Trials

Question 1

Alliance A11102 (2024)

Answer 1

Phase 2. BCS for multi focal disease. *mcT1-2 cN0-1.
Age 40 or older with two to three foci of biopsy-proven cN0-1 BC, at least one focus being invasive , were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds.

At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4).

Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002).

Conclusion

The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

Question 2

SOUND (2024)

Answer 2

N = 1405. cT1 cN0 with negative pre-op axillary US. SLNB versus no SLNB for BCS only (no TM). 13.7% had positive SLN, but LRR, distant recurrence, death <2%. Median FU 5.7 years.
0.6% had 4+ positive LN (high risk).
98% had XRT (82% conventional, 10% ELIOT)
8.5-8.6% were ILC. 4.7-6.1% TNBC.
17.9-18.5% G3.

Conclusion: Omission of SLNB is non-inferior to SLNB in setting of XRT.

Considerations: Proceed with SLNB if axillary staging would change adjuvant recommendations (pre-menopausal, or G3 and potential candidates for CK4/6i due to node positivity), for ILC, or if XRT NOT planned.

Question 3

IDEA (2024)

Answer 3

Omission of adjuvant XRT with ET planned - pT1 pN0, age 50-69 (postmenopausal), Oncotype Dx 18 or less. ER and PR positive. HER2 negative. BCS, margins at least 2mm clear. XRT and ET x5y expected.
Axillary staging —> pN0
Note: 85% compliance with ET. 100% 5 year OS. 1% LRR. Median FU 5.2 years.
N=200 (feasibility study?). DEBRA seems to be the validation study.

Question 4

B-51 (2024)

Answer 4

Post-NACT regional node irradiation (RNI) versus no RNI for an axillary pCR (cN1 to pN0 after NACT). 80% had breast pCR as well, but not all. No difference in LRR, OS, or other outcomes. Median FU 60 months.

Conclusion: No added benefit for RNI in axillary pCR after NACT regardless of residual breast disease. Considerations: Tumor subtype analysis may show difference for TNBC, more data needed. TM performed in 41%.

Question 5

KATHERINE (2024 update)

Answer 5

Adjuvant TDM1 versus trastuzumab for residual disease after NACT for HER2 pos. At 8.4 years, 13.7% absolute benefit.

Question 6

DESTINY-04 (Phase III 2024)

Answer 6

T-Dxd (ADC: trastuzumab deruxtecan/Enhertu): HER2 LOW metastatic BCA (previously only treated HER2 3+).
ER/PR pos patients had to be refractory to ET
Trastuzumab deruxtecan improved median progression-free survival by 4.8 months and median overall survival by 6.6 months compared with standard single-agent chemotherapy in this heavily pretreated patient population.
Note: 15% developed idiopathic interstitial lung disease, treat with steroids.
Ongoing question: Can this replace TDM1 for residual disease? What is the optimal sequencing of ADC?

Question 7

COMPASSHER2 -pCR / EA1181 (Active -2024)

Answer 7

At least anatomic IIA (to IIIA): At least cT2 cN0 or cT1 cN1. Excludes cT4 and cN3. Ipsilateral tumors eligible if all are HER2 pos.
Evaluating de-escalation of carboplatin for NACT (wT/H/P - weekly paclitaxel, H/P)
If pCR, continue with adjuvant H/P (with or without XRT, with or without ET).
If residual Dx, proceed with TDM1.

 Note:  Weekly paclitaxel tolerated better than q3 week docetaxel, equivalent based on E1199
 Questions:  Are 6 cycles really necessary compared with 4?  Increased toxicity.

Question 8

COMPASSHER2 - RD / A11801 (Active 2024, at Renown)

Answer 8

After NACT for HER2 pos (de-escalated the carboplatin? T/H/P only? CompassHER2 pCR trial): Residual disease randomized to TDM1 x14 cycles (current standard) versus TDM1 plus tucatinib x14 cycles. Escalation trial.

Question 9

KEYNOTE 522 (2024 update)

Answer 9

Carboplatin and paclitaxel x12 weeks plus pembrolizumab for NACT (TNBC). Conclusions: Long term benefit even for those without pCR. EFS improved by 10%.
Note: Q 2week dosing is standard, but often not tolerated or not easily aligned with the pembro, so commonly, q 3week dosing is used instead.
Even PDL1 negative patients get benefit.
Questions: Is adjuvant pembro still needed if pCR? (Does tumor need to be present for benefit, plus toxicity concerns)

Question 10

NeoPACT (Phase II, 2024)

Answer 10

Anthracycline-free NACT regimen for TNBC: Carbo/paclitaxel/pembro. PCR 58%. RCB 0/1: 69%. Grade 3 AE: 3.5%.

