Lec 4 Feb 29 ©Allinahealthsystems 1

Lec 4 Feb 29

Updates in Breast Oncology • No Disclosures

Jasmine Kamboj MD Medical Oncology, Hematology Allina Health 02/29/2020

You are not alone…. and it is not your fault…. Agenda

• Duration of Endocrine Therapy • Predictive tools • CDK 4/6 Inhibitors • Immune‐therapy in BC • HER 2 BC updates • Lifestyle • Obesity • Plasma utility

1. 70 y/o lady with ER+, PR+, HER2‐ve Stage II Breast Cancer has Shannen Doherty, Actress, Beverly Hills, 90210 and Charmed concluded 5 years of anti‐estrogen therapy and she asks the benefit for long term anti estrogen Rx? • 10‐year results of NSABP B‐42/NRG Oncology • 3966 Pts 09/2006 to 01/2010 • Observation, Phase III, ext L for additional 5 years (+5), SS improvement in 10‐ year DFS of postmenopausal women w HR+ BC : HR 0.84, P=0.011 • SS improvement in BCFI (26% decrease is risks of BCFI events), distant recurrence 29% reduction • No diff in OS • No significant diff in risk of osteoporotic # and arterial thrombotic events • Median follow up 9.3 years

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ASCO GUIDELINE

• Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) • The Panel recommends that women with node‐positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years • Risk of BC recurrence reduced by 33% when AI was given 5 additional • Many women with node‐negative breast cancer should consider extended years after Tamoxifen; 19% after prior AI therapy, based on considerations of RR using established prognostic markers; however as RR is lower, benefits are likely narrower • Benefit increases for more #of LNs • Women w low risk, node negative tumors should not routinely be offered • Japanese AERAS trial, 5‐year DFS was 91.9% w ext rx vs 84.4% w 5 ext anti‐estrogen therapy years • A substantial portion of the benefit for extended adjuvant AI therapy is derived from prevention of second breast cancers. • Shared decision making between clinicians and patients for individualized risks vs benefits • No more than 10 years

2. Doc which tool could predict benefit from Christina Applegate, BRCA1 +ve, diagn @ 36 extended Rx ? • Prediction vs Prognostication

• BCI “only” for predictions • Node positive and BCI high should be offered extended rx

Prognostic predictors Cynthia Nixon, Actress

‐CTS‐5 : Nodal status, tumor size, tumor grade, age; prognostic tool for menopausal women for intermediate and high risk by Oncotype Dx ‐BCI ‐Oncotype RS ‐Mammaprint ‐Real time assessment of measurable residual dis (MRD) • CTC • ctDNA

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3. 71 y/o lady, presents with dyspnea on exertion, CXR c/w b/l Pulm Nodules and med LAP, bx reveals ER+, PR+, HER2‐ve Breast cancer PEARL Trial

CDK 4/6 inhibitors + ET • Phase III • 601 pts HR+ HER‐ve met BC, progressed on AI • Metastatic • Cohort 1 : Exemestane + Palbo vs Cape alone • Neoadjuvant • Cohort 2 : Fulvestrant + Palbo vs Cape alone (added in 2016, when data suggested ESR1 mutations ~ resistance to AI) • Resistance Mechanism • Median follow up 13.5 months, median PFS for F+P vs C (7.5 vs 10 months, HR 1.09, P Value = 0.537) NS difference • Median FU of 19.0 months, without ESR1 mutations, median PFS ET+P vs C (8.0 vs 10.6 months, HR 1.08, P= 0.526) NS diff • ET + P did not offer PFS adv over capecitabine • Better tolerated, Rx discontinuation was lower for ET, combination of ET+P was not superior to C for ESR1 WT tumors

CORALLEEN Trial Olivia Newton John, faces breast cancer for a 3rd time

• Ribociclib + L vs Chemo for postmenopausal women w HR+ve, HER2‐ve, luminal B BC, Early stage BC (I‐IIIA) • Open Label, multicenter, randomized Phase II • 6 * 28 days Ribociclib 60 mg po once daily 3 weeks on and 1 week off plus L VS AC/21*4 + Weekly Taxol *12 • Total neoadjuvant Rx = 24 weeks • PAM 50 Low risk of relapse (ROR) at surgery • @ surgery 46.9% (Ribo+L) vs 46.1% (chemo) = low ROR • ADR Neutropenia/ LFTs vs Neutropenia/ NF • No Deaths • Conclusions : High risk, early stage HR+ HER2‐ve BC  molecular downstaging w CDK4/6 Inhibition and ET

