Early Stage Breast Cancer Flashcards

Question

- HORMONE RECEPTOR NEGATIVE T ≤ 0.5cm pN1m HER2 NEGATIVE Systemic Adjuvant TREATMENT

Answer 1

± adjuvant chemotherapy 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy.

Answer 2

± adjuvant chemotherapy +trastuzumab (if chemo administered) Consider adjuvant chemo with weekly paclitaxel and trastuzumab particularly for ER-, HER2+, stage I cancer

Answer 3

± adjuvant chemotherapy 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy.

Answer 4

± adjuvant chemotherapy +trastuzumab (if chemo administered) Consider adjuvant chemo with weekly paclitaxel and trastuzumab particularly for ER-, HER2+, stage I cancer

Answer 5

+ adjuvant chemotherapy 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy.

Answer 6

+ adjuvant chemotherapy + trastuzumab

Answer 7

+ adjuvant chemotherapy - 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy

Answer 8

+ adjuvant chemotherapy + trastuzumab ± pertuzumab (if trastuzumab administered)

Answer 9

See previous algorithm

Answer 10

+ adjuvant chemotherapy + trastuzumab ± pertuzumab (if trastuzumab administered) + adjuvant endocrine therapy - Consider extended adjuvant neratinib following adjuvant trastuzumab-containing therapy in HR-positive, HER2-positive patients with perceived high risk of recurrence

Answer 11

Data suggests that patients with greater percentage of ER/PR positivity will have a higher probability of positive outcomes with endocrine therapies (OS, DFS, etc.) The NCCN® panel recommends considering endocrine therapy in patients whose breast tumors show at least 1% ER+ and/or PR+ cells and withholding endocrine therapy if less than 1% for both ER and PR. The guidelines state that ER-low-positive cancers (1-10%) often behave similar to ER-negative cancers and this should be considered in decision-making for adjuvant therapy

Answer 12

Endocrine therapy given concurrently during chemotherapy has been shown to decrease DFS Chemotherapy is typically given first and then endocrine therapy, sequentially. Endocrine therapy may be given sequential or concurrent with radiation

Answer 13

ASCO and NCCN® recommendations for initial therapy: - Tamoxifen for 5 years - Consider combination of ovarian ablation or suppression (OAS) + tamoxifen x 5 years or OAS + AI x 5 years for patients at higher risk of recurrence After 5 years of tamoxifen alone: - If patient remains premenopausal, consider an additional 5 years of tamoxifen (total of 10 years) or no further therapy. (CONFLICTING DATA > 5yrs)

Answer 14

AI for 5-10 years - ASCO: AI for 10 years for women node-positive BRCA - NCCN: Optimal duration uncertain (7.5-10 yrs)

Answer 15

Treat similarly to postmenopausal women except that if AIs are used, they must be combined with an agent to suppress testicular steroidogenesis (such as an LHRH agonist) Tamoxifen x 5-10 yrs preferred. May consider LHRH + AI

Answer 16

CYP2D6 inhibitors (see details in survivorship section)

Answer 17

- hot flashes - vaginal discharge or dryness - menstrual irregularities - sexual dysfunction - venous thromboembolism (VTE) - cataracts - endometrial cancer and uterine sarcoma (postmenopausal patients) - decline in bone mineral density in premenopausal patients (protective effect on bone mineral density in postmenopausal patients) - hyperlipidemia

Answer 18

NONSTEROIDAL: - Anastrozole - Letroxole STEROIDAL: - Exemestane

Answer 19

Side effects: - hot flashes - arthralgias/myalgias - mild headache - diarrhea - bone loss (osteoporosis, fractures) - vaginal dryness - cardiovascular events

Answer 20

- up to 50% ow women receiving AI - onset typical 6 weeks may worsen over 1 yr - often not responsive to NSAID/APAP - Duloxetine, acupuncture, and exercise are several treatment strategies that have shown a decrease in AI-associated arthalgias - 40% may tolerate different AI

Answer 21

Anastrozole – approved for adjuvant therapy for early stage breast cancer (1 mg daily for 5 years); ATAC trial found anastrozole superior to tamoxifen in terms of disease-free survival (DFS) Letrozole – approved for adjuvant therapy for early stage breast cancer (2.5 mg daily for 5 years); superior to tamoxifen (BIG 1-98 trial found letrozole superior to tamoxifen in terms of DFS Exemestane – The TEAM trial evaluated exemestane x 5 years vs. sequential tamoxifen x 2.5-3 years followed by anastrozole to complete 5 years. DFS at 10 years was 67% in both arms