Question 11

MonarchE (2024)

Answer 11

For high risk luminal BCA: Adjuvant ET versus ET plus abemaciclib (CK4/6i) for two years (total ET 10 years). Benefits persist beyond discontinuation of abemaciclib. 5,637 patients
Cohort 1 (n = 5,120 [91%]) included patients with either at least four positive pathologic axillary lymph nodes (pALNs) or one to three pALNs with additional high-risk features of either grade 3 disease or tumor ≥5 cm.
Cohort 2 (n = 517 [9%]) included patients with one to three positive pALNs and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%.
The addition of abemaciclib to ET also resulted in an improvement in DRFS compared with ET alone (HR, 0.675 [95% CI, 0.588 to 0.774]; nominal P < .001; Fig 1B). At 5 years, the absolute benefit in DRFS rates increased to 6.7% compared with 5.3%, 4.1%, and 2.5% at 4, 3, and 2 years, respectively

FDA approved abemaciclib in 2023 for high risk patients as defined by:
4 or more positive nodes
1-3 positive nodes and either G3 or tumor size 5cm or larger

Question 12

NATALEE (2024)

Answer 12

For high risk luminal: Adjuvant ribociclib for three years. Conclusion: Risk of invasive recurrence and DFS reduced by 25%. Note: Study included node neg as well as node pos, with similar overall outcomes.

Pre and post menopausal women and men with HR+/HER2- with
Stage IIA
pN0 with G2 and Ki67 20% or higher
pN0 with G3
pN1
ODx 26 or higher (or high risk via other genomic score)
Stage IIB (pN0 or N1)
Stage III
Prior ET and/or (neo)adjuvant CT permittted

Question 13

PALLAS AND PENELOPE (2024)

Answer 13

Adjuvant palbociclib showed NO benefit.

Question 14

Cancer and Acute Leukemia Group B (CALGB) 9343

Answer 14

Women age 70 years and older with clinical or pathologic stage I breast cancer treated with BCS and ET to receive or omit adjuvant radiotherapy. Locoregional recurrence at 10 years was 10% among those randomly assigned to omission and 2% among those assigned to radiotherapy.

Question 15

PRIME II

Answer 15

Post-Operative Radiotherapy In Minimum-Risk Elderly (PRIME)

Women age 65 years and older with node-negative tumors ≤3 cm in size treated with BCS and ET to receive or omit radiotherapy. The local recurrence rate at 10 years was 10% among those randomly assigned to omission, compared with 1% among those assigned to radiotherapy

Question 16

LUMINA

Answer 16

Prospective trial of BCS and ET without radiotherapy in Canada, which included patients age 55 years or older with pT1N0 grade 1-2 tumors resected with margins ≥1 mm with “luminal A” features:
ER ≥1%, progesterone receptor [PR] >20%, HER2-negative, and Ki67 ≤13.25%).
The cumulative incidence of local recurrence was 2.3% at 5 years.
However, the median age of patients was 67 years

Question 17

Florence phase III APBI vs WBI (2020)

Answer 17

10-year safety and efficacy of 5-fraction accelerated partial-breast irradiation with an external-beam intensity-modulated technique reported equivalent disease control to whole-breast irradiation while reducing patient burden and with improved cosmetic outcomes

Question 18

FAST FORWARD (XRT) 2020

Answer 18

Favorable 5-year outcomes after ultrahypofractionated 5-fraction whole-breast radiotherapy regimens. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results. Multicentre, non-inferiority.