4. Our lady responded to ET+ CDKi for 18 months but developed liver mets, which were biopsied and found to have PI3K mutation! Carly Simon, Singer

Mechanisms of Resistance

• PI3K/AKT‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐PI3K inhib/ AKT inhib • MAPK‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐MEK inhib/ ERK inhib • FGFR‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐FGFR inhib • CDK4/6, RB alterations‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐CDK7 inhib/ AURORA kinase inhib • Cycline E1/ CDK2 alterations‐‐‐‐‐‐‐‐‐‐‐‐DDR inhibi/ CDK2 inhib • ESR1 mutations (Y375)‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐CDK7 inhib/ Oral SERDs

• Jeselsohn, SABCS Mini‐Symposium 2019

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5. 43 y/o L comes with weight loss, abd pain and persistent nausea. She IMpassion 130 endorses loss of appetite for 1.5 months. She gets CT A/P in the ER which suggests multiple liver lesions which on biopsy are found to be • Phase III, Untreated met TNBC : Atezo + Abraxane vs Placebo + Abraxane TNBC. Her family questions about the role of immunotherapy since one of their friends w melanoma is receiving the same. • EP : PFS and OS • Median PFS 7.2 vs 5.5 months, HR 0.80 for progression or death • Immune chk point inhibitors in met TNBC • For PDL1 +, PFS 7.5 m vs 5.0 m, HR 0.62 • Immune chk point in neoadjuvant TNBC • Median OS 21.3 m vs 17.6 m, HR 0.84 • PDL1 Testing • For PDL1+, OS 25.0 m vs 15.5 m, HR 0.62 • Multiple trials (PCD4989g), KN‐119, SAFIR‐02 support that PDL1 expression is required for anti PD1/PDL1 act in metBC • SP142 most specific to identify the right cohort of pts to benefit from A

KEYNOTE 522 I‐SPY2

• Presented @ ESMO 2019 • Phase II • First Phase III to demonstrate anti‐PDL1 Rx significantly improved path CR, • Addition Keytruda + NAC Improved pathCR in High risk stage II/III HER2‐ regardless of PDL1 status, when used w NAC for TNBC ve BC • Interim analysis, @ 15.5 m, showed path CR 64.8% for K + NAC vs 51.2% for • Ongoing, multiple inv groups in parallel NAC alone, p = 0.00055 • 181 women to Std NAC (AC‐T) vs 69 to 4*K + Std NAC • NAC 4*Carbo/taxol + 4* doxo or epirubicin wwo KSx Placebo vs K*9 • Path CR • pathCR higher in PDL1+ TNBC ( 68.9% w K + NAC VS 54.9% w NAC); PDL‐ve ‐17 VS 44% : all her2‐ve BC (45.3% vs 30.3%) ‐13 VS 30% : HR+/her2‐ve BC • Not FDA approved yet ‐22 VS 60% : TN • Longer follow up needed • Pts w path CR in both groups had excellent 3‐year EFS, 93% in K group

6. 58 y/o L presents with right breast lump and is found to have a 5.5 Sheryl Crow, Singer cm mass in right breast with LAP in right axilla. On Biopsy she is found to be ER+ PR+ HER2+ breast cancer. • KATHERINE Trial • Phase III, Open label, HER2+ EBC with residual dis in breast/axilla after neoadj rx w taxane +/‐ anthracycline + Herceptin • Adj TDM1 vs Herceptin for 14 cycles • EP : inv DFS • 1486 pts 743 vs 743 inv dis/death in 12.2% in TDM1 vs 22.2% in T • % of pts free of disease @ 3 years 88.3% TDM1 vs 77.0% T • Inv DFS significantly higher in TDM1 vs T, HR 0.50, P< 0.001 • Distant recurrence as first invasive disease event 10.5% w TDM1 vs 15.9% w T

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7. Our lady has received appropriate Rx and done well for 3 years, Edie Falco, Actress presented w stage IV dis and received T, P, TDM1 over 2 years, and now presents with headaches and unfortunately is found to have brain metastases. Brain Biopsy confirms HER2 positive breast cancer

• HER2CLIMB : Tucatinib • T is an oral highly selective inhibitor of HER2 TK • Previously received : H, P, TDM1 • T + Trastuzumab + Capecitabine • PFS at 1 year 33.1% vs 12.3%, HR 0.64 • Median duration of PFS is 7.8 months vs 5.6 months • OS at 2 years 44.9% vs 26.6% • Median OS 21.9 m vs 17.4 m • Amongst pts w Brain mets, PFS at 1 year 24.9% in T cohort and zero in placebo combination group • Diarrhea, HFS/PPE, N, F, V, D, elev transaminases

