0018. 6-month PFS %, (95% CI): 34.3 (27.2-41.5) | 20.4 (14.1 to 26.7). 12-month PFS, % (95% CI): 22.3 (15.2 to 29.4) | 9.4 (4.0 to 14.8)] Hortobagyi G.N. Ann Onc 2018; Jhaveri K. et al NEJM 2025; Bidard F.C. JCO 2022 Paolo Tarantino, MD, PhD | 2026 3 --- [Slide 3] Considerations on ADC Sequencing for ER+ MBC - Multiple retrospective and prospective datasets suggest that, after progression on a prior ADC, a second ADC may lead to relatively poor outcomes - Based on these data, it is reasonable to prioritize standard chemotherapy after progression on a TOPO1 ADC - Nonetheless, given that patients with ER+ MBC often receive multiple lines of therapy along the treatment journey, a second ADC may be offered in late lines of treatment Paolo Tarantino, MD, PhD | 2026 28

[Slide 2] How to apply to ADC sequencing? TOPO1 (circle) – TROP2, HER2, HER3 → Targets are redundant → Cross-resistance is likely → Target internalization; Payload (TOPO1, ABC); ADC processing (internalization / lysosome) → Cumulative toxicities Predictive biomarkers often 'soft' Sequencing two ADCs is not biologically 'neutral' PFS (2nd 'modern' ADC) ~2-3mo Sequencing ADC is not commutative but influential on post-PD efficacy of another ADC Ascione, The Onc 2023; Guidi, Cancers 2023; Sledge, NPJ breast 2025; Coates, Cancer Disc 2021; Rampa, CCR 2026; Cerci, Drug Res Up 2026; de Almeida, CTR 2026 --- [Slide 3] How to identify a sequencing vs single-drug trials? # | Question | Yes 1 | Is the study question defined as a treatment strategy, not a single-drug comparison? | ☐ 2 | Are treatment decision points (switch rules) explicitly prespecified? | ☐ 3 | Is expected attrition to second line estimated and incorporated in the design/analysis? | ☐ 4 | Is access to second-line therapy protocol-governed and balanced between arms? | ☐ 5 | Is the primary or key secondary endpoint appropriate for sequencing (PFS2, OS)? | ☐ 6 | Are longitudinal toxicity burden and PRO trajectories formally captured? | ☐ 7 | Is post-progression management predefined (treatments, censoring, missing data)? | ☐ 8 | Are biological resistance mechanisms measured, not only hypothesized? | ☐ 9 | Is the clinical setting transferable to real-world practice (population, imaging, access)? | ☐ 10 | Is “strategy success” defined as net clinical benefit (efficacy vs toxicity & attrition)? | ☐ --- [Slide 4] Take home messages • ADCs are reshaping the treatment of patients with solid tumors. Novel clinical trials are needed to assess if… • ADC sequencing provides a clinical benefit • «Sooner» is always «better» • Well-designed clinical trials can answer these important clinical questions and inform clinical practice, while balancing clinical needs with feasibility. • Innovative designs can improve the feasibility of clinical trials

[Slide 2] How do breast cancer treatments alter sexuality? Columns: Treatment | Menopause | Vaginal/rectal stenosis/dyspareunia | CIPN (including genitalia) | Fatigue | Body Image alterations Surgery | X | X | | | X Radiation Therapy | X | X | | X | X Chemotherapy | X | | X | X | Inhibitors of Estrogen action or production | X | X | | | X --- [Slide 3] Specific Challenges: Young adult Relationships to others - Engagement in life - Sexuality - Intimacy Sense of self - Identity - Feeling damaged, physically and emotionally --- [Slide 4] NEUROPATHIC ADJUVANTS - Corticosteroids - Cannabinoids - Gabapentinoids - Antidepressants - Sodium channel blockers (Anatomical spine diagram labels: Cerebrospinal Fluid (CSF), Dura, Vertebral Body, Posterior Longitudinal Ligament, Herniated Disc, Ligamentum Flavum; cervical vertebrae C1-C7)