Chemo hormonal and targeted therapy in ca breast

Slide 1

ChemotherapyHormonal Therapy Targeted Therapy- IN BREAST CARCINOMA22-Jun-161dr rahul ts

Outline ChemotherapyEvolution AdjNeo-adjMetastaticHormonal therapyTargeted therapyTreatment guideline - NCCN

22-Jun-162dr rahul ts

Chemotherapy


IndicationGenerally recommended for >1 cm tumors

Node positive disease.

Consider for all triple negative tumors,

Given high rates of recurrence and lack of options for targeted or endocrine therapies.

Risk Stratification for Adjuvant Therapy based onOncotype DX and MammaPrint 22-Jun-164dr rahul ts

Various Prognostic FactorsAnatomic: Size of tumor Lymph node (LN) involvement The most powerful prognostic factor

Histologic: Tumor gradeLV Invasion,poorly differentiatedMarkers of increased proliferation:mitotic index,high Ki67,elevated S-phase fraction

Molecular factors: ER/PR statusHER2/neu over expression21-gene or 70-gene recurrence score


5

Oncotype Dx: The 21-Gene AssayRT-PCR was used to quantify gene expression from fixed, parafin-embedded tumor tissueDesigned to quantify the risk of distant recurrence in patients with newly diagnosed,eariy stage,LN(-), ER(+) tumors receiving tamoxifen.recurrent score calculated from 0-100

NSABP trial B-14 ,patients classified according to the recurrent scores(RS) based on 10 year distant disease free survival into high risk(RS 31&above),intermediate risk(RS 18 and 1 cm.Category 2B: The recommendation is based on lower level evidence, and there is nonuniform NCCN consensus (but no major disagreement). http://www.nccn.org/professionals/physician_gls/categories_of_consensus.asp

National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed [Apr 27, 2009].

MammaprintDNA microassay

consisting of 70 genes regulating cell cycle, invasion, metastasis, and angiogenesis.

Requires fresh tumor tissue

Gene expression signature that was strongly prognostic for development of distant metastasis in lymph node negative patients was identified

Both ER negative and ER-positive patients were included


Evolution Improvements in disease-free survival (DFS) with single-agent chemotherapy after radical mastectomy in the 1970s.

Polychemotherapy was first evaluated by Bonadonnarandomized women with node-positive breast cancer to 12 monthly cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy or no further therapy after radical mastectomy22-Jun-1610dr rahul ts

NSABP B-20 (Fisher et al. 2004): 2,306 patients status post sur gery with pathologically LN, ER+ breast ca randomized to

tamoxifen alone vs. tamoxifen + MF chemotherapy vs. tamoxifen + CMF chemotherapy.

The addition of chemotherapy to tamoxifen improved 12-year DFS (HR = 0.52) and OS (HR = 0.78, p = 0.068).22-Jun-1611dr rahul ts

NSABP-B28 (Mamounas et al. 2005): 3,060 LN+ patients randomized to

AC 4 Paclitaxel.

Addition of taxane improved 5-year DFS (7276%) and LRR, despite delay of RT (9.7 vs. 3.7%).22-Jun-1612dr rahul ts

CALGB 9344 (Sartor et al.2005;Henderson et al. 2003)

Randomization : Standard dose AC vs. dose escalation of doxorubicin sequential addition of paclitaxel. The sequential Continued addition of adjuvant paclitaxel to AC for LN+ patientsimproves DFS and OS vs. adjuvant AC alone, and further improves 5-year LRC in patients treated with BCS+RT despite delaying RT delivery.

No DFS or OS improvement with dose escalation of doxorubicin.22-Jun-1613dr rahul ts

CALGB 9741 (Citron et al. 2003).

Four arm randomized trial:sequential vs. concurrent addition of paclitaxel (T) to AC chemotherapy, every 3 weeks vs. every 2 week (dose dense) dosing.

Increased 4-year DFS with dose-dense chemo (82 vs. 75%),No difference between sequential or concurrent delivery.22-Jun-1614dr rahul ts

USOT (Jones et al. 2009): 1,016 Stage IIII patients randomized to AC 4 vs. TCx4.

With a median of 7-year follow-up, TC improved DFS (81 vs. 75%) and OS (87% TC v 82).TC improved outcomes regardless of age, hormone receptor, or HER2 expression status.22-Jun-1615dr rahul ts


Taxane CALGB9344: ER-, ER+/Her2+NSABP B-28: ER+PACS01: ER-/PR+BCIRG 001: no differenceFavored LN 1-3 more than >4

Anthracycline Her2+ER-- subset analysis22-Jun-1617dr rahul ts

Principles of Adjuvant TherapyDecrease the risk of recurrence and death from breast cancer with local therapy alone

Endocrine therapy benefits only those with hormone receptor positive disease

Chemotherapy benefits everyone

To eradicate micrometastasis

Combination chemotherapy is more effective than monotherapy


Adjuvant chemotherapy reduces LR after lumpectomy + RT

Anthracycline (doxorubicin)-based regiments ( taxanes for high-risk disease) have been associated with superior outcomes(USOT 9735, Jones et al. 2009).