Answer 22

Anastrozole – 1 mg daily to complete 5 years of adjuvant endocrine therapy; superior to tamoxifen alone for 5 years. - At 36-month follow-up, 45 events vs. 17 events (p=0.0002). DFS and local recurrence-free survival also significantly longer in anastrozole group Exemestane (IES trial) – 25 mg daily to complete 5 years of adjuvant endocrine therapy; superior to tamoxifen alone for 5 years. - At 30.6 month follow-up, 449 first events vs. 266 events

Answer 23

Letrozole (MA-17 trial) – 2.5 mg daily for another 5 years superior to placebo; DFS (HR 0.52; 95% CI 0.45-0.61) and OS (HR 0.61; 95% CI 0.52-0.71) was superior with letrozole compared to placebo Exemestane (NSABP B-33) – 25 mg daily for another 5 years vs. placebo; stopped when MA-17 results available; recent report of available data (about half of initial accrual goal) indicate non-significant benefit in 4-year DFS (91% vs. 89%; RR = 0.68; p=0.07) with 30 months median follow-up.

Answer 24

5 years vs. 10 years - OS did not significantly differ between groups 7 years vs. 10 years Conclusion: Extending hormone therapy by 5 years to total of 10 years provided no benefit over 2-year extension to total of 7 years All three selective AIs (anastrozole, letrozole, exemestane) have similar antitumor efficacy and similar toxicity profiles

Answer 25

ASCO Guidelines recommend that 2 years of adjuvant abemaciclib + endocrine therapy may be offered to patients with HR-positive, HER2-negative, LN-positive early breast cancer with a high risk of recurrence and a Ki-67 score ≥ 20%. The panel also recommends this combination may be offered to the broader ITT population (based on high-risk criteria as defined by MonarchE). NCCN Guidelines® state to consider 2 years of adjuvant abemaciclib for patients meeting high-risk criteria as defined by MonarchE. MonarchE: High-risk defined as: ≥ 4 positive LN OR 1 – 3 positive LN and tumor ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%

Answer 26

The optimal regimen in any clinical situation has not been determined; no standard regimen; many acceptable, evidence-based regimens demonstrate improvement in reducing the risk of recurrent breast cancer LN-negative vs. LN-positive: controversial whether to include a taxane in addition to an anthracycline-based regimen in LN-negative disease ASCO guidelines recommend the use of an anthracycline and taxane regimen for patients with high-risk features (including patients with LN-positive disease).

Answer 27

Consider use of taxane-based regimens, such as docetaxel and cyclophosphamide (TC), for patients with lower risk disease features or those who are not candidates for an anthracycline TC x 4 cycles offers improved DFS and OS compared with AC x 4 cycles. Higher risk of infection with TC HER2-negative: DFS improved with Tax+AC vs. TCx6

Answer 28

Use of anthracyclines reduced recurrence by 25% (absolute difference of 8%) and reduced overall mortality by 16% (absolute decrease 5%) compared to no chemotherapy An optimal-dose anthracycline 3-drug regimen (cumulative doxorubicin ≥ 240 mg/m2 or epirubicin ≥600 mg/m2 but no higher than 720 mg/m2) should be considered for patients with high-risk disease who will not receive a taxane Cumulative dose of doxorubicin in two-drug regimens should not exceed 240mg/m2

Answer 29

Incorporation of TAXANE significantly reduces the risk of: - distant recurrence - any recurrence - breast cancer mortality - overall mortality TC x 4 cycles provides improved DFS and OS compared to AC x 4 cycles

Answer 30

LN-positive breast cancer patients in the CALGB 9741 study were randomized after surgery to sequential versus concurrent chemotherapy: - AC -> Pac vs. A -> Pac -> C) and standard dose (Q 3 week) versus dose dense (AC -> Pac) - Pts receiving q2wk chemo had significantly prolonged DFS vs q3wk - NCCN lists dose dense AC regimens followed by a taxane over conventional AC q3wks followed by a taxane -Growth factor support is recommended for all cycles of dose-dense chemotherapy

