Early Stage Breast Cancer Flashcards
EARLY STAGE BREAST CANCER
POOR Prognostic factors other than staging
- Primary resistance to systemic chemotherapy
- Estrogen- and/or progesterone-negative receptor status
- High levels of proliferative markers (e.g. Ki-67, mitotic index)
- Lymphatic/vascular invasion
- Aneuploid tumors
- Diabetes
- Obesity
- HER2 amplification/overexpression (predicts response to HER2-directed therapy)
Treatment Decision Making for Early-Stage Breast Cancer
Oncotype DX®
= Commercially available gene expression assay – screens for expression of 21 genes (16 cancerrelated genes and 5 control genes), resulting in a recurrence score (RS) from 0 to 100.
The higher the score the greater the risk of recurrence and greater the benefit for chemotherapy
Preferred by NCCN® because it provides prognosis and predicts benefit of chemotherapy
Plan B trial suggests no clinical benefit with chemo for patients with high clinical risk and low RS
Oncotype DX® can predict the benefit of adjuvant chemotherapy in women with HR-positive, HER2-negative, LN-POSITIVE breast cancer.
NCCN® lists Oncotype DX® as an option for select patients with 1 – 3 ipsilateral axillary lymph nodes (pN1) to guide the addition of combination chemotherapy to standard hormone therapy.
Treatment Decision Making for Early-Stage Breast Cancer
Mammaprint®
FDA approved gene expression assay – screens for expression of 70 genes, resulting in either a good prognosis or a poor prognosis classification on basis of risk of distant recurrence at 5 and 10 years
Treatment Decision Making for Early-Stage Breast Cancer
PAM50 (Prosigna®)
Gene expression assay that screens for expression of 50 genes (+ 5 control genes).
Predicts distant relapse-free survival and likelihood of recurrence at 10 years in ER-positive postmenopausal patients with LN-negative or LN-positive breast cancer treated with endocrine therapy.
Treatment Decision Making for Early-Stage Breast Cancer
Breast Cancer Index (BCI)
Predictive of benefit of extended adjuvant endocrine therapy
- BCI (H/I) in the high range (5.1 – 10) demonstrated significant improvements in DFS with extended adjuvant endocrine therapy
- BCI low patients (range 0 – 5) did not benefit from extended adjuvant therapy
Treatment of Early Stage and Locally Advanced Breast Cancer
DCIS
Local management
NO SURIVIVAL DIFFERENCES BETWEEN 3 APPROACHES
- Breast conserving surgery (BCS) (aka lumpectomy) + radiation therapy OR
- Total mastectomy ± reconstruction OR
- BCS without radiation
-> After BCS, radiation reduces recurrence rates of DCIS by about 50%; half of recurrences are invasive and half are DCIS
Treatment of Early Stage and Locally Advanced Breast Cancer
DCIS
Endocrine Tx
Following BCS +/- RT, consider endocrine therapy for 5 years to decrease risk of ipsilateral recurrence in patients with ER-positive DCIS
- PREmenopausal patients - Tamoxifen
- POST menopausal patients - Aromatase inhibitors or tamoxifen
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
GOALS OF THERAPY: CURE
Summary - Most patients are eligible for primary surgery ± radiation therapy. However, some patients who otherwise are candidates for BCS except for the size of the tumor (in relationship to the size of the breast) may be better served with neoadjuvant/preoperative chemotherapy to attempt to shrink the tumor and possibly allow for BCS.