Dose-dense regimens may have increased efficacy in highrisk patients.Principles of Adjuvant Therapy22-Jun-1619dr rahul ts








Her 2 +







Principles of Neoadjuvant chemotherapy22-Jun-1633dr rahul ts



35

Neoadjuvant chemotherapy is considered standard of care in high-risk populations such as

young patients and/or advanced-stage disease, Stage IIbIII breastInflammatory caT4, N3, bulky or matted N2Principles of Neoadjuvant chemotherapy22-Jun-1636dr rahul ts

Principles of Neoadjuvant chemotherapyTypically, similar indications as adjuvant chemotherapy Advantages of neoadjuvant chemotherapy: assessment of disease response, increased rate of BCTNeoadjuvant chemotherapy converts 2030% of patients initially ineligible for BCT to eligibleComplete clinical (cCR) and pathological response rates2040% achieve cCR , 1020% achieve pCRAlow time for genetic testing

Diminished response noted in ER+, low grade, or invasive lobular cancers


In HER2 positive


In HER2 positive


Metastatic breast cancerExcept in rare cases stage IV cancer is considered incurableFocus of treatment should be on palliation of disease related symptoms






22-Jun-16dr rahul ts45

Pregnant and Recently Postpartum1/3000 pregancies or 1-4% of BrCa in women under 50

Greatest risk from chemo in 1st trimester

In 2nd/3rd trimester still carries risk of IUGR, etc

Mostly AC or FAC, little data for taxanesDont use MtxGenerally, dont recommend delaying chemo

Stensheim et al, JCO, 200922-Jun-1646dr rahul ts

46


Hormonal Therapy


Rationale for endocrine therapy of breast cancerRisk factors for Br Ca include prolonged estrogen exposure states such as early menarche, late menopause,nulliparity andestrogen replacement therapy.


ESTROGEN RECEPTORProtein molecule- mainly in nucleussmall amount in cytoplasm and plasma memb

2 isoforms ER and ER ER - predominates in uterus, breast, pituitary, bone, CNS,CVSER - predominates in prostate, ovary,


Mech. of carcinogenesisER is overexpressed in as many as 70% of breast cancers .

Estrogen exerts its actions by bothGenomic - through nuclear receptorsNongenomic - cytoplsmic receptors.22-Jun-1651dr rahul ts

NSABP B-14 (Fisher et al. 2004):2,644 patients status-post surgery for breast ca (pathologically LN, ER+) randomized to tamoxifen 5 years vs. placebo. Adjuvant tamoxifen improved 15-year DFS (HR = 0.58) and OS (HR = 0.80).22-Jun-1652dr rahul ts

ATAC Trial (2002; Lancet 2005): Arimidex, Tamoxifen, Alone or in Combination 9,366 postmenopausal patients (both ER +/-) status-post definitive therapy for earlystage breast ca randomized to anastrozole, tamoxifen, or both given concurrently. Anastrozole alone improved 3-year DFS compared with tamoxifen (89 vs. 87%) or both (87%). Benefit observed only in ER+ patients. Anastrozole better tolerated with respect to side-effects.22-Jun-1653dr rahul ts

Goss (Goss et al. 2003): 5,187 postmenopausal patients (98% ER+) status-post definitive therapy and adjuvant tamoxifen 5 years for early-stage breast ca randomized to letrozole (2.5 mg) or placebo daily 5 years. Addition of letrozole improved 4-year DFS (8793%).22-Jun-1654dr rahul ts

BIG 1-982498028 patients on RCT with 4 groups Tamoxifen (Tam) x 5yr;Letrozole (Let) x 5yr;Tam x 2yr Let x 3yrLet x 2yr Tam x 3yr51months follow up the use of upfront letrozole for 5 years resulted in a significant reduction in the risk of an event (HR.82; P = .007) compared with upfront tamoxifen for 5 years22-Jun-1655dr rahul ts

Types of endocrine therapy ovarian suppression /ablation surgical oopherectomyradiation ,,medical ,, ,,anti estrogen drugs. SERM, SERD, AI


Drugs used in Hormone RxSERD

Fulvestrant.

SERM

TamoxifenDroloxifeneToremifeneRaloxifene AI -

EXEMESTANELETROZOLEANASTROZOLE


22-Jun-16dr rahul ts58

Mechanism of ActionANDROSTENEDIONEESTRONE

AROMATIZATIONESTRIOL

TESTOSTERONEESTRADIOLAromaters inhibitorsType 1- steroidal and irreversiblee.g.. EXEMESTANEType 2-nonsteroidal and reversiblee.g.. LETROZOLE ANASTROZOLE In peripheral tissues22-Jun-1659dr rahul ts

NCCN guidelines.All pts. c. invasive Br. Cancer, who are ER or PR +ve should be considered for adj. hormonal therapy, regardless of Age LN status Her 2 status Adj.chemo given or not22-Jun-1660dr rahul ts

Radiation oopherectomyRadiation used for ablation of ovarian function.

