oncology grand rounds

Endocrine Therapy for Primary and

Secondary Prevention After Diagnosis of
High-Risk Breast Lesions or Preinvasive
Breast Cancer
Alison Laws, MD, MPH1 and Rinaa S. Punglia, MD, MPH2

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical
context. A case presentation is followed by a description of diagnostic and management challenges, a review of
the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this
series is to help readers better understand how to apply the results of key studies, including those published in
Journal of Clinical Oncology, to patients seen in their own clinical practice.
Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast
cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer
improved survival, thus the side effects of primary/secondary prevention must be considered relative to the
benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations
for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for
patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens
differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg
once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase
inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to
patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a
particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable
risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and
appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy
that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing
in the setting of secondary prevention.

CASE PRESENTATION 1 estrogen receptor (ER)–positive breast cancer. As

A 45-year-old premenopausal woman presents for such, clinical management centers around diligent
annual screening breast magnetic resonance imaging screening with breast imaging and use of chemo-
(MRI) because of elevated lifetime breast cancer risk. prevention medications.
Her risk factors include a family history of breast cancer
in her mother at age 55 years as well as extremely dense There is level I evidence supporting the efficacy of both
mammographic breast density. Prior panel genetic selective estrogen receptor modulators (SERMs) and
testing was negative for pathogenic mutations. She has aromatase inhibitors (AIs) for breast cancer risk re-
ASSOCIATED no current breast complaints. Screening MRI identifies duction (Table 1). The landmark National Surgery
CONTENT a 2-cm area of linear nonmass enhancement in the Adjuvant Breast and Bowel Project (NSABP) P-1 trial
See accompanying lower outer quadrant of the right breast (Fig 1). MRI- randomized premenopausal and postmenopausal
article on page 3116 women to 20-mg once-daily tamoxifen for 5 years
guided core needle biopsy is performed demonstrating
Author affiliations versus placebo. Tamoxifen was associated with a
atypical ductal hyperplasia (ADH).
and support 49%-50% relative risk reduction in invasive and
information (if Case 1: Clinical Challenges in Evaluation
applicable) appear
noninvasive breast cancer events, with even greater
and Treatment risk reduction (86%) in women with history of AH.1
at the end of this
article. High-risk breast lesions (HRLs) including atypical However, tamoxifen increased the risk of endometrial
Accepted on March hyperplasia (AH) and lobular carcinoma in situ cancer (absolute annual risk per 1,000: 2.3 v 0.9) and
24, 2023 and (LCIS) confer a moderately elevated risk of breast venous thromboembolic events (VTEs; absolute an-
published at nual risk of pulmonary embolism/deep vein throm-
cancer, with long-term (15-year) absolute risks of
ascopubs.org/journal/
jco on May 1, 2023:
19%-26% or approximately 1%-2%/y. HRLs are bosis per 1,000: 2.0 v 1.0), both occurring primarily in
DOI https://doi.org/10. well-established indicators of both ipsilateral and women age 50 years and older. Hot flashes and
1200/JCO.23.00455 contralateral risk, the majority of which being vaginal discharge were more common with tamoxifen;

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Endocrine Therapy of HRLs or Preinvasive Breast Cancer

