ExclUsive endocRine Therapy Or Partial Breast Irradiation for Women Aged 70 Years Early Stage Breast Cancer

  • End date
    Jan 15, 2030
  • participants needed
  • sponsor
    Azienda Ospedaliero-Universitaria Careggi
Updated on 16 April 2021


Rationale and relevance for patients and the scientific community. In low risk early stage patients 70 years, exclusive Partial Breast Irradiation (PBI) as radiation therapy (RT) approach might be superior in terms of Health-Related Quality of Life (HRQoL), when compared to exclusive endocrine therapy (ET) following breast-conserving surgery (BCS). Assuming an equal rate of disease control, unnecessary long-term toxicity of ET may be avoided.


Study Background. BCS has been established as the preferred treatment option for early stage breast cancer (BC) or for initially inoperable tumors that respond sufficiently to preoperative therapy. BCS plus RT obtains at least the same results in terms of survival, without the huge impact on the patient's body image and HRQoL as that seen after mastectomy. For decades, standard whole breast irradiation (WBI) consisted of 45-50 Gy delivered at 1.8-2.0 Gy/fraction over 4.5-5 weeks with or without a boost dose to the surgical bed. Large phase 3 trials evaluating different hypofractionation schedules proved that overall treatment time could be reduced without compromising local control and safety profile.

PBI has been introduced as an alternative treatment method for selected patients with early stage BC. Potential advantages of accelerated PBI include shorter treatment time, equivalent disease control, improved safety profile, and cost reduction as compared to standard WBI. The role of PBI has been investigated in large-scale prospective phase 3 clinical trials (i.e., NSABP-B29/RTOG 0413, IRMA, RAPID, IMPORT-LOW, GEC-ESTRO trials).

5-year results of the IMPORT-LOW trial showed non-inferiority of PBI when compared to WBI in women with low risk early BC, with a 5-year local recurrence (LR) rate of 0.5%. Ongoing research explores other modalities of RT that will minimize toxicities without reducing effectiveness. Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a further increase in dose conformity compared with three-dimensional techniques, with increased normal tissue sparing. To date, only the Florence IMRT-APBI phase 3 trial reported the outcomes of exclusive IMRT accelerated PBI compared to WBI, demonstrating no significant difference between the two groups in terms of ipsilateral breast tumor recurrences (IBTR). The PBI group presented significantly better results considering acute (p=0.0001), late (p=0.004), and cosmetic outcome (p=0.045). The subgroup analysis evaluating patients aged 70 years or older, showed a 5-year IBTR rate of 1.9% for both groups, and significantly better results in terms of acute skin toxicity, in favor of the PBI arm. Therefore, a significant impact on patients' compliance to RT could translate into a consistent improvement of overall HRQoL.

Heart exposure to ionizing radiation during RT for BC increases subsequent rates of ischemic heart disease (IHD). The increase is proportional to the mean dose to the heart. Women with pre-existing cardiac risk factors have greater absolute increases in risk from RT. An age >70 years seems to be one of the most significant factor for IHD occurrence. PBI represents one of several effective strategies to reduce cardiac radiation dose when compared to WBI.

Postoperative RT in the elderly is a matter of constant debate. RT was shown to benefit these patients with regards to local control; however, the absolute benefit is small (for low risk subtypes). Moreover, considering the poor compliance of elderly patients to conventional RT treatment time (3-6 weeks), conventional RT is often omitted in cases of low-risk BC, at the expense of reducing the local control rate by less than 4%.

In an unplanned subgroup analysis of the PRIME-II trial by estrogen receptor (ER) score, LR at 5 years for women in the rich ER subgroup was lower than in the whole population; for patients assigned no RT, 3% had a LR compared with 1% of women allocated WBI (5-year IBTR was 3.3%, and 1.2%, respectively).

The British Association of Surgical Oncology (BASO)-II trial confirmed that patients treated with either exclusive adjuvant RT or ET with tamoxifen had an equivalent LR rate per year of 0.8%. These data suggested that RT or ET alone resulted in excellent disease control in older women with early BC, and that the combination of treatments may have less benefit than expected. A direct comparison between PBI or ET omission as adjuvant treatment is lacking in the existing literature.