Answer 31

CREATE-X was a phase III open-label trial that randomized 910 patients with HER2-negative stage I – IIIB breast cancer with residual disease following neoadjuvant chemo and surgery to placebo or adjuvant capecitabine 1,250 mg/m2 BID on days 1 – 14 every 21 days x 6 or 8 cycles (protocol extended to 8 cycles after 1st 50 patients were enrolled). - DFS/OS favorable to capecitabine group - For Triple Negative: DFS and OS favored capecitabine

Answer 32

NCCN® and ASCO guidelines recommend considering the use of 6-8 cycles of adjuvant capecitabine in patients with TNBC and pathologic invasive residual disease following standard neoadjuvant treatment with taxane-, alkylator-, and anthracycline-based chemotherapy - NCCN® guidelines recommend administering following completion of XRT - ASCO guidelines state that the capecitabine dose of 1,250 mg/m2 BID used in the CREATE-X study is associated with higher toxicity in patients ≥ 65 years old

Answer 33

Consider OLAPARIB in pts who have germline BRCA1/2 mutation AND: - TNBC if: ≥pT2 or ≥pN1 disease after adjuvant chemotherapy OR residual dx following neoadjuvant tx - HR+, HER- if: ≥ 4 positive LN after adjuvant chemotherapy OR residual dx following neoadjuvant tx

Answer 34

Adjuvant ado-trastuzumab emtansine x 14 cycles is recommended by NCCN® for patients with HER2-positive breast cancer and residual disease following preoperative therapy based on the results of the KATHERINE trial (see additional information in the HER2-Directed Therapy section below). May be administered concurrent with XRT.

Answer 35

Adjuvant pembrolizumab for up to 9 cycles of the q21 day regimen (or 400 mg every 6 weeks x 5 cycles) if patient received pembrolizumab + chemotherapy in the neoadjuvant setting (see more information in section below: Choice of neoadjuvant Regimen)

Answer 36

Doxorubicin 60 mg/m2 - d1 Q14 days x 4 cycles Cyclophosphamide 600 mg/m2 - d1 Q14 days x 4 cylcles

Answer 37

[EPIRUB 100] d1 Q21 days x 8 cycles [CTX 830] d1 Q21 days x 8 cycles

Answer 38

- [Dox 60] d1 Q21 days x 4 cycles - [CTX 600] d1 Q21 days x 4 cycles - [PAC 80] over 1h QW Q7 days x 12 wks

Answer 39

- [DOX 60] d1 Q21 days x 4 cycles - [CTX 600] d1 Q21 days x 4 cycles - [DOC 100] d1 Q21 days x 4 cycles

Answer 40

- [Doc 75] d1 Q21d x 6 cycles - [Dox 50] d1 Q21d x 6 cycles - [CTX 500] d1 Q21d x 6 cycles

Answer 41

NCCN Preferred Regimen: - [DOC 75] d1 Q21d x 4 cycles - [CTX 600] d1 Q21d x 4 cycles

Answer 42

NCCN preferred - [DOX 60] d1 q14d x 4 cycles - [CTX 600] d1 q14d x 4 cycles - [PAC 175] d1 q14d x 4 cycles OR - [PAC 80] d1 q7d x 12 weeks

Answer 43

- Pembrolizumab 200mg d1 Q21d x 4 cycles - [Paclitaxel 80] d1, d8, d15 Q21d x 4 cycles - [Carbo AUC 5] d1 Q21d x 4 cycles

Answer 44

- Pembro 200mg d1 Q21d x 9 cycles - [DOX 60] d1 Q21d x 4 cycles - [CTX 600] d1 Q21 x 4 cycles

Answer 45

- [CTX 100 PO] d1-14 Q28d x 6 cycles - [MTX 40] d1, d8 Q28d x 6 cycles - [5-FU 600] d1, d8 Q28d x 6 cycles

Answer 46

- [Paclitaxel 80] d1, 8, 15 Q 21 days x 4 cycles - [Carbo 5 or 6] d1 Q21 days x 4 cycles

Answer 47

- [Paclitaxel 80] d1, 8, 15 Q 28 days x 6 cycles - [Carbo 1.5-2 ] d1, 8, 15 Q 28 days x 6 cycles