poor (6%-25% of eligible patients). Perceived and actual

side effects have been consistently identified barriers to both
uptake and adherence, particularly with tamoxifen 20 mg
once daily.
The more recent Tam01 study randomly assigned 500 pre-
menopausal or postmenopausal women to low-dose (5 mg
once daily) tamoxifen for a shorter duration (3 years) versus
placebo. In the trial’s initial publication, at 5-year median
follow-up, tamoxifen 5 mg once daily was associated with 52%
reduction in invasive or noninvasive breast cancer.9 In the
FIG 1. A 45-year-old woman with 2 cm of nonmass enhancement companion to this article, Lazzeroni et al8 report a durable
in the lower outer quadrant of the right breast. 42% risk reduction at nearly 10 years of median follow-up.
Unlike with tamoxifen 20 mg once daily, there does not ap-
for example, quite a bit or extremely bothersome hot flashes pear to be an increased risk of endometrial cancer or VTE with
were reported by 46% versus 29% on placebo. These 5 mg once daily, although the sample size may be too small to
findings from NSABP P-1 were consistent across several capture these rare events. Women on tamoxifen 5 mg once
other trials in both premenopausal and postmenopausal daily reported significantly more hot flashes, although the
subgroups, with continued long-term (15-year) risk re- absolute difference from placebo was small (mean 2.1/d v 1.5/
duction after tamoxifen cessation.2-5 d), with no differences in hot flash intensity or vaginal or
Raloxifene was first identified as a breast cancer prevention musculoskeletal symptoms.8
agent as a secondary finding of the Multiple Outcomes of Given the comparator for the Tam01 study was placebo,
Raloxifene trial, which evaluated raloxifene in postmeno- direct comparisons of low-dose tamoxifen versus traditional
pausal women with osteoporosis with a primary end point of chemoprevention regimens are lacking. Nonetheless, the
vertebral fractures. The subsequent NSABP Study of Ta- effect measures appear comparable even with long-term
moxifen and Raloxifene (STAR) trial randomly assigned follow-up, despite an arguably higher-risk population, given
postmenopausal women to 5 years of tamoxifen 20 mg the inclusion of patients with DCIS. The excellent side-
once daily versus raloxifene 60 mg once daily.5 Raloxifene effect profile of low-dose tamoxifen further supports the
was 76% as effective as tamoxifen at preventing invasive adoption of this regimen in the context of poor uptake and
breast cancer, a statistically significant difference, with an adherence with traditional regimens. As such, tamoxifen
extrapolated relative risk reduction of 38%. Unlike ta- 5 mg once daily for 3 years is now recommended by
moxifen, raloxifene was not associated with increased multiple clinical practice guidelines.
endometrial cancer risk and had 25% less VTE risk.
At our institution, we consider and discuss chemo-
Finally, the Mammary Prevention.3 (MAP.3) trial6 and In- prevention with all patients age 35-70 years diagnosed with
ternational Breast Cancer Intervention Study II (IBIS-II)7 HRLs, emphasizing a shared decision-making approach.
evaluated the AIs exemestane 25 mg once daily and Other breast cancer risk factors such as BMI and family
anastrozole 1 mg once daily, respectively, versus placebo in history do not significantly modulate risk in this population,
postmenopausal women. Both AIs reduced the risk of in- and traditional personalized risk calculators such as the
vasive and noninvasive breast cancer by 53% at 3 to Tyrer Cuzick model perform poorly. Thus, we counsel
5 years of follow-up, with an even greater effect again seen women of a 1%-2% annual breast cancer risk, tailoring
among women with history of AH/LCIS (63%-69%). No-
long-term risk estimates to patient age. Choice of regimen is
tably, risk reduction with anastrozole beyond the 5-year dependent on menopausal status, side-effect profile, and
treatment duration was smaller (37%), although still signif- the patient’s motivations, preferences, and risk tolerance.
icant. Vasomotor symptoms and vaginal dryness were more None of the chemoprevention trials have demonstrated a
common with AIs, along with arthritis/arthralgias and joint survival benefit, thus we have a relatively low threshold to
stiffness, although absolute differences in musculoskeletal discontinue therapy if not well tolerated.
symptoms were small (,5%). There was no increased
In premenopausal women, we favor a goal of tamoxifen
fracture risk or bisphosphonate use with AIs, nor increased
20 mg once daily for 5 years, given more robust long-term
risks of any secondary cancers or VTE.
data and lesser risk of serious adverse events such as VTE
Thus, tamoxifen 20 mg once daily, raloxifene, anastrozole, and endometrial cancer in this age group. A prior subgroup
and exemestane have served as the available chemo- analysis of Tam01 suggested less efficacy of tamoxifen
prevention regimens for the past two decades, although 5 mg once daily in premenopausal versus postmenopausal
tamoxifen 20 mg once daily has been the only option for patients (27% v 70% risk reduction), although this inter-
premenopausal patients. Despite the clinically significant action was not statistically significant.10 In this updated
risk reducing effects of these medications, uptake has been analysis, differences in effect by menopausal status