Question 19

TAXIS (2024-2029)

Answer 19

TAS (targeted axillary surgery: Excision of biopsied and clipped node, palpable nodes, SLN, to “clear” the gross disease). cN+ to cN0. De-escalation of ALND to AXRT.
Includes upfront surgery and post-NST.
After confirmed nodal disease, randomized to either RNI including axilla, vs. cALND and RNI (avoiding us dissected axilla)

Question 20

ACOSOG Z0011

Answer 20

Patients with primary breast cancer ≤5 cm, palpably negative axillary LN, breast conserving surgery with adjuvant radiotherapy, and one or two SLN with metastases (i.e., micro- and macrometastases without gross extracapsular extension) in the removed lymph nodes were randomized to receive either ALND or no further axillary treatment. After 10 years, no differences in locoregional recurrence, disease-free and overall survival were noted

Question 21

AMAROS

Answer 21

patients with breast cancer up to 5 cm, clinically negative axilla, breast conserving surgery and whole breast irradiation or mastectomy, and tumor metastases in a SLN. Patients with either micro- (40% of patients) or macrometastases (60%) were randomly assigned to either ALND or axillary radiotherapy. After 10 years, no difference in axillary recurrence was noted, with strikingly low event rates in both groups, even though the comparison was formally underpowered. Furthermore no difference in overall survival, distant metastasis-free survival, and locoregional recurrence were reported

Question 22

OTOASOR

Answer 22

Patients with breast cancer ≤3 cm, cN0, who received breast conserving surgery or mastectomy and showed metastasis in at least one SLN (60% macrometastasis, 34% micrometastasis, 6% isolated tumor cells). This cohort was randomized to receive either regional nodal irradiation (RNI) or ALND (whereas 23% received ALND followed by RNI). After 8 years, no difference in regional recurrence, disease free survival and overall survival were seen.
Significantly increased rates of compound morbidity (lymphedema, arm swelling, arm pain, paresthesia, and decreased shoulder mobility) in the ALND group (15.3%), compared to the SLNB group (4.7%) after one year. The subgroup of patients receiving ALND followed by RNI showed even higher rates of compound morbidity of 31.5%

Question 23

IBCSG 23–01

Answer 23

patients with primary breast cancer ≤5 cm, breast conserving surgery or mastectomy, and one or more micrometastases (i.e., ≤2 mm without extracapsular extension) in the removed lymph nodes, could safely be spared ALND without any further therapy. After a median follow-up of 9.7 years, no differences in DFS was seen

Question 24

AATRM

Answer 24

(Smaller version of IBCSC-21) confirmed these findings, randomizing patients with micrometastases in the SLN and breast conserving surgery or mastectomy for primary breast cancer ≤3.5 cm and clinically unremarkable nodal status to either ALND or no further axillary treatment. After a median follow-up of 5 years, no differences in disease-free survival was noted

Question 25

SINODAR-ONE

Answer 25

3-year follow-up data as the first ACOSOG Z0011 validation trial. Here, SLNB was shown to be non-inferior compared to ALND for both survival and relapse rates in patients with primary breast cancers up to 5 cm, and up to two macrometastatic LN.
≥pN2 stage was present in 9.8–22% of patients undergoing ALND, with oncologic outcomes still not comprised.
The number of retrieved SLN correlates with a decreased false-negative rate, which is overall around 17%, but can be decreased to <10% when three or more lymph nodes are removed.
Importantly, 96.3% of lymph node metastases are identified when removing three SLN, compared to 99.1% once 5 SLN are removed

Question 26

ALMANAC

Answer 26

Assigning node-negative patients to either SLNB, with either delayed ALND or axillary radiotherapy if SLN positive, or upfront ALND, quality of life and morbidity were investigated as primary outcomes.
Lymphedema occurred significantly more often in patients receiving ALND (moderate or severe: 13% in ALND vs. 5% in SLNB group after 12-months)
Sensory deficits were more common after ALND (62% after ALND vs. 16% after SLNB one month postoperatively; and 31% vs. 11% after 12 months).
Shoulder motion showed significant differences in flexion and abduction after 1 month, which however was not evident subsequently

Question 27

DEBRA (Phase III active trial 2024)

Answer 27

NRG-BR007: A phase III trial evaluating de-escalation of breast radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, hormone receptor+, HER2-, RS ≤18 breast cancer. pT1N0M0. Axillary staging required (SLNB or ALND). Expected ET x5y.
Inclusion criteria seem identical to IDEA. Age over 50. Target N=1670 (validation of IDEA)
If Mammaprint already performed and found to be low risk, ok to use rather than also do ODx.

