Treatment/Prognosis

Question 1

What are the overall management options for early-stage breast cancers?

Answer 1

a. Lumpectomy (BCS) w/ surgical axillary staging + RT
b. Total mastectomy w/ surgical axillary staging +/– reconstruction
c. If T2 or T3 and fulfills criteria for BCS other than size, can consider preop systemic therapy with thorough staging f/b either a. or b.

Question 2

When should adj chemo be utilized in the management of early-stage node-negative breast cancers?

Answer 2

TN or HER2/neu (H2N +): tumor >1 cm (consider for tumor 0.6–1 cm)
ER+ AND H2N– AND tumor >0.5 cm: consider using 21-gene assay (Oncotype DX to determine role of adj chemo).

Question 3

What does the Oncotype DX score tell you?

Answer 3

Risk of distant recurrence within 10 yrs of Dx with 5 yrs endocrine therapy alone in ER+, N0 pts who undergo upfront Sg.

Low-recurrence score (<18) → adj endocrine Tx

Intermediate-recurrence score (18–30) → adj endocrine +/– chemo

High-recurrence score (≥31) → adj endocrine + chemo

Question 4

When should adj endocrine therapy be used in early-stage breast cancer?

Answer 4

ER+ AND tumor >0.5 cm (consider for tumors ≤0.5 cm)

Question 5

What are some general principles of administering adj endocrine therapy?

Answer 5

General principles for administration of adj endocrine therapy:

1. If the pt is premenopausal, tamoxifen (20 mg/day) is given for 5 yrs. Consider an additional 5 yrs of tamoxifen (if pt remains premenopausal) or an AI (Aromatase inhibitor).
2. If the pt is postmenopausal, AI × 5 yrs is the most common approach. For women who cannot or will not take an AI, tamoxifen × 5 yrs and consider an additional 5 yrs of tamoxifen.

Question 6

What is the major contraindication to the use of AIs?

Answer 6

Premenopausal status or unknown menopausal status. AIs are not effective in women with estrogen-producing ovaries.

Question 7

What are the major side effects of tamoxifen and AIs?

Answer 7

Tamoxifen: blood clots, strokes, uterine cancer, and cataracts. Gyn exam q12 mos should be performed in women with a uterus.

AI: bone loss and osteoporosis, as well as joint pain and stiffness. Bone mineral density should be assessed at baseline and monitored periodically.

Question 8

What are the major chemo agents used in breast cancer?

Answer 8

A: doxorubicin

E: epirubicin

C: cyclophosphamide or carboplatin

T: paclitaxel or docetaxel

F: 5-FU

H: trastuzumab

Question 9

What are the major chemo combinations used in breast cancer?

Answer 9

AC: doxorubicin + cyclophosphamide

EC: epirubicin + cyclophosphamide

FAC/FEC: 5-FU, doxorubicin/epirubicin, cyclophosphamide

AC/EC/FAC/FEC + T: the T is paclitaxel

TC: docetaxel + cyclophosphamide

TCH: docetaxel + carboplatin + trastuzumab

Question 10

What chemo regimens are recommended for HER2– tumors?

Answer 10

The preferred chemo regimens are:

1. Dose-dense AC (q2wk × 4 instead of q3wk × 4–6) f/b paclitaxel q2wk × 4
2. Dose-dense AC f/b paclitaxel q1wk × 12
3. TC q3wk × 4–6

Question 11

What chemo regimens are recommended for HER2+ tumors?

Answer 11

The preferred chemo regimens are:

1. AC f/b T plus concurrent trastuzumab +/– pertuzumab (various schedules), f/b single-agent trastuzumab q3wk for a total of 1 yr
2. TCH q3wk × 6 +/– pertuzumab, f/b single-agent trastuzumab q3wk for a total of 1 yr

Question 12

What data support the equivalence of BCT (lumpectomy + radiotherapy) to mastectomy with regard to survival?

Answer 12

Several large randomized trials (NSABP B06, Milan III, Ontario, Royal Marsden, EORTC 10801) support this, but B06 has the longest (20-yr) f/u data. Recent Oxford meta-analysis summarizes the data and survival outcomes:

NSABP B06 (Fisher B et al., NEJM 2002): 1,851 stages I–II pts randomized to (a) total mastectomy, (b) lumpectomy alone, or (c) lumpectomy + RT (50 Gy). 20-yr f/u results showed that there was no difference in DFS, OS, or DM.