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3094 © 2023 by American Society of Clinical Oncology

TABLE 1. Randomized Chemoprevention Trials With Breast Cancer Primary End Points
Median
Trial Population Randomization Follow-Up, Years Breast Cancer Outcomes
NSABP P-11 N 5 13,388 Tam v placebo (5 years) 5 Invasive: RR, 0.49
Age 35-70 years, premenopausal and postmenopausal, Noninvasive: RR, 0.50
$1 risk factor: age ,60 years or 5-year Gail risk
$1.66% or HRL history
IBIS-I2 N 5 7,154 Tam v placebo (5 years) 16 Invasive 1 DCIS: HR, 0.71 (95% CI, 0.60 to 0.83)
Age 35-70 years, premenopausal and postmenopausal, all ER-positive: HR, 0.66 (95% CI, 0.54 to 0.81)
$23 increased risk by family history/HRL history
Royal Marsden trial3 N 5 2,471 Tam v placebo (8 years) 13 Invasive 1 DCIS: HR, 0.84 (95% CI, 0.64 to 1.10)
Age 30-70 years, premenopausal and postmenopausal, ER-positive: HR, 0.61 (95% CI, 0.43 to 0.86)
family history
Italian Tamoxifen study4 N 5 5,408 Tam v placebo (5 years) 11 Invasive 1 DCIS: RR, 0.84 (95% CI, 0.60 to 1.17)
Age 35-70 years, premenopausal and postmenopausal, High-risk cohort (exploratory): RR, 0.24 (95% CI,
average-risk with hysterectomy 0.10 to 0.59)
STAR5 N 5 19,747 Raloxifene v Tam (5 years) 7 Invasive: RR (Raloxifene:Tam), 1.24 (95% CI,

Laws and Punglia

Age $35 years, postmenopausal, 5-year Gail risk $1.66% 1.05 to 1.47)
Noninvasive: RR (Raloxifene:Tam), 1.22 (95% CI,
0.95 to 1.59)
MAP.36 N 5 4,560 Exemestane v placebo (5 years) 3 Invasive 1 DCIS: HR, 0.47 (95% CI, 0.27 to 0.79)
Age $35 years, postmenopausal, $1 risk factor: age ER-positive: HR, 0.27 (95% CI, 0.12 to 0.60)
,60 years, 5-year Gail risk $1.66%, HRL or DCIS
history
IBIS-II7 N 5 3,864 Anastrozole v placebo (5 years) 11 Invasive 1 DCIS: HR, 0.51 (95% CI, 0.39 to 0.66)
Age 40-70 years, postmenopausal, all $1.53 increased ER-positive: HR, 0.46 (95% CI, 0.33 to 0.65)
risk by family history/gynecologic risk factors/HRL or
DCIS history
Tam018 N 5 500 Low-dose Tam v placebo (3 years) 10 Invasive 1 DCIS: HR, 0.58 (95% CI, 0.35 to 0.95)
Age #75 years, premenopausal and postmenopausal,
ER- or PR-positive ADH, LCIS, or DCIS

Abbreviations: ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HR, hazard ratio; HRL, high-risk breast lesion; IBIS-I, International Breast Cancer Intervention
Study I; IBIS-II, International Breast Cancer Intervention Study II; LCIS, lobular carcinoma in situ; Low-dose Tam, 5 mg once daily; MAP.3, Mammary Prevention.3; NSABP, National Surgery Adjuvant Breast
and Bowel Project; PR, progesterone receptor; RR, relative risk; STAR, Study of Tamoxifen and Raloxifene; Tam, tamoxifen 20 mg once daily.
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 Endocrine Therapy of HRLs or Preinvasive Breast Cancer