Neoadjuvant therapy is also preferred for patients with
HER2-positive disease and TNBC if T ≥ 1c or N ≥ 1 (see additional information in section “Primary
(preoperative, neoadjuvant) systemic chemotherapy
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
Locoregional therapy (surgery ± radiation therapy)
Total mastectomy + surgical axillary staging (if w/ axillary lymph node dissection, then called
modified radical mastectomy) ± reconstruction
OR
BCS (segmental mastectomy, lumpectomy, etc.) + surgical axillary staging + XR
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
BCS + XRT CONTRAINDICATIONS
ABSOLUTE
- Radiation prohibited during pregnancy
- Diffuse suspicious or malignant appearing macrocalcifications on mammogram
- Widespread disease that cannot be incorporated by local excision through a single incision that achieves negative margins with a satisfactory cosmetic result
- Diffusely positive pathologic margin
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
BCS + XRT CONTRAINDICATIONS
RELATIVE
- Prior radiation therapy to chest wall or breast
- Active connective tissue disease involving the skin (especially scleroderma and lupus)
- Positive pathologic margin
- Women with known or suspected genetic predisposition to breast cancer (consider prophylactic bilateral mastectomy)
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
Surgical Axillary Staging
- Axillary lymph node dissection (ALND)
Required if:- Clinical LN-positive at diagnosis OR
- Sentinel LN-positive or not identified
- Lymphatic mapping with sentinel lymph node biopsy (SLNB) preferred
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
Radiation therapy after mastectomy
See recommendations for RT in figure “Locoregional treatment of early stage breast cancer”
NOT RECOMMENDED FOR:
- Negative axilliary lymph nodes
AND
- Tumors <= 5cm
AND
- Negative Margins
Common for radiation therapy to follow chemotherapy when both are indicated
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
Systemic adjuvant therapy for early-stage breast cancer
Appropriate therapies
Goal of therapy is CURE
Appropriate therapies:
- Endocrine Therapy
- Chemotherapy
- HER2-directed therapies
- Bisphosphonates
Treatment of Early Stage and Locally Advanced Breast Cancer
Stage IA, IB, IIA, IIB Invasive Breast Cancers (Early Stage)
or
T3 N1 M0
Systemic adjuvant therapy for early-stage breast cancer
ASCO Guidelines for when to consider adjuvant chemotherapy
- LN Positive (>= 1 with macrometastatic deposit > 2mm)
- ER-negative tumors with T > 5 mm
- HER2-positive tumors
- High-risk LN negative tumors with T > 5mm and >= 1 other high-risk feature: grade 3, triple negative, LVI positive, Oncotype Dx RS associated with an estimated distant relapse rate of > 15% at 10 years, or Her2-positive
- Adjuvant! Online 10-year risk of death from breast cancer > 10%
- HORMONE RECEPTOR-POSITIVE
- HER2-POSITIVE (PRE- OR POSTMENOPAUSAL)
- T <0.5cm
pN0
Systemic Adjuvant TREATMENT
Consider adjuvant endocrine therapy
± adjuvant chemotherapy
+ trastuzumab (if chemo administered)
- HORMONE RECEPTOR-POSITIVE
- HER2-POSITIVE (PRE- OR POSTMENOPAUSAL)
- T <0.5cm
pN1m
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
+ trastuzumab (if chemo administered)
+ adjuvant endocrine therapy
- HORMONE RECEPTOR-POSITIVE
- HER2-POSITIVE (PRE- OR POSTMENOPAUSAL)
- T = 0.6 - 1cm
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
+ trastuzumab (if chemo administered)
+ adjuvant endocrine therapy
- HORMONE RECEPTOR-POSITIVE
- HER2-POSITIVE (PRE- OR POSTMENOPAUSAL)
- T > 1cm
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
+ trastuzumab
+ adjuvant endocrine therapy
- HORMONE RECEPTOR POSTIVE
- HER2-NEGATIVE
- POSTMENOPAUSAL
T < 0.5cm and pN0
Systemic Adjuvant TREATMENT
± adjuvant endocrine therapy a
- HORMONE RECEPTOR POSTIVE
- HER2-NEGATIVE
- POSTMENOPAUSAL
T > 0.5cm and pN1m
Systemic Adjuvant TREATMENT
Strongly consider 21-gene RT-PCR assay if candidate for
chemotherapy
ASSAY results:
- NOT DONE: ± adjuvant chemotherapy
+ adjuvant endocrine
- RS <26: ± adjuvant chemotherapy
- RS >26: + adjuvant chemotherapy
+ adjuvant endocrine therapy
- HORMONE RECEPTOR POSTIVE
- HER2-NEGATIVE
- POSTMENOPAUSAL
pN2/pN3 (≥ 4 positive nodes)
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
+ adjuvant endocrine therapy
- HORMONE RECEPTOR NEGATIVE
T ≤ 0.5cm
pN0
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
no adjuvant therapy
- HORMONE RECEPTOR NEGATIVE
T ≤ 0.5cm
pN0
HER2 POSITIVE
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
+trastuzumab (if chemo administered)
Consider adjuvant chemo with weekly paclitaxel and trastuzumab particularly for ER-, HER2+, stage I cancer
- HORMONE RECEPTOR NEGATIVE
T ≤ 0.5cm
pN1m
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion
of adjuvant chemotherapy.