Conversely, the toxicity profile of ET is well known, and could significantly impact long term HRQoL of these potentially frail patients. Elderly patients with early BC are a unique population with regards to good prognosis and potential comorbidities, thus minimizing treatment to maintain HRQoL without compromising survival is extremely important. In the decision-making process for adjuvant therapy, estimates of the patient's risk of benefit and/or harm with treatment should be performed together with an assessment of baseline comorbidities, life expectancy and care preferences. Many large phase III studies reported on the detrimental effects of postmenopausal ET on bone density and fractures incidence, thromboembolic complications, sexual, and cognitive functionality. Moreover, patient's compliance and oral treatment adherence may be a concern, and some patients would like to avoid the toxicities associated with ET.

Considering that the potential benefit of PBI alone could be better than that of the RT-only effect reported in the above WBI-using trials, it may be possible to avoid the long term toxicity of ET and favorably impact HRQoL in selected patients, such as elderly patients with a good prognosis.

Importantly, all previously published de-escalation studies were designed and performed in order to evaluate RT omission, regardless of efficacy and compliance of ET. When expecting a comparable efficacy among tested treatment modalities, HRQoL might be the factor with the most influence on the treatment decision-making process and should therefore be the primary endpoint.

Condition Breast Cancer, Breast Cancer, Breast Cancer Diagnosis, breast carcinoma, cancer, breast
Treatment Partial Breast Irradiation (PBI), Endocrine Therapy (ET): letrozole, anastrozole, exemestane, tamoxifen
Clinical Study IdentifierNCT04134598
SponsorAzienda Ospedaliero-Universitaria Careggi
Last Modified on16 April 2021


Yes No Not Sure

Inclusion Criteria

Women aged 70 years
histologically proven invasive adenocarcinoma of the breast
pathological T1 (pT1) stage (clinical T1-2 [cT1-2] stage is allowed)
clinical and pathological N0 (cN0 and pN0) stage (isolated tumor cells [i+] allowed)
any tumor grade (if pT 10 mm), G1-2 tumor grade (if pT between 11 and 19 mm)
Luminal-A by immunohistochemistry (IHC)-based on local assessment (consistent with 14th St. Gallen consensus definition)
ER+ (defined as 10% by IHC staining)
PgR+ (in any case PgR should be at least >20% by IHC staining)
Human epidermal growth factor receptor 2 (HER2)- (0 or 1+ following IHC staining and proven negative by in-situ hybridization [ISH] in case of 2+), and
Ki67 20% by IHC staining
surgically treated with BCS with or without sentinel node biopsy (SNB)
no clinical evidence of distant metastases. Imaging work up is not mandatory to enter the trial. If there are signs/symptoms suggesting the presence of local relapse or distant metastasis, an appropriate work up should be performed according to the treating physician standard practice. A patient with confirmed local relapse or distant metastasis will no longer be eligible for the trial
postoperative final surgical margins negative (no ink on tumor)
baseline HRQoL questionnaires completion
adjuvant bisphosphonates and denosumab are allowed
before patient registration/randomization, written informed consent must be given

Exclusion Criteria

Preoperative systemic treatments (i. e., chemotherapy, endocrine therapy)
current treatment with any hormonal agents such as tamoxifen, raloxifene or other selective estrogen receptor modulators (SERMs), either for osteoporosis or BC prevention (patients are eligible if these medications are discontinued prior to randomization)
prior breast or thoracic RT
known disorders associated with a higher risk for complications following RT such as collagen vascular disease, dermatomyositis, systemic lupus erythematosis or scleroderma
prior diagnosis, detection, or treatment of any other invasive cancer (except basal or squamous cell carcinoma of the skin that has been definitely treated)
any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; these conditions should be discussed with the patient before registration
patients must not be considered a poor medical risk due to serious, uncontrolled medical disorder, non-malignant systemic disease, or active uncontrolled infection. Examples include but are not limited to uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction or uncontrolled major seizure disorder
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