interestingly were lesser in magnitude (33% v 57%). tamoxifen 20 mg once daily as recommended, but experi-
Depending on the patients’ aversion to potential adverse enced bothersome daily hot flashes. After 12 weeks without
effects, we may either initiate 5 mg once daily with a plan to any improvement, the tamoxifen dose was reduced to 5 mg
titrate up to 20 mg once daily or begin with 20 mg once daily once daily and the hot flashes resolved. She continues on
with a contingency plan to reduce the dose to 5 mg once this dose with a plan to complete at least 3 years of therapy.
daily if not well tolerated. For those who cannot tolerate
20 mg once daily, completing a 5-mg once-daily course is CASE PRESENTATION 2
still a preferred option to no therapy.
A 61-year-old postmenopausal woman is determined to
In postmenopausal women, we typically recommend low- have an 8-mm cluster of calcifications in the central right
dose tamoxifen as first-line therapy and do not strongly breast noted on routine screening mammography. Mag-
advocate for 20 mg once daily. Patients with contraindi- nification views confirm fine linear calcifications (Fig 2),
cations to SERMs, such as personal history of VTE, are and stereotactic core needle biopsy is recommended.
offered an AI. In those with osteoporosis, we may consider Biopsy pathology reveals ductal carcinoma in situ (DCIS),
raloxifene for its additional fracture reduction benefits, comedo-type with 85% ER staining, intermediate to high
recognizing the moderately decreased efficacy compared nuclear grade. The patient’s medical history is notable for
with other chemoprevention regimens. hyperlipidemia treated with a lipid-lowering agent. Family
Whether the option of tamoxifen 5 mg once daily for 3 years history is significant for a sister with invasive breast cancer
will translate into increased use of chemoprevention re- diagnosed at age 62 years. Genetic testing revealed no
mains to be seen. In our experience, after adopting low- pathogenic mutations, and breast-conserving surgery was
dose tamoxifen, we observed a nonsignificant 5% increase selected. Pathology revealed high-nuclear-grade DCIS over
in chemoprevention uptake in both premenopausal and a 9-mm area with closest margin to the specimen edge at
postmenopausal patients. One-year discontinuation rates .2-mm distance. The patient wishes to consider adjuvant
were nonsignificantly lower for those on tamoxifen 5 mg therapy options.
once daily compared with all other regimens (7% v 15%-
Case 2: Clinical Challenges in Evaluation and Treatment
20%).11 Ongoing follow-up and other real-world data are
needed in this area. The incidence of DCIS has increased corresponding to the
adoption of screening mammography. Over 70% of DCIS
Case 1: Our Approach to Management cases are now treated with breast-conserving surgery, and
The patient was seen in consultation by a breast surgeon. in more than half of these patients, radiation therapy (RT) is
Surgical excision of the area was performed, confirming the added, although there is significant regional variation in its
diagnosis of ADH with no underlying in situ or invasive use. Endocrine therapy is used in fewer than half of eligible
malignancy identified. She was counseled that in the setting
of ADH, her subsequent breast cancer risk was approxi-
mately 1%/y. We do not routinely recommend screening
breast MRI for this moderate-risk population; however, given
her extremely dense breast tissue on mammogram, she was
recommended to continue screening MRI in addition to
annual screening mammograms.
The surgeon recommended a trial of chemoprevention,
citing the association of ADH with ER-positive breast cancer
and the particularly excellent risk reduction in those with AH.
Given her premenopausal status, tamoxifen was recom-
mended, preferably at 20 mg once daily for 5 years, which
would result in $50% risk reduction. The option of 5 mg
once daily for 3 years was also discussed, recognizing a
possibly smaller magnitude of risk reduction (approximately
30%) in premenopausal women. Tamoxifen at both doses
has also been associated with reduction in breast density,
which may improve the sensitivity of her screening mam-
mograms. Serious but rare risks of VTE and endometrial
cancer with tamoxifen 20 mg once daily (but not 5 mg once
daily) were reviewed; the patient had no risk factors for ei-
ther. More common nuisance estrogen deprivation side FIG 2. A 61-year-old woman with 8 mm
effects were discussed, in addition to the more favorable of calcifications in the central right
profile of tamoxifen 5 mg once daily. The patient initiated breast.