- HORMONE RECEPTOR NEGATIVE
T ≤ 0.5cm
pN1m
HER2 POSITIVE
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
+trastuzumab (if chemo administered)
Consider adjuvant chemo with weekly paclitaxel and trastuzumab particularly for ER-, HER2+, stage I cancer
- HORMONE RECEPTOR NEGATIVE
T = 0.6 - 1cm
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion
of adjuvant chemotherapy.
- HORMONE RECEPTOR NEGATIVE
T = 0.6 - 1cm
HER2 POSITIVE
Systemic Adjuvant TREATMENT
± adjuvant chemotherapy
+trastuzumab (if chemo administered)
Consider adjuvant chemo with weekly paclitaxel and trastuzumab particularly for ER-, HER2+, stage I cancer
- HORMONE RECEPTOR NEGATIVE
T > 1cm
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion
of adjuvant chemotherapy.
- HORMONE RECEPTOR NEGATIVE
T > 1cm
HER2 POSITIVE
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
+ trastuzumab
NODE POSITIVE
Stage IIA, IIB
HR NEGATIVE
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
- 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy
NODE POSITIVE
Stage IIA, IIB
HR NEGATIVE
HER2 POSITIVE
Systemic Adjuvant TREATMENT
+ adjuvant chemotherapy
+ trastuzumab
± pertuzumab (if trastuzumab administered)
NODE POSITIVE
Stage IIA, IIB
HR POSITIVE
HER2 NEGATIVE
Systemic Adjuvant TREATMENT
See previous algorithm
NODE POSITIVE
Stage IIA, IIB
HR POSITIVE
HER2 POSITIVE
Systemic Adjuvant TREATMENT
+ 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
Endocrine therapy
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
Timing of adjuvant endocrine therapy
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
Endocrine options for premenopausal women
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)
Endocrine options for postmenopausal women
AI for 5-10 years
- ASCO: AI for 10 years for women node-positive BRCA
- NCCN: Optimal duration uncertain (7.5-10 yrs)
Endocrine options for males with breast cancer
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
Tamoxifen (pre- and postmenopausal women)
Drug Interactions
CYP2D6 inhibitors (see details in survivorship section)
Tamoxifen (pre- and postmenopausal women)
SIDE EFFECTS
- 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
Aromatase Inhibitors (postmenopausal women)
Agents
NONSTEROIDAL:
- Anastrozole
- Letroxole
STEROIDAL:
- Exemestane
Aromatase Inhibitors (postmenopausal women)
SIDE EFFECTS
Side effects:
- hot flashes
- arthralgias/myalgias
- mild headache
- diarrhea
- bone loss (osteoporosis, fractures)
- vaginal dryness
- cardiovascular events
Aromatase Inhibitors (postmenopausal women)
MYALGIA/ARTHRALGIA
- 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
AROMASTASE INHIBITORS (Postmenopausal women)
First-line adjuvant therapy compared with tamoxifen
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
AROMASTASE INHIBITORS (Postmenopausal women)
Sequential adjuvant therapy after 2-3 years of tamoxifen (switching strategy)
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
AROMASTASE INHIBITORS (Postmenopausal women)
Second adjuvant therapy after 5 years of tamoxifen (extended strategy)
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.
AROMASTASE INHIBITORS (Postmenopausal women)
Extending duration of AI
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
AROMASTASE INHIBITORS (Postmenopausal women)
CDK4/6 inhibitor + endocrine therapy for adjuvant treatment
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%
Systemic adjuvant therapy for early-stage breast cancer
Adjuvant Chemotherapy
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).
Systemic adjuvant therapy for early-stage breast cancer
TAXANE Based Regimens
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
Systemic adjuvant therapy for early-stage breast cancer
ANTHRACYCLINE Based Regimens
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
Systemic adjuvant therapy for early-stage breast cancer
Taxane-containing regimens
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
Systemic adjuvant therapy for early-stage breast cancer
Dose-dense (DD) therapy (every 2 weeks)
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
Systemic adjuvant therapy for early-stage breast cancer
Role of additional adjuvant chemotherapy for patients with residual disease following
neoadjuvant chemotherapy
CAPECITABINE
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
Triple Negative Breast CA
CAPECITABINE
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
Role of additional adjuvant chemotherapy for patients with residual disease following
neoadjuvant chemotherapy
OLAPARIB
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
Role of additional adjuvant chemotherapy for patients with residual disease following
neoadjuvant chemotherapy
Adjuvant ado-trastuzumab emtansine
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.