Answer 48

Designated by NCCN® as a preferred regimen - Olaparib 300mg BID q28d x 1 year

Answer 49

ADJUVANT: - [Capecitabine 1,000-1,250] PO BID D1 – 14 Q 21d X 6 – 8 cycles * Recommended in adjuvant setting only. Considered a NCCN® preferred regimen for patients with TNBC and residual disease after preoperative therapy. Considered “useful in certain circumstances” as maintenance therapy for TNBC following adjuvant chemotherapy. MAINTENANCE - [Capecitabine 650] PO BID D 1 – 28 Q 28 days 1 year

Answer 50

NCCN Guidelines® recommend to complete up to 1 year of HER2 targeted therapy with trastuzumab +/- pertuzumab

Answer 51

NCCN® and ASCO guidelines recommend adotrastuzumab emtansine alone x 14 cycles. If ado-trastuzumab emtansine is discontinued for toxicity, then it is recommended to administer trastuzumab +/- pertuzumab to complete 1 year of therapy

Answer 52

- Recommended for all HER2-POS patients with tumors > 1 cm - NCCN® and ASCO: trastuzumab should be considered in HER2-positive patients with tumors < 1 cm due to poor recurrence-free survival in pt population - Preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen - d/t CARDIOTOXICITY RISKS - Typically given concurrent with taxane-portion of the regimen - Can be administered with any acceptable adjuvant chemo

Answer 53

NCCN® and ASCO guidelines include a recommendation to consider the addition of pertuzumab to trastuzumab in the adjuvant setting to complete up to 1 year of HER2 targeted therapy for patients with LN-positive disease - insignificant benefit in node negative There was a greater incidence of ≥ grade 3 diarrhea in the pertuzumab group

Answer 54

KATHERINE trial: Patients received adjuvant adotrastuzumab emtansine 3.6 mg/kg every 21 days or trastuzumab for 14 cycles - 3-year iDFS was significantly higher in the ado-trastuzumab emtansine group compared to the trastuzumab group (88.3% vs. 77%) ATEMPT trial: stage I HER2+ breast cancer 3:1 to adotrastuzumab emtansine 3.6 mg/kg IV every 3 weeks x 17 cycles or paclitaxel + trastuzumab (TH – paclitaxel weekly x 12 weeks + trastuzumab x 1 year) - Less neuropathy, alopecia for pts receiving kadycla - 3-year iDFS was 97.8% for ado-trastuzumab emtansine Added to NCCN Guidelines® as an option in the adjuvant setting

Answer 55

NCCN® recommends to consider the use of extended adjuvant neratinib following adjuvant trastuzumab-containing therapy in HR-positive patients with a perceived high risk of recurrence ASCO recommends to consider use in patients with early-stage, HER2-positive, HR-positive, node-positive disease. Patients who began neratinib within 1 year of trastuzumab completion, those with LN-positive disease, and those with HR-positive disease appeared to derive the greatest benefit

Answer 56

Diarrhea: prophylaxis with loperamide +/- colestipol or budesonide or neratinib dose escalation strategies have been shown to reduce the rate, severity, and duration of neratinib-associated grade ≥ 3 diarrhea Two-week dose escalation is recommended to minimize diarrhea * Week 1 (days 1 – 7) -> 120 mg daily * Week 2 (days 8 – 14) -> 160 mg daily * Week 3 and beyond -> 240 mg daily If dose escalation is not utilized, antidiarrheal prophylaxis is recommended with 1st 2 cycles (56 days) of treatment and should be initiated with the 1st dose of neratinib. Recommended loperamide prophylaxis: * Weeks 1 – 2 -> 4 mg TID * Weeks 3 – 8 -> 4 mg BID * Weeks 9 – 52 -> 4 mg as needed (not to exceed 16 mg/day)

Answer 57

NCCN Guidelines® recommend to consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3 – 5 years in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive disease Adjuvant BMAs are not recommended for men with early-stage breast cancer to prevent recurrence but may be used to prevent or treat osteoporosis.

