Breast cancer has been one of the most common malignant tumors in women, accounting for 23%
of all the malignancies. There are estimated 1,300,000 new cases of breast cancers and
400,000 deaths due to breast cancers every year in the world. Hormone receptor-positive
breast cancer accounts for about 70% of all breast cancers.
Since ovarian resection was first used in the treatment of advanced breast cancer in the late
19th century, with more than a century of development, endocrine therapy has become the most
important adjuvant therapy for hormone receptor-positive breast cancers, especially for
advanced breast cancers. Increasing clinical trials of adjuvant endocrine therapy such as
ATAC, BIG1-98, and IES, which have been implemented since 2002, have ascertained the effect
of adjuvant endocrine therapy with aromatase inhibitor, and the guidelines for the diagnosis
and treatment of breast cancer have been also changed accordingly.
Although early-stage hormone receptor-positive breast cancer patients have a better prognosis
than HER-2 positive and triple-negative patients, there is still a long-lasting risk of
postoperative recurrence, which has been confirmed in two large-scale meta-analyses reported
by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). A meta-analysis released
by the EBCTCG in 1998 indicated that early-stage hormone receptor-positive breast cancer
patients, especially lymph node-positive patients, experienced the second recurrence peak at
2-3 years and 7-9 years after completion of endocrine therapy. In 2016, the EBCTCG released
another relevant study at the annual meeting of the American Society of Clinical Oncology
(ASCO), in which the long-term recurrence rate within 5-20 years was up to 14% in T1N0 breast
cancer patients who had undergone 5 years of adjuvant endocrine therapy. Therefore, the 5
years of standard adjuvant endocrine therapy cannot eliminate the risk of recurrence. Most
scholars have suggested that the duration of endocrine therapy should be extended to reduce
the recurrence risk of breast cancer.
Numerous clinical trials have focused on the use of extended endocrine therapy in patients
with specific types of breast cancer. In the MA17R trial, patients received 3-5 years of
tamoxifen or 5 years of aromatase inhibitor treatment, followed by another 5 years of
aromatase inhibitor treatment. The extended aromatase inhibitor treatment was found to
significantly improve the disease-free survival time of hormone receptor-positive early
breast cancer patients, while also reducing the risk of contralateral breast cancer and
distant relapse. In the NSABP B42 trial, patients who had received initial 5 years of
aromatase inhibitor treatment or initial 5 years of tamoxifen + aromatase inhibitor treatment
were all treated with extended aromatase inhibitor. Although the primary endpoint (P = 0.048)
did not reach the expected value, extended treatment with aromatase inhibitors significantly
reduced the secondary endpoints - breast cancer-free interval and distant relapse, confirming
the conclusion of the MA17R study. In the DATA trial, although extended treatment with
aromatase inhibitor did not benefit in general, subgroup analysis showed that some high-risk
patients, such as patients with positive lymph nodes, tumors larger than 2 cm in diameter, or
receiving chemotherapy, could benefit from 6 years of anastrozole treatment. The IDEAL trial
showed that there is a trend of benefit in patients with positive lymph nodes. With the
support of many large-scale clinical studies published in succession, the NCCN practice
guidelines for breast cancer released in 2017 recommends an additional 5 years of aromatase
inhibitor treatment following the initial 5-year treatment in postmenopausal patients with
early-stage breast cancer at high risk for relapse. As per the Chinese Society of Clinical
Oncology guidelines published in 2019, the extended endocrine therapy is also recommended for
postmenopausal hormone receptor-positive patients who have been well tolerated to the initial
5-year adjuvant treatment. However, there are some restrictions, such as positive lymph
nodes, G3 or other risk factors that require adjuvant chemotherapy. For premenopausal hormone
receptor-positive patients who have been well tolerated to the initial 5 years of endocrine
treatment, extended endocrine therapy is also recommended in some situations, such as the
presence of positive lymph nodes, G3, less than 35 years old at diagnosis, high-level Ki-67
or pT2 and above.
However, the extended endocrine therapy also has some adverse events. Multiple studies have
shown that long-term use of tamoxifen can significantly increase the incidence of adverse
reactions such as endometrial cancer, thrombotic disease, and dyslipidemia. Similarly,
long-term treatment with aromatase inhibitors can also increase the incidence of adverse
reactions such as osteoporosis, fractures, dyslipidemia, and hypertension. In the ATLAS
trial, the incidence of endometrial cancer in patients treated with 10 years of tamoxifen was
higher than that in patients treated with 5 years of tamoxifen. Similar results are
discovered in the aTTom trial. In the IDEAL trial, the incidence rates of osteoarthritis and
osteoporosis in patients treated with 5 years of letrozole was increased by 14% and 10% of
that in patients undergoing 2.5 years of treatment. A study involving nearly 100,000 breast
cancer patients showed that only 49.9% of breast cancer patients died of breast cancer, 16.3%
died of cardiovascular disease, and 33.8% died of other causes. Among them, breast cancer and
cardiovascular disease were the main causes of death in well- and poor-tolerated patients,
respectively. This suggests that although anti-cancer treatment can reduce cancer deaths, it
may increase the death due to cardiovascular disease. Such deaths are often offset, which
often improves the BCFI, but does not benefit the overall survival.
Therefore, an effective predictor for relapse risks that can accurately determine the
necessity of extended endocrine therapy is expected to be discovered. The use of this
predictor will both improve patient's prognosis and reduce treatment-related side effects.
The author's team recently discovered a possible factor with a long tubular structure in
breast cancer lesions using immunofluorescence staining, which was named as sj-subway. The
authors conducted a retrospective analysis based on the specimen library and case follow-up
library of the Breast Center of Shengjing Hospital Affiliated to China Medical University.
They found that sj-subway was positively expressed in various subtypes of breast cancer
tissues, and mostly expressed in the hormone receptor-positive subtype. The group with more
sj-subway expression had a higher positive expression of hormone receptor/ progesterone
receptor. Further survival analysis also revealed the worse prognosis of patients with the
existence of higher sj-subway expression. Therefore, the authors speculate that positively
expressed sj-subway may become a predictor of recurrence and metastasis in high-risk patients
with hormone receptor positive. However, the clinical use of this factor to screen the
population benefiting from extended endocrine therapy remains to be studied.
This real-world study intends to observe the difference in the clinical efficacy of extended
endocrine therapy under different sj-subway expression in high-risk hormone receptor-positive
breast cancer patients, and to analyze whether the use of sj-subway can further screen out
the population with benefit from extended endocrine therapy, thus further improving the
survival of such patients without additional adverse events.