Question 28

NAUTILUS: No Axillary Surgical Treatment in Clinically Lymph Node-Negative Patients after Ultrasonography

Answer 28

phase III randomized controlled trial investigating whether SLNB can be safely omitted in clinically node-negative T1–2 breast cancer patients treated with breast-conserving therapy. The primary endpoint is 5 years of disease-free survival between the non-SLNB (study arm, n = 867) and SLNB (control arm, n = 867) groups. The secondary endpoints are overall survival, distant metastasis rate, regional recurrence rate, local recurrence rate, and self-reported complications.
Age: 19 or older.
CN0 or biopsy proven negative minimally suspicious axillary node.

Question 29

AXSANA (AXillary Surgery After NeoAdjuvant Treatment)

Answer 29

multinational prospective cohort study (NCT04373655) which enrolls cN+ patients undergoing NACT who convert to ycN0. Axillary staging procedures and treatment modalities are chosen at the discretion of the treating physicians and according to national and institutional guidelines. (Seems designed to just gather data and see what shakes out)

Question 30

PHERGAIN

Answer 30

Phase 2 RCT chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer

2024: 3 year IDFS 94.8%

Question 31

OFSET (NRG BR-009 - Active 2024)

Answer 31

Evaluating role of chemotherapy for premenopausal women undergoing OST/AI.
1. *pN0 with RS 21-25
2. *pN0 with RS 16-20 and high clinical risk (G1, tumor over 3cm; G2, tumor over 2cm; G3, tumor over 1cm)
3. *pN1 with RS 0-25
Addressing consideration for omitting chemo for patients 50 or older, small T1, limited nodal involvement, with commitment to compliance with OST and ET, especially if absolute or relative contraindications for chemo.

Question 32

Cctg MA.39 Tailor RT (phase 3, active since 2019)

Answer 32

Randomized trial of omitting regional radiotherapy in biomarker low-risk node-positive breast cancer.

Hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT

Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed.

Question 33

WSG-ADAPT-TP

Answer 33

Published 2022. Phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR).

Interpretation

The WSG-ADAPT-HER2+/HR– trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing.

Question 34

JBCRG20 study (Neo-peaks)

Answer 34

Phase 2. Long-term outcomes of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) and docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) for HER2-positive primary breast cancer.

Conclusions
In patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity.

Question 35

Z11102 : Local recurrence after BCT in pts with multiple ipsilateral breast cancer. (Phase 2 - 2023)

Answer 35

Women 40yo and older with two to three foci of biopsy proven N0-1. Lumpectomies with negative margins followed by WBI with boost to all lumpectomy beds.
N-204. Median FU 66 months.
5 year LRR = 3.1%.

Question 36

INSEMA

Answer 36

In this prospective, randomized, noninferiority trial, we investigated the omission of axillary surgery as compared with sentinel-lymph-node biopsy in patients scheduled to undergo breast-conserving surgery.

Clinical tumor stage of T1 or T2 (tumor size, ≤5 cm) and node-negative status according to clinical assessment (cN0) and imaging (iN0). Routine pre-op axillary ultrasonography. In cases of cN0 status in which ultrasonography indicated the presence of cancer in a lymph node (iN+ status), a negative core biopsy or a fine-needle aspiration biopsy of the lymph node was required before randomization. A cortical thickness greater than 2.5 mm or the absence of a fatty hilum were recommended as criteria for the identification of metastatic lymph nodes by axillary ultrasonography.

Patients who underwent sentinel-lymph-node biopsy and were found to have pathological sentinel-node–positive status (one to three macrometastases) underwent subsequent randomization in a 1:1 ratio to undergo completion axillary-lymph-node dissection or to proceed without dissection (having undergone sentinel-lymph-node biopsy alone).

All patients underwent unilateral breast-conserving surgery with postoperative whole-breast irradiation regardless of the intrinsic cancer subtype. Use of high tangents or regional nodal irradiation was not permitted except for patients with four or more axillary lymph node metastases.

In the surgery group, 579 of 3854 patients (15.0%) with sentinel lymph nodes detected and a known nodal status had cancer-positive sentinel nodes; 133 patients (3.5%) had micrometastases, 438 (11.4%) had one to three macrometastases, and 8 (0.2%) had at least four positive nodes. [How was this group then randomized? Not yet reported. Among the 253 patients who underwent completion axillary-lymph-node dissection, 169 (66.8%) had pathological N1 (pN1) cancer (one to three macrometastases) and 33 (13.0%) had pN2 cancer (at least four positive nodes) according to results for both sentinel and nonsentinel nodes.]