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 Laws and Punglia

patients and is associated with use of RT.12 Long-term breast, the effect of endocrine therapy on ipsilateral breast
outcomes of endocrine therapy and RT after breast- cancers after DCIS is unclear. The NSABP B-24 sought to
conserving surgery for DCIS have been consistently shown determine the impact of tamoxifen in addition to RT after
to reduce the risk of future breast cancer diagnoses.13,14 breast-conserving surgery for DCIS. Patients were enrolled
However, the lack of survival benefit seen with these without testing for ER status. When ER staining was per-
treatments, even with meta-analyses of randomized trials,14 formed in 41% of the enrolled cohort, any benefit of ta-
renders decision making about DCIS therapy complicated. moxifen was restricted to the ER1 cohort.13 Tamoxifen
decreased the risk of any breast cancer diagnosis among
RT. Randomized clinical trials comparing lumpectomy ER1 patients (HR, 0.58; 95% CI, 0.415 to 0.81;
followed by radiotherapy to lumpectomy alone established P 5 .0015). However, while this benefit was statistically
a local control benefit for radiotherapy in the treatment of significant for contralateral breast cancers when analyzed
patients with DCIS. About half of the breast events with or separately (HR, 0.50; 95% CI, 0.28 to 0.88; P 5 .02), it did
without RT in the trials were recurrence of in situ disease not reach significance for ipsilateral cancers (HR, 0.68;
with the other half development of invasive disease. The 95% CI, 0.44 to 1.03; P 5 .07), suggesting that the benefit
Early Breast Cancer Trialists’ Collaborative Group meta- to endocrine therapy after RT for the breast diagnosed with
analysis of individual patient data from four seminal trials DCIS is modest.
showed that the addition of adjuvant radiotherapy reduced
the 10-year risk of either recurrent DCIS or invasive cancer in Tamoxifen was compared with anastrozole as adjuvant
the ipsilateral breast by 15% in all patients, regardless of age, therapy in two large double-blinded randomized trials of
margin status, use of tamoxifen, focality, grade, or tumor postmenopausal patients with DCIS. In the IBIS-II DCIS study,
size. However, there was no improvement in breast cancer– where 71% of patients had also received radiation, the two
specific mortality or all-cause mortality with radiotherapy.14 endocrine regimens revealed no clear differences at a median
follow-up of 7.2 years in terms of efficacy or adherence.17 By
By contrast, an analysis specifically studying the impact of contrast, the NSABP B-35 study, where all participants had
having an invasive cancer diagnosis in the ipsilateral breast undergone RT, revealed a small benefit to anastrozole over
using data from the NSABP B-17 and B-24 trials found that tamoxifen for all breast events (HR, 0.73; 95% CI, 0.56 to
having such a recurrence after DCIS treatment increased 0.96; P 5 .02) and those in the contralateral breast (HR,
risk of mortality with a hazard ratio of 1.75 for death (95% 0.64; 95% CI, 0.43 to 0.96; P 5 .03), but not the ipsilateral
CI, 1.45 to 2.96; P , .001).15 In contrast to invasive di- breast (HR, 0.83; 95% CI, 0.56 to 1.22; P 5 .34), at a median
agnoses, DCIS recurrence was not associated with in- follow-up of 9 years.18 However, this benefit to anastrozole
creased risk of mortality. However, both types of diagnoses, was restricted only to women younger than 60 years (HR for
invasive cancer or recurrence of DCIS, lead to additional breast cancer–free interval, 0.53; P 5 .0026) versus those
morbidity including additional imaging, surgery, and po- age 60 years and older (HR, 0.95; P 5 .78).
tentially systemic treatment.
The only randomized study to isolate the effect of endocrine
The benefit in terms of ipsilateral risk reduction with ra- therapy on DCIS outcomes was the UK, Australia, and New
diation appears to be increasing in more recent years Zealand (UK/ANZ) study, which included an endocrine
(Table 2), perhaps due to improvements in imaging, therapy randomization as well as a RT randomization.19
pathologic evaluation, or radiation localization. Consider- However, because patients were allowed to select which
able work has gone into identifying subgroups of patients randomization to enter (endocrine therapy, RT, or both),
who may be at low enough risk of local recurrence without the four arms were not completely balanced. Nevertheless,
RT as the absolute benefit of radiation is proportional to this study revealed that the benefit of tamoxifen on ipsi-
underlying risk of recurrence. The Eastern Cooperative lateral events was small and restricted only to patients who
Oncology Group-American College of Radiology Imaging had not received RT (HR, 0.77; 95% CI, 0.59 to 0.98; P 5
Network E5194 was a single-arm prospective trial of .04) versus those who had received radiation (HR, 0.93;
lumpectomy alone where eligible patients had margin width 95% CI, 0.50 to 1.75; P 5 .8).
3 mm or more and either low- or intermediate-grade DCIS
# 2.5 cm in size (cohort 1) or high-grade DCIS # 1 cm in The reduction of breast cancer diagnoses with low-dose
size (cohort 2). The study found 12-year rates of ipsilateral tamoxifen presented in the TAM-01 study was significant
breast cancer to be 14.4% for cohort 1 and 24.6% for with a HR of 0.50 (95% CI, 0.28 to 0.91; P 5 .02) among
cohort 2 despite the smaller size of DCIS in the second the subset of patients with DCIS.8 However, this benefit was
cohort.16 The 12-year rate of invasive ipsilateral breast not separated by location (ipsilateral or contralateral breast) for
cancer was 13.4% for cohort 2 in this study, suggesting that patients with DCIS in the current or previous reports of the
grade may be an important factor when deciding whether or study. And among patients who received RT (45% of cohort,
not to pursue radiation. and assuming radiation was restricted to DCIS, 62% of the
patients with DCIS), the benefit of low-dose tamoxifen on
Endocrine therapy. Although endocrine therapy is known to breast diagnoses did not meet significance (HR, 0.67; 95%
decrease the risk of new breast cancers in the contralateral CI, 0.32 to 1.39). These findings again suggest that the benefit