Given in pts. c. medical c/i for tamoxifen,

Can be considered in young highrisk pt. completd 5 yrs of tamo. or who progressed while on tamoxifen.

Now, medical oopherectomy is preferred.22-Jun-1661dr rahul ts

Radiation oopherectomy Target vol. is true pelvis.

Sup.brdr. ----- inferior brdr. of S1 jt.L5/S1Infr. brdr ----- lower brdr. of obturator fora.Lateral .. ---- bony pelvic sidewall AP PA portals. usually 12 x 12 cm field Dose. 15 Gy in 5 # given22-Jun-1662dr rahul ts

Duration ?Scottish Adjuvant Tamoxifen Trial patients who were disease free at 5 years were randomly assigned either to stop taking tamoxifen or to continue taking it indefinitely until relapse or death. With a median follow-up of 15 years, No additional benefit was observed in taking tamoxifen beyond 5 years.22-Jun-1663dr rahul ts

Despite the preponderance of evidence suggesting that extension of tamoxifen therapy beyond 5 years is not beneficial, two large ongoing trials,

ATLAS (Adjuvant Tamoxifen-Longer Against Shorter) and

aTTom (Adjuvant Tamoxifen Treatment-Offer More) may offer new insight into the optimal duration of tamoxifen therapy.


Cdk @22-Jun-1665dr rahul ts

Targeted Therapy


HER-2 is overexpressed or gene amplified in 20% to 25% of breast cancers. The anti-HER-2 monoclonal antibody trastuzumab targets HER-2-positive tumors, inhibits proliferation, and induces cell death 22-Jun-1667dr rahul ts


NSABP B-31 & NCCTG N9831 (Romond et al. 2005):

3,351 patients with resected LN+ or high-risk LN, HER2+ breast cancer randomized to ACT chemo (doxorubicin, cyclophosphamide, and paclitaxel) vs. chemo + trastuzumab (ACT-H). Trastuzumab increased 3-year DFS (7587%) and OS (9294%), but was associated with increased risk of heart failure or cardiac death (34%).


HERA BIG 01-01 (Piccart-Gebhart et al. 2005): 5,090 patients status postsurgery RT and neoadjuvant or adjuvant chemo HT (if ER/PR+) with HER2 overexpression randomized toObservation , 1-year trastuzumab (q3 week), or 2-year trastuzumab. On interim analysis, trastuzumab 1 year improved 2-year DFS (7786%), but no difference in OS (9596%).


Pertuzumab - perjetainhibition of heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4Pertuzumab binds to a different HER2 epitope than trastuzumab 22-Jun-1671dr rahul ts

The dosage of pertuzumab used in the pivotal phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial was as follows: IV 840mg loading dose followed by IV 420mg every three weeks

MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breast cancer) and APHINITY (HER2-positive nonmetastatic breast cancer)On going trials22-Jun-16dr rahul ts72

Ado-trastuzumab emtansine anantibody-drug conjugateconsisting of themonoclonal antibodytrastuzumab(Herceptin) linked to thecytotoxicagentemtansine (DM1)EMILIA clinical trial

for treatment of HER2-positive mBC , treated previously with trastuzumab and a taxane(paclitaxelordocetaxel), and who have already been treated for mBC or developed tumor recurrencewithin six months ofadjuvant therapy22-Jun-16dr rahul ts73

EMILIA study, 991 people with unresectable, locally advanced or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab andtaxane chemotherapya phase IIIclinical trialthat compared trastuzumab emtansine Vscapecitabine(Xeloda) pluslapatinib(Tykerb). This trial showed improvedprogression-free survivalin patients treated with trastuzumab emtansine (median 9.6 vs. 6.4 months), along with improvedoverall survival(median 30.9 vs. 25.1 months)22-Jun-16dr rahul ts74

LapatinibInhibits thetyrosine kinaseactivity associated with twooncogenes,EGFR(epidermal growth factor receptor) andHER2/neu(Human EGFR type 2)

ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such asanthracycline,taxane-derived drugs, ortrastuzumab 22-Jun-16dr rahul ts75

Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial an international research study that will randomize more than 8000 patients to receive trastuzumab alone for 52 weeks, lapatinib alone for 52 weeks, trastuzumab for 12 weeks, followed by a 6-week break, followed by lapatinib for 34 weeks, or lapatinib in combination with trastuzumab for 52 weeks22-Jun-1676dr rahul ts

Olaparib (AZD2281) an oral PARP inhibitor 600mg o.din the treatment of patients with metastatic previously treated breast The use of inhibitors of poly (ADP-ribose) polymerase in triple negative metastatic breast cancer has been reported in a randomized phase II trial of gemcitabine/carboplatin with or without PARP inhibition 22-Jun-1677dr rahul ts

Treatment guideline


Adj22-Jun-1679dr rahul ts






Neo-adj





Metastatic 22-Jun-1689dr rahul ts






Thnak yuo22-Jun-1695dr rahul ts

Chemo hormonal and targeted therapy in ca breast

Health & Medicine

Transcript of Chemo hormonal and targeted therapy in ca breast