Answer 58

Current guidelines state that data are insufficient to make a recommendation on the use of denosumab in the adjuvant setting except to reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant endocrine therapy - Denosumab significantly delayed time to first clinical fracture

Answer 59

1) See guidelines for early stage breast cancer (listed above). 2) Local therapy or neoadjuvant systemic therapy followed by local therapy based on patient and disease factors (see below)

Answer 60

- Primary (preoperative, neoadjuvant) systemic chemotherapy; HER2-directed therapy should be incorporated if HER2-positive. - If a response is demonstrated and tumor is operable, then local therapy would be performed. - Mastectomy or BCS +/- RT may be considered, depending on clinical situation.

Answer 61

1) Decrease the size of the tumor to minimize surgery 2) Determine response to chemotherapy (an important prognostic indicator especially for triple-negative disease and HER2+ disease) 3) Allows modification or addition of adjuvant regimens among patients with HER2-positive and TNBC with residual disease 4) Allows time for genetic testing 5) Allows time to plan breast reconstruction in patients electing mastectomy

Answer 62

Meta-analysis of neoadjuvant vs. adjuvant systemic treatment - No significant difference in death, disease progression, or distant recurrence

Answer 63

1) Preferred for patients with inoperable breast cancer (inflammatory breast cancer, bulky or matted cN2 axillary nodes, cN3 nodal disease, cT4 tumors) 2) Patients with operable breast cancer, neoadjuvant therapy is preferred for those with: - HER2-positive disease or TNBC, if cT ≥2 or cN ≥ 1 - Consider neoadjuvant therapy for cT1,N0 - Large primary tumor relative to breast size in a patient that desires breast conservation - With clinically node-positive disease likely to become node-negative with preoperative systemic therapy 3) Patients in whom definitive surgery may be delayed

Answer 64

NCCN Guidelines® recommend that in general, those chemotherapy regimens recommended in the adjuvant setting may also be considered in the preoperative setting Preferred to complete standard regimen prior to surgery

Answer 65

ASCO guidelines state that patients with TNBC should be offered an anthracycline and taxane-containing regimen. - Carboplatin may be offered to patients with TNBC to increase pathologic CR (pCR) especially in patients at high clinical risk (such as node-positive disease) - Consider a taxane-based regimen, such as docetaxel and cyclophosphamide, for lower-risk patients or those with cardiac risk factors -Pembrolizumab + chemotherapy can be considered

Answer 66

In general, those chemotherapy regimens recommended in the adjuvant setting may also be considered in the neoadjuvant setting and vice versa - Patients with HER2-positive disease should receive preoperative systemic therapy incorporating TRASTUZUMAB - Patients with node-positive or high-risk node-negative disease should be offered neoadjuvant therapy with an anthracycline and taxane or non-anthracycline-based regimen in combination with trastuzumab +/- pertuzumab

Answer 67

Pertuzumab received accelerated approval from the FDA in combination with docetaxel and trastuzumab for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (ESBC) - Addition of pertuzumab to trastuzumab and docetaxel resulted in significant improvement in pCR

Answer 68

Historically utilized for locally advanced breast tumors in elderly patients with poor PFS or limitations to chemo - NCCN® includes option of endocrine therapy alone for patients with ER-positive disease based on comorbidities or low-risk luminal biology based on clinical characteristics and/or genomic signatures. - ASCO recommends that postmenopausal patients with HR-positive, HER2-negative disease can be offered hormone therapy with an aromatase inhibitor to downstage disease PREMENOPAUSAL: Should NOT routinely be offered neoadjuvant endocrine therapy POSTMENOPAUSAL: AI preferred over tamoxifen Optimal duration of neoadjuvant endcocrine tx not known (3-6mo)

Answer 69

- Total Mastectomy + surgical axillary staging ± reconstruction OR - BCS + surgical axillary staging All patients should receive chest XRT Pts w/ lymph nodes should receive XRT to nodes

Answer 70

- Change to non-cross-resistant chemotherapy OR - Radiation to breast and supraclavicular area If no response to non-cross resistant chemotherapy, then go to radiation Residual disease following preoperative chemotherapy (see section above “Role of additional adjuvant chemotherapy for patients with residual disease following neoadjuvant chemotherapy “)

Answer 71

- Distinct clinical entity; rare; poor prognosis; aggressive - often ER-neg; HER2-pos - no standard of care - treat as locally advanced dx - chemo similar to pts w/ locally advanced dx and trastuzumab + pertuzumab should be considered in HER2-pos