EBCTCG Oxford meta-analysis (EBCTCG Collaborators, Lancet 2011): 10,801 women enrolled in 17 trials for BCS +/– RT. The 10-yr 1st recurrence risk reduction was 15.7% (19.3% in RT vs. 35% in BCS alone). The 15-yr breast cancer mortality was reduced by 3.8% (21.4% vs. 25.4%) with RT. Pts with pN0 Dz had 15.4% and 3.3% absolute reduction in recurrence and breast cancer mortality. Pts with pN+ Dz had 21.2% and 8.5% absolute risk reduction in recurrence and breast cancer mortality, respectively. For all risk groups, RT halves the risk of recurrence and decreases breast cancer mortality by one-sixth. For every 4 women prevented to have LR, 1 woman is saved (4:1 ratio).

Question 13

What % of pts are eligible for BCT for early-stage breast cancers?

Answer 13

In early-stage breast cancers, 75%–80% of pts are eligible for BCT. (Morrow M et al., Cancer 2006)

Question 14

What are the contraindications for BCT for pts with early-stage breast cancer?

Answer 14

Absolute contraindications for BCT in early-stage breast cancer: (NCCN 2018)

1. Prior RT to the chest
2. Extent of Dz that excision could not achieve –margins with an acceptable cosmetic result (note that multicentricity and multifocality are not necessarily contraindications to BCT).
3. Diffuse microcalcifications
4. 1st or 2nd trimester of pregnancy
5. Persistently +margin
6. Homozygous for ATM mutation

Question 15

Is there a contraindication for BCT in pts with a positive family Hx of breast cancer?

Answer 15

No. There is no evidence that demonstrates increased ipsi or contralat breast cancers in pts with a positive family Hx after BCT. (Vlastos G et al., Ann Surg Oncol 2007)

Question 16

Are BRCA mutations an absolute contraindication for BCT?

Answer 16

No. Multiple case-control studies have not established a higher IBTR rate in BRCA1/BRCA2 mutation carriers compared to wild-type individuals, particularly if oophorectomy is performed in BRCA carriers. However, contralat breast cancer development is a major risk for BRCA carriers. Contralat breast cancer risk can be reduced with tamoxifen, oophorectomy, or both, but is most effectively reduced with prophylactic total mastectomy. BRCA+ breast cancer pts who elect contralat prophylactic total mastectomy will frequently also choose an ipsi total mastectomy for Tx of their known breast cancer. Note that the NCCN guidelines do state that genetic mutations are a relative contraindication to BCT

Question 17

What are the dose fractionation schedules for WBI?

Answer 17

Standard fractionation schedules:

1. 50 Gy in 2 Gy fx
2. 45–50.4 Gy in 1.8 Gy fx

Hypofractionated schedules:

1. 42.56 Gy in 2.67 Gy fx
2. 40.05 Gy in 2.67 Gy fx

Question 18

What data support the use of hypofractionated WBI?

Answer 18

Per NCCN 2018, 4 randomized trials with ≥10-yr f/u suggest the same outcomes using a hypofractionated approach, with potentially better side effect profile. (Canadian, START pilot, START A/B trials)

Canadian regimen (Whelan TJ et al., JNCI 2002; Whelan TJ et al., NEJM 2010): RCT using 42.5 Gy in 16 fx (2.65 Gy/fx) vs. 50 Gy in 25 fx (2 Gy/fx) with no boost; 1,234 T1–2N0 pts, all with –SMs. Women with >25-cm breast width were excluded (to reduce heterogeneity of dose to the breast). 10-yr f/u: no difference in LR, DFS, or cosmesis. Good to excellent cosmesis was equivalent (71.3% standard vs. 69.8% hypofractionated).

British regimen (START A/B trials, Lancet 2008): 2,215 women with pT1–3N0–1 s/p Sg randomized to 50 Gy in 25 fx vs. 40 Gy in 15 fx (2.67 Gy/fx). Boost and adj systemic Tx were optional. After 10-yr f/u, there was no difference in IBTR (∼4%–5% START B; ∼6%–7% START A). Physician assessed markers of cosmetic outcome better with hypofractionation. Outcomes did not vary by age, BCS vs. mastectomy, nodal status, tumor grade, or the receipt of boost or adj chemo.

Question 19

According to ASTRO guidelines, who can be offered hypofractionated WBI?