Patients in the surgery-omission group as compared with those in the surgery group had reduced incidence of lymphedema (1.8% vs. 5.7%), restriction of arm or shoulder mobility (2.0% vs. 3.5%), and pain with arm or shoulder movement (2.0% vs. 4.2%). Still 2% of pts had symptoms even if no axillary surgery performed

Conclusion: In clinically node-negative, T1 or T2 invasive breast cancer (90% with clinical T1 cancer and 79% with pathological T1 cancer), omission of surgical axillary staging was noninferior to sentinel-lymph-node biopsy after a median follow-up of 6 years. Only 527 patients (10.8%) were enrolled at less than 50 years of age. Over 90% were luminal subtypes. Nearly all were T1. *Cautious interpretation of data - this was NON-INFERIORITY. For HER2 pos and TNBC, still consider NACT. Nodal status still has implications for choice of XRT (WBI vs APBI), locations of XRT (axillary vs not), systemic therapy (CK4/6i, pertuzumab, etc).

Question 37

COMET (2 year reporting in 12/24, prelim)

Answer 37

Prospective, randomized noninferiority trial enrolling 995 women aged 40 years or older with a new diagnosis of hormone receptor–positive grade 1 or grade 2 DCIS without invasive cancer. Participants were randomized to receive active monitoring (follow-up every 6 months with breast imaging and physical examination; n = 484) or guideline-concordant care (surgery with or without radiation therapy; n = 473). The primary outcome was 2-year cumulative risk of ipsilateral invasive cancer diagnosis. Felt to be NON-INFERIOR.

Patients randomized to guideline-concordant care could choose either lumpectomy or mastectomy for surgery. Patients who opted for lumpectomy were offered RT. Patients in both groups could opt for endocrine therapy. Follow-up mammograms occurred at 12-month intervals.

In the active monitoring arm, patients had diagnostic mammograms every 6 months for the affected breast and every 12 months for the unaffected breast. If a new lesion developed or imaging detected concerning changes in breast tissue, a core needle biopsy was recommended. Surgery was required if the biopsy revealed invasive cancer. For benign breast changes, atypia, or DCIS, continued active monitoring was recommended. Patients who wished to have surgery at any time, for any reason, proceeded to surgery in consultation with their treating surgeon, with the reason for surgery and pathology diagnosis at surgical excision recorded.

The 2-year Kaplan-Meier cumulative rate of ipsilateral invasive cancer was 4.2% in the active monitoring group vs 5.9% in the guideline-concordant care group, a difference of −1.7% (upper limit of the 95% CI, 0.95%), indicating that active monitoring is not inferior to guideline-concordant care. However, in the subset who actually had surgery, the 2-year rate of invasive cancer increased to 8.7% (Dr. Morrow). Also, only 50% of those in the “guideline-concordant” arm received surgery at 6 months.

In support of their viewpoint, Morrow and Barrio cited recent studies of surgery for low-risk DCIS. The ECOG-ACRIN E1594 trial showed 12-year rates of any ipsilateral breast events and invasive events of 14.4% and 7.5%, respectively, with no plateau in either rate. In the RTOG 9804 trial, patients with DCIS were randomized to surgery alone or with radiotherapy (RT). In the surgery-alone group, the 15-year rates of any recurrence and invasive recurrence were 15.1% and 9.5%. A joint analysis of NSABP B-17 and B-24 and a separate analysis of EORTC 10853 showed that invasive recurrence after treatment for DCIS was associated with an increased risk of breast cancer mortality compared with no recurrence.

* Adjuvant radiation was received by 26.6% of women (n = 126) in the guideline-concordant care group compared with 7.4% (n = 36) in the active monitoring group. Chemotherapy was received by 5 women (1.1%) in the guideline-concordant care group and 6 (1.2%) in the active monitoring group.*

Patients in both groups could elect to take endocrine therapy in consultation with their treating physician. Around 70% of pts used ET in BOTH groups. Could this have lowered rate of subsequent invasive cancer?

Question 38

SUPREMO (BIG 2-04 MRC) - presented at ASCO 2024 but not yet published

Answer 38

Takeaway: PMRT does not improve survival in intermediate risk BCA, even if 1-3 pos nodes. (Still give for 4 or more). OS 81-82% at 10y regardless of PMRT.
Per Hardacre:
If favorable histology and 1-2 pos nodes, avoid PMRT.
If unfavorable histology and/or 3+ pos nodes, consider PMRT.