Andrea Mitchell, NBC Chief Foreign Affairs 8. What if she progresses through multiple lines of Rx? Correspondent • Destiny‐ Breast01 Trastuzumab Deruxtecan : DS 8201A • Phase II, single arm study • DS8201A is a HER2 targeting AB‐drug conjugate‐> using ADC tech TD attaches a topoisomerase I inhibitor payload via tetrapeptide linker to humanized HER2 AB, allowing enhanced cancer cell destruction upon release inside the cell • 2 or more prior lines; median of 6 prior therapies for met BC • Monotherapy 5.4 mg/kg • ORR 59% in Phase I • ORR 60.9%, 6% CR, 54.9% PR • DCR of 97.3%, median DOR 14.8 months, median PFS 16.4 months, estimated surv @ 1 year 86% • Interstitial Lung disease, myelosuppression, nausea, fatigue • 4 deaths sec to ILD (2.2%)

Julia Louis‐Dreyfus, Actress, Earned Another Emmy 9. 51‐year‐old L with stage IIA breast cancer has concluded her Nomination After Cancer Treatment chemo/surgery/ XRT treatments and is now formulating her surveillance plan while on anti‐Estrogen Rx. What Lifestyle modifications do you discuss with her?

Women’s Health Initiative Dietary Modification Trial • Fat diet w increased vegetable, fruit and grain intake reduce BC mortality in Postmenopausal women, 02/13/2020 • 19.6 year follow up, reduction in risk of death due to BC; 0.037% = 132 women VS 0.047%= 251 women, HR 0.79 and p value 0.02 • Amongst diagnosed BC, 10‐year BC‐OS 82% in intervention vs 78% in control group • Rowan T. Chlebowski/ JCO

Joan Lunden, Journalist and TV personality

Obesity and Cancer : ASCO Statement

• Dr. Monica M. Bertagnolli, 02/04/2019 • Obesity related cancers are rising, esp in young adults • Estimated that obesity will lead to > 500,000 additional cases of cancer each year in the US by 2030 • Obesity is set to overtake tobacco as the leading cause of “preventable cancer‐related death.” • 80% Americans for tobacco; only 35% for obesity (ASCO 2018 Natl Cancer Opinion Survey.) • Address obesity epidemic at all ages • Global Health issue

Wanda Skykes, Comedian, DM for prev. 10. 65‐year‐old lady wants to have IV iron infusions and SQ B12 shots while she is on chemo for her breast cancer to improve her fatigue? • DELCap SWOG S0221 study : Diet, Exercise, Lifestyle and Cancer Prognosis • Phase III • Antioxidants (Vit A, C, E, Carotenoids, co‐enzyme Q) could reduce chemo efficacy • AO before and during Rx, were a/w increased hazard of recurrence, HR 1.41; to a lesser extent death HR 1.40 • For non‐Oxidants, Vit B12 a/w poorer DFS, HR 1.83, p < 0.01 and OS, HR 2.04, p < 0.01 • Use of iron during chemo a/w recurrence HR 1.79, p < 0.01 and poorer OS • MVI use was not a/w surv outcomes

Peter Criss, Drummer; Mathew Knowles, Father of 11. Doc can you test my blood and tell me my prognosis? Beyonce, BRCA2 gene and BC

• Association with Distant Disease‐Free Survival • Ct DNA • CTC • Both together provide complimentary info for detection of MRD

• Milan Radovich

Take Home Points References  NSABP B‐42/NRG Oncology/ SABCS 2019 Abstr GS4‐01  ASCO Guidelines • Duration of Endocrine Therapy  PEARL Trial/ SABCS 2019  CORALLEEN Trial The Lancet 12/11/2019 • Predictive tools  IMpassion 130/ NEJM 11/29/2018  KEYNOTE 522/ ESMO Congress 2019 • CDK 4/6 Inhibitors  I‐SPY2/ JAMA Oncology 2/18/2020  KATHERINE trial/NEJM 2/14/2019 • Immune‐therapy in BC  HER2CLIMB/ NEJM 2/13/2020  Destiny‐ Breast01/SABCS 2019 and NEJM • HER 2 BC updates  Women’s Health Initiative Dietary Modification Trial/JCO 2/13/2020 •  DELCap SWOG S0221 STUDY / JCO 12/19/2019 Lifestyle  Plasma Utility SABCS 2019 • Obesity • Plasma utility