Answer 19

ASTRO guidelines (Smith BD et al., IJROBP 2011 [note new guidelines are slated to be published 2017/2018]) state task force consensus for pts meeting all these criteria:

1. ≥50 yo
2. pT1–2N0, treated with BCS
3. No systemic chemo
4. Good homogeneity: dose along central axis +/– 7% of Rx dose.

Question 20

What data support the use of a tumor bed boost?

Answer 20

2 studies have demonstrated an improved LC rate with a 10–16 Gy boost after initial whole breast dose to 45–50 Gy. In general, a boost of 10–16 Gy should be considered particularly for pts at higher risk for LR (age <50 yrs, +LVI, or close SMs). This can be administered with brachytherapy, electrons, or photons.

EORTC boost trial (Bartelink K et al., JCO 2007; Bartelink et al., JCO 2015): 5,318 women with BCT, 10-yr update: 50 Gy vs. 50 Gy + 16 Gy boost (SM–) or + 26 Gy boost (SM+). 10-yr LF: 6.2% + boost vs. 10.2% – boost. Absolute benefit was greatest in women <50 b/c they have a higher risk of LR (24% – boost vs. 13.5% + boost for women <40 yo), but proportional benefits were seen across all age groups. No difference in 20-yr OS.

Lyon boost trial (Romestaing P et al., JCO 1997): 1,024 pts, 50 Gy vs. 50 Gy + 10 Gy boost. At 3-yr f/u, LF was reduced in the boost arm (3.6% vs. 4.5%).

Question 21

Is there a need for a higher tumor boost dose in pts with incomplete tumor excision after BCS?

Answer 21

No. In the EORTC boost trial, 251 pts with microscopically incomplete tumor excision were randomized to low (10 Gy) vs. high (26 Gy) boost. With median f/u of 11.3 yrs, there was no difference in LC or survival. There was significantly more fibrosis in the high-dose arm. (Poortmans PM et al., Radiother Oncol 2009)

Question 22

What is the next step in the management for a pt who undergoes a lumpectomy with a focal +margin?

Answer 22

This is controversial. Most would advocate taking the pt back to Sg for re-excision, which may diminish the 10-yr risk of LR to baseline levels (initial SM–: 7%, SM+: 12%; SM close: 14%; re-excision SM–: 7%, re-excision persistent SM+: 13%, re-excision persistent SM close: 21%). (Freedman G et al., IJROBP 1999)

Question 23

Is there a subset of women whose LR risk may not be substantially influenced by margin positivity after BCS?

Answer 23

Possibly. There are data to suggest that the effect of margin positivity on LR may be dependent on age <40 yrs. In an analysis of 1,752 pts, 193 were SM+. Overall 10-yr LR rate was 6.9% (SM–) vs. 12.2% (SM+). 5-yr LR rate for pts ≤40 yo was 8.4% (SM–) and 37% (SM+) (p = 0.005); for pts >40 yo, the LR rate was 2.6% (SM–) and 2.2% (SM+). (Jobsen JJ et al., IJROBP 2003)

Question 24

Should women with T1–2N0 invasive breast cancer treated with mastectomy to a +margin be treated with adj RT to the CW as well?

Answer 24

In a British Columbia retrospective study (Truong PT et al., IJROBP 2004), of 2,570 women with early-stage breast cancer treated with mastectomy, 94 pts had a +margin. About half (41 pts) were treated with PMRT. B/c of the small numbers, there was a trend to improvement with PMRT in pts >50 yrs, T2 tumor, grade III, and LVI. In pts without these features, there was no LR without PMRT.

Question 25

What is EIC?

Answer 25

EIC is defined as DCIS both admixed and adjacent to invasive Dz, and comprising >25% of the total tumor mass. DCIS with focal microinvasive Dz also fits this category.

Question 26

Does EIC have prognostic significance in the LR risk of pts treated with BCT?

Answer 26

Yes, but it is largely dependent on SM status. From studies mainly out of JCRT, EIC is only prognostic for LF if the margin status is considered. If there is a close or +margin, EIC is associated with a higher risk of recurrence. (Gage I et al., Cancer 1996)

Question 27

What data suggest that results of BCT can be further improved with the use of tamoxifen?