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Journal of Clinical Oncology

TABLE 2. Ipsilateral and Contralateral Breast Cancer Risks for DCIS in Selected Trials
Endocrine Ipsilateral Breast Event Annual Ipsilateral Contralateral Breast Event Annual Contralateral
Trial Arms Therapy Use Risk/Follow-Up, %/Y Event Risk, % Risk/Follow-Up, %/Y Event Risk, %
NSABP B-1715 BCS alone None 35.0/17.2 3.35 7.9/17.2 0.76
BCS 1 RT None 19.8/17.2 1.65 7.9/17.2 0.77
ECOG-ACRIN E519416 Cohort 1—no RT 31% 14.4/12 1.29a 6.7/12 0.58a
a
Cohort 2—no RT 24% 24.6/12 2.32 12.0/12 1.06a

Endocrine Therapy of HRLs or Preinvasive Breast Cancer

NSAPB B-2415 RT alone None 16.6/13.6 1.62 8.1/13.6 0.79
RT 1 Tam All 13.2/13.6 1.22 4.9/13.6 0.45
IBIS-II DCIS 17
Tam 6 RT 67% 3.0/7.2 0.42 a
2.1/7.2 0.29a
AI 6 RT 67% 2.8/7.2 0.40 a
1.7/7.2 0.24a
NSABP B-3518 Tam 1 RT 70% 3.6/9 0.40a 3.9/9 0.44a
AI 1 RT 70% 3.0/9 0.34a 2.5/9 0.29a
19
UK/ANZ BCS alone None 25.4/10.0 2.54 5.3/10.0 0.53
RT alone None 9.0/11.3 0.79 2.6/11.3 0.23
RT 1 Tam All 7.0/11.2 0.62 2.8/11.2 0.25
Tam alone All 19.8/10.6 1.86 1.9/10.6 0.18
Tam018 6RT None 12/9.7b 1.3a 8/9.7b 0.86a
Low-dose Tam 6 RT All 7/9.7b 0.7a 3/9.7b 0.31a