Role of additional adjuvant chemotherapy for patients with residual disease following
neoadjuvant chemotherapy
Adjuvant pembrolizumab
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)
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Dose-dense AC
Doxorubicin 60 mg/m2 - d1 Q14 days x 4 cycles
Cyclophosphamide 600 mg/m2 - d1 Q14 days x 4 cylcles
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
EC
[EPIRUB 100] d1 Q21 days x 8 cycles
[CTX 830] d1 Q21 days x 8 cycles
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
AC ⇒ Paclitaxel
- [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
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
AC ⇒ Docetaxel
- [DOX 60] d1 Q21 days x 4 cycles
- [CTX 600] d1 Q21 days x 4 cycles
- [DOC 100] d1 Q21 days x 4 cycles
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
TAC
- [Doc 75] d1 Q21d x 6 cycles
- [Dox 50] d1 Q21d x 6 cycles
- [CTX 500] d1 Q21d x 6 cycles
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
TC
NCCN Preferred Regimen:
- [DOC 75] d1 Q21d x 4 cycles
- [CTX 600] d1 Q21d x 4 cycles
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Dose-Dense AC FOLLOWED by
- Dose-Dense Pac
OR
- Weekly Pac
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
Selected Regimens for Neoadjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Pembrolizumab + chemo
Preoperative:
- Pembrolizumab 200mg d1 Q21d x 4 cycles
- [Paclitaxel 80] d1, d8, d15 Q21d x 4 cycles
- [Carbo AUC 5] d1 Q21d x 4 cycles
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Pembrolizumab + chemo
Postoperative:
- Pembro 200mg d1 Q21d x 9 cycles
- [DOX 60] d1 Q21d x 4 cycles
- [CTX 600] d1 Q21 x 4 cycles
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
CMF
- [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
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Weekly paclitaxel + carboplatin
(neoadjuvant only)
- [Paclitaxel 80] d1, 8, 15 Q 21 days x 4 cycles
- [Carbo 5 or 6] d1 Q21 days x 4 cycles
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Weekly paclitaxel + weekly carboplatin
- [Paclitaxel 80] d1, 8, 15 Q 28 days x 6 cycles
- [Carbo 1.5-2 ] d1, 8, 15 Q 28 days x 6 cycles
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Olaparib (adjuvant only)
Designated by NCCN® as a preferred regimen
- Olaparib 300mg BID q28d x 1 year
Selected Regimens for NeoAdjuvant/Adjuvant Therapy for HER2-negative Breast Cancer
Olaparib (adjuvant only)
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
Adjuvant HER2-Directed Therapy
TREATMENT option if NO RESIDUAL DISEASE PRESENT
- After therapy or if not therapy is given
NCCN Guidelines® recommend to complete up to 1 year of HER2 targeted therapy with trastuzumab +/- pertuzumab
Adjuvant HER2-Directed Therapy
TREATMENT option if RESIDUAL DISEASE PRESENT
- After therapy or if not therapy is given
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
Adjuvant HER2-Directed Therapy
TRASTUZUMAB
- 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
Adjuvant HER2-Directed Therapy
PERTUZUMAB
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
Adjuvant HER2-Directed Therapy
Ado-trastuzumab emtansine
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
Adjuvant HER2-Directed Therapy
Neratinib
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
Neratanib
SIDE EFFECTS
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)
Adjuvant bone-modifying agents (BMAs)
GUIDELINES
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.
Adjuvant bone-modifying agents (BMAs)
DENOSUMAB
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Operable stage IIIA (T3, N1, M0)
GUIDELINES
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)
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
All other stage IIIA, IIIB, IIIC (non-inflammatory)
GUIDELINES
- 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.
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Preoperative (neoadjuvant) systemic chemotherapy
Benefits of neoadjuvant therapy:
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Neoadjuvant (primary, preoperative) vs. adjuvant systemic therapy
Meta-analysis of neoadjuvant vs. adjuvant systemic treatment
- No significant difference in death, disease progression, or distant recurrence
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
NCCN Guidelines® - candidates for neoadjuvant therapy
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- TNBC
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Regimens for HER2-positive disease
TRASTUZUMAB
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Regimens for HER2-positive disease
PERTUZUMAB
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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Postoperative Endocrine Therapy
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)
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Local therapy following primary/postoperative systemic therapy
- 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
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Nonresponders to primary/preoperative systemic therapy or less than operable tumors
- 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 “)
Stage IIIA, IIIB & IIIC Invasive Breast Cancers (locally advanced, non-inflammatory)
Choice of neoadjuvant regimen
- Inflammatory Breast Cancer (IBC) (Any T4d)
- 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