Answer 27

NSABP B21 (Fisher B et al., JCO 2002): 1,009 pts with ≤1-cm tumors s/p lumpectomy randomized to 3 arms: (a) tamoxifen alone (10 mg bid × 5 yrs), (b) RT alone (50 Gy), and (c) RT + tamoxifen. After 8-yr f/u, the IBTR was 16.5% with tamoxifen alone vs. 9.3% with RT alone vs. 2.8% with RT + tamoxifen. There was no difference in OS. No benefit was seen in ER– tumors. Contralat breast tumor recurrence was 0.9%, 4.2%, and 3.0% in the 3 arms, respectively.

Question 28

Are there pt subgroups with a low risk of LR who can be treated with BCS and systemic therapy alone without RT?

Answer 28

Yes. Recent trials suggest that pts with advanced age (≥65–70 yrs) and ER+ T1N0 tumors have an acceptably low rate of LR with Sg and endocrine Tx, although LR risk is further reduced by RT. The data suggest that the risk is very low only for pts >70 yo and possibly in those with very small tumors (<1 cm), so a discussion can be made about withholding RT if the pt is being treated with tamoxifen. The 3 most important trials are the Toronto, CALGB 9343/Intergroup, and PRIME II trials:

Princess Margaret Hospital/Canadian trial (Fyles AW et al., NEJM 2004): 769 women ≥50 yo (median age 68 yrs) with T1 or T2 (≤5 cm) –nodes (in women age ≥65 yrs, either clinical or pathologic evaluation was sufficient and SLN Bx was not routinely done) underwent lumpectomy to –margins and were randomized to (a) tamoxifen alone (20 mg/day × 5 yrs) vs. (b) tamoxifen + RT (40 Gy in 16 fx with a boost of 12.5 Gy in 5 fx). After 8-yr f/u, RT reduced LR from 17.6% to 3.5%. But for tumors ≤1 cm, the risk of relapse was 2.6% vs. 0% for the RT group (p = 0.02). In those ≥60 yo with ≤1-cm tumor, the risk was no different b/t the 2 arms (1.2% vs. 0%), but this was unplanned analysis with a short f/u.

CALGB 9343/Intergroup trial (Hughes KS et al., NEJM 2004; updated JCO 2013): 636 women ≥70 yo with T1, clinically N0, ER+ tumors were randomized to tamoxifen vs. tamoxifen + RT after lumpectomy with –margins. Axillary dissection was allowed but not encouraged. RT was 45 Gy to the whole breast with a boost of 14 Gy. At a median of 12.6-yr f/u, the 10-yr LF rate in the tamoxifen alone arm was 10% vs. 2% in tamoxifen + RT. There was no difference in time to mastectomy, DM, breast cancer survival, or OS.

PRIME II (Kunkler, Lancet Oncol 2015): 1,326 women ≥65 yo T1–T2 (up to 3 cm) N0, ER+ tumors receiving adj endocrine Tx randomized to WBI (40–50 Gy) or no RT. 5-yr IBTR 1.3% with RT and 4.1% no RT (p < .05). While addition of RT was SS, they question the need for RT given relatively low rates of recurrence.

Question 29

Can RT be used in the Tx of axillary nodes in place of Sg if axillary nodal dissection is not performed?

Answer 29

In certain cases. Previous era trials in cN0 pts (esp NSABP B04 and Institut Curie) have demonstrated equivalent LC, DM, and OS with nodal RT vs. axillary dissection. In the modern era, the AMAROS trial randomized SLN+ pts to completion ALND or nodal RT; 5-yr results showed no significant difference in LRR, DM, or OS and overall better arm function in the RT arm. (Donker M et al., Lancet Oncol 2014) 5-yr axillary recurrence 0.4% ALND vs. 1.2% with axillary RT.

Question 30

Are there data supporting WBI + RNI for early-stage breast cancer after BCS?

Answer 30

Yes. 2 randomized trials (MA.20 and EORTC 22922/10925) have examined this question. MA.20 (Whelan TJ et al., NEJM 2015) targeted women with +axillary nodes or –nodes but with high-risk features (≥5 cm tumor, or ≥2 cm tumors with inadequate nodal dissection or adverse tumor features. There was a decrease in regional recurrences (2.7% vs. 0.7%) with the addition of nodal irradiation to the upper axillary nodes, SCV region and IM nodes. Distant recurrence was also decreased from 17.3% to 13.4% and DFS increased from 77% to 82% at 10 yrs. EORTC 22922/10925 (Poortsmans PM et al., NEJM 2015) targeted women with centrally/medially localized primary tumor +/– axillary nodes or externally localized primary with + axillary nodes. At 10-yr f/u, there was a decrease in regional recurrences from 4.2% to 2.7% and a distant metastases rate decrease from 19.6% to 15.9%, as well as breast cancer mortality (14.4%–12.5% [HR 0.82, p = 0.02]). However, neither trials showed OS benefit.