Abbreviations: AI, anastrozole; BCS, breast-conserving surgery; DCIS, ductal carcinoma in situ; ECOG-ACRIN, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network;
IBIS-II, International Breast Cancer Intervention Study II; Low-dose Tam, 5 mg once daily; NSABP, National Surgery Adjuvant Breast and Bowel Project; RT, radiation therapy; Tam, tamoxifen 20 mg once
daily; UK/ANZ, UK, Australia, and New Zealand.
a
Estimated with constant rate assumption.
b
Estimated from Kaplan-Meier plot of total and contralateral events.
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 Laws and Punglia

of tamoxifen in addition to radiation is small, and appears to be this patient met with a radiation oncologist and surgeon to
driven mainly by a reduction in contralateral breast diagnoses discuss the risks and benefits of radiation and endocrine
or new breast cancers, secondary prevention. therapy in context of the surgical pathology. The benefits of
Independent decisions. Updated results from a random- radiation in terms of reduction in local recurrence were
ized study of radiation for patients with low-risk DCIS presented relative to the risks of radiation and treatment
reveal that the reduction in actual endocrine therapy use burden. Likewise, the benefits of endocrine therapy, es-
relative to intended usage was four-fold greater among pecially related to prevention of future breast events, were
those who received radiation.20 Patients may be more described relative to side effects.
likely to discontinue endocrine therapy if they have had Given the elevated risk of recurrence conferred by the high
some form of adjuvant treatment—a phenomenon only grade of this patient’s DCIS (both elevated ipsilateral and
uncovered when comparing balanced groups versus retro- contralateral risk), she opted to pursue a hypofractionated
spective comparisons, which are likely to have confounding. course of radiation with a boost. After completion of RT, she
The benefit of RT is restricted to the ipsilateral breast, will try tamoxifen 5 mg once daily under the care of an NP
whereas that of endocrine therapy seems mainly through specifically designated to manage endocrine therapy side
reduction in contralateral breast events. If patients wish to effects, with a low threshold to discontinue should these
receive at least one form of adjuvant therapy, foregoing effects not be acceptable.
radiation, which is generally recommended to begin within
In conclusion, endocrine therapy for HRLs or preinvasive
2-3 months from surgery, may be difficult, given that tol-
breast lesions may be primarily thought of as primary/
erance of endocrine therapy cannot be easily ascertained
secondary prevention of new breast cancers. Given the
during this time period.
lack of demonstrable survival benefit with endocrine
Case 2: Our Approach to Management therapy for these lesions, communicating the benefits and
Newly diagnosed patients with DCIS meet with their sur- risks of treatment options, as well as assessing the burden
geon and have an option to meet with a radiation oncologist imposed by treatment for an individual patient, is critical in
to discuss treatment options around the time of their initial ensuring treatment is consonant with patient preferences.
consultation. Patients with DCIS are given information The favorable side-effect profile and absence of risk of
about available clinical trials with a focus on patient- serious adverse events with low-dose tamoxifen may make
centered decision making. After breast-conserving surgery, this prevention strategy more feasible.

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

1
Division of Breast Surgery, Department of Surgery, Brigham and INTEREST
Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA Disclosures provided by the authors are available with this article at DOI
2
Department of Radiation Oncology, Brigham and Women’s Hospital/ https://doi.org/10.1200/JCO.23.00455.
Dana-Farber Cancer Institute, Boston, MA

AUTHOR CONTRIBUTIONS
CORRESPONDING AUTHOR Conception and design: All authors
Alison Laws, MD, MPH, Division of Breast Surgery, Department of Collection and assembly of data: All authors
Surgery, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Data analysis and interpretation: All authors
450 Brookline Ave, Boston, MA 02215; e-mail: alison_laws@dfci. Manuscript writing: All authors
harvard.edu. Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
No potential conflicts of interest were reported.

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