Question 31

How should chemo be sequenced with radiotherapy after BCS?

Answer 31

JCRT sequencing trial (“Upfront-Outback” trial) (Bellon J et al., JCO 2005): per the initial report (Recht A et al., NEJM 1996), the 5-yr crude rate of distant recurrence was better in the chemo 1st arm (20% vs. 32%). However, in the 11-yr f/u update, there was no difference in DFS, LR, DM, or OS. For those with a –margin, the crude LR rate was 6% in the chemo 1st arm vs. 13% in the RT 1st arm. However, the study was not powered to show any differences. Thus, either sequence is acceptable, depending on pt convenience. Often, the Oncotype DX takes a few wks to return, and radiotherapy can be given in the meantime.

Question 32

What U.S. trial investigated the role of accelerated partial breast irradiation (APBI)?

Answer 32

NSABP B39/RTOG 0413, which randomized women with stage 0, 1, or 2 breast cancer with tumors ≤3 cm and ≤3 +LN to whole breast RT vs. APBI by any of 3 methods (interstitial, intracavitary, or EBRT). Publication pending.

Question 33

What is the dose and duration of Tx for APBI on the U.S. randomized trial?

Answer 33

34 Gy in 3.4 Gy bid fx for interstitial and intracavitary Tx and 38.5 Gy in 3.85 Gy bid fx for EBRT. All APBI is given over 5 days. The volume treated is the surgical cavity plus a 1-cm margin for brachytherapy and a 2–2.5 cm for EBRT.

Question 34

Who can be offered PBI?

Answer 34

ASTRO has published updated guidelines on who may be considered for PBI (Correa C et al., PRO 2017). “Suitable” pts are ≥50 yo, Tis or T1, with DCIS allowed only if screen-detected, low to intermediate grade, size ≤2 cm and resected with margins negative at ≥3 mm. Age 40–49 are allowed if all other “suitable” criteria are met. Pts ≥50 yo may have one of the adverse pathologic factors without DCIS >3 cm. Pts with <2 mm margins, DCIS ≤3 cm without meeting “suitable” criteria, or age <40 yrs should be considered cautionary.

Question 35

Is there good evidence to support the use of IMRT for WBI for early-stage breast cancer?

Answer 35

There is potentially data to indicate that homogeneous dose distribution of IMRT benefits pts in terms of acute effects and late-term cosmesis.

Canadian study (Pignol JP et al., JCO 2008) demonstrated in 358 pts that IMRT reduced the occurrence of moist desquamation c/w standard wedge technique (31.2% vs. 47.8%, p = 0.002). MVA shows breast IMRT and smaller breast sizes were associated with decreased risk of moist desquamation.

British study (Mukesh MB et al., JCO 2013) showed in 1,145 pts with 5-yr f/u that overall cosmesis was improved with IMRT c/wstandard techniques (OR 0.68, p = 0.027) as well as skin telangiectasia (OR 0.58, p = 0.021). This benefit was maintained on multivariable analysis. In these settings, IMRT refers to advanced planning techniques that can be achieved with forward planning with dose modulation.

Question 36

Are there subsets of women who undergo mastectomy for early-stage breast cancers (T1–2N0) who may benefit from PMRT?

Answer 36

Only in limited circumstances. NCCN 2018 guidelines recommend no RT for −axillary nodes, tumor ≤5 cm and margins ≥1 mm. For all other pts, the decision is based on other risk factors, including close or +margins, extensive LVSI, central/medial tumors, young age, etc. If there are +margins, tumor >5 cm, or +axillary nodes, RNI is recommended. PMRT in node-negative pts does not improve survival per EBCTCG 2005 meta-analysis data.

Question 37

How should a Dx of breast cancer be managed in a pregnant woman?

Answer 37

Management depends on the stage of pregnancy. Timing of Sg depends on need for chemo and RRs to fetus and mother. Chemo can be used to delay Sg until after delivery. Non-taxane chemo (most commonly, FAC) can be used in the 2nd and 3rd trimesters of pregnancy; chemo should be D/C 3 wks before expected delivery to reduce infection and bleeding risks. RT and endocrine therapy must be deferred until postpartum.