International experts have been meeting annually since 1977 to share current information on breast cancer research. The goal is to balance clinical, translational, and basic research and to provide a forum for interaction, communication, and education to a broad spectrum of researchers, health care professionals, and individuals with a special interest in breast cancer. The current focus is on approaches for a targeted therapy regime.
Results from the prospective phase II ACOSOG Z11102 clinical trial show that in patients with multiple tumors in the same breast who underwent lumpectomy followed by radiotherapy, the rate of local recurrence is comparable to that previously observed in patients with a single tumor [1]. The study included women over the age of 40 who had two or three breast cancer sites in the same breast separated by normal breast tissue. All patients had undergone mammography and/or ultrasonography, and most had also undergone breast MRI. Fourteen of the participating patients underwent mastectomy because the margins remained positive and breast-conserving therapy was not possible. The remaining patients were treated with lumpectomy followed by whole-breast irradiation with radiation boosts to all lumpectomy sites. The primary endpoint was local recurrence five years after completion of radiation.
Of the 204 evaluable patients, six patients developed local recurrence after a median follow-up of 66.4 months, corresponding to a five-year local recurrence rate of 3.1%. This rate was similar to local recurrence rates observed in previous studies in patients with a single breast tumor after breast-conserving therapy. The rate of local recurrence was higher in the 15 patients who did not undergo breast MRI examination before surgery than in the 189 patients who did (22.6% versus 1.7%). It has been discussed that this may be due to the fact that more foci of disease were detected prior to surgery in patients who underwent breast MRI, which allowed for a more thorough resection. The risk of local recurrence was not related to patient age, number of breast lesions, tumor biology, or pathologic staging. No affected patients had regional recurrence, but distant recurrence occurred in four patients, breast cancer in the other breast in six patients, and new primary tumors outside the breast in three patients.
Interruption of endocrine therapy in case of desire to have children
What are the implications of interrupting endocrine therapy if young breast cancer patients want to become pregnant? This question was investigated by the POSITIVE study [2]. From December 2014 to December 2019, 518 women aged 42 or younger who wanted to become pregnant participated in the study and chose to discontinue endocrine therapy for about two years. Before interrupting their treatment, the women had completed 18 to 30 months of adjuvant endocrine therapy. A data security oversight committee conducted three interim security analyses. If more than 46 breast cancer recurrences had occurred within the average follow-up period of about three years, the study would have had to be terminated. This threshold was not reached. At a median follow-up of 41 months, 44 participants had experienced breast cancer recurrence. The three-year rate of recurrence was 8.9%-similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials evaluating adjuvant endocrine therapy in premenopausal women. However, study participants were strongly advised to resume endocrine therapy after a pregnancy attempt or success. To date, 76.3% have resumed their therapy. These data underscore the need to incorporate patient-centered reproductive health care into the treatment and follow-up of young women with breast cancer.
Estradiol promotes brain metastases
It has been hypothesized that premenopausal hormones such as estradiol (E2) may promote brain metastasis by having effects on the brain microenvironment. It is known that the hormone acts on ER+ astrocytes to secrete growth factors that can activate tumor-promoting signaling pathways in triple negative breast cancer (TNBC). Both brain and ovarian estrogen can affect the brain tumor microenvironment in younger women. Mouse models of TNBC show that ovariectomy alone or in combination with letrozole prevents brain tumor colonization and restoration of premenopausal E2 levels promotes brain tumor colonization. By combining multiple mouse models that mimic the current standard of care for TNBC, researchers were able to investigate how E2 depletion alone or in combination with brain irradiation might affect the progression of existing brain metastasis in TNBC [3]. E2 suppression in combination with brain irradiation was shown to decrease the progression of brain metastasis. E2 suppression alone had no effect.
Chemotherapy well considered
Chemotherapy is often associated with tumor-associated cognitive impairment. The RxPONDER trial has now looked more closely at the impact of endocrine therapy alone vs. chemo followed by endocrine therapy [4]. For this, 5083 patients with hormone receptor-positive (HR+), HER2-negative (HER2-) nonremote metastatic tumors and one to three affected lymph nodes (LN+) were included. The results show that cognitive impairment was more severe with chemotherapy plus endocrine therapy than with endocrine therapy alone. In some cases, these impairments last for more than three years. Therefore, it is important to ensure that chemotherapy is only used in patients who will truly benefit from it.
On the way to better therapy
An understanding of how and why somatic mutations accumulate is required to elucidate cancer evolution. DNA replication during each cell cycle is an essential and highly regulated process that ensures the correct replication of the entire genome. The timing of DANN replication has been indirectly linked to mutation acquisition and genome instability. However, the extent and significance of the altered replication timing (ART) from normal cells to cancer cells, and whether this process directly influences mutation acquisition during cancer development, have not yet been explored. Therefore, the effects of ART were examined by analyzing data from 1271 whole-genome sequenced lung and breast cancer genomes, along with replication timing sequencing data from multiple cancer and normal cell lines [5]. It has been found that 6-18% of the genome in cancer cells is subject to ART. Genomic regions subject to a shift from early to late replication in cancer cells exhibit increased mutation rates in tumors and are associated with different mutational signatures compared to unaltered regions with early replication. Accordingly, ART is a relatively early event during the development of breast cancer. In summary, changes in replication timing during malignant transformation are widespread and have a significant impact on the genomic and transcriptomic landscape during tumor evolution.
Breast cancer screening – the impact of pathogenic BRCA1/2 variants.
The risk of ipsilateral breast tumor recurrence (IBTR) and prognosis of breast-conserving surgery (BCS) in carriers of pathogenic germline variant BRCA1/2 (BRCA1/2+) remain controversial. Therefore, differences in IBTR and prognosis between BRCA1/2+ carriers and non-carriers were investigated after BCS in breast cancer [6]. The incidence of IBTR and prognosis, including overall survival (OS), breast cancer-specific survival (BCSS), and survival without distant recurrence (DRFS), were compared. The analysis included 551 patients (587 breasts with cancer), including 30 BRCA1+ carriers (32 breasts) and 31 BRCA2+ carriers (32 breasts). The median follow-up time was 5.8 years. Among carriers, breast cancer was more likely to be estrogen receptor negative (56.2% for BRCA1+ carriers and 15.6% for BRCA2+ carriers vs. 22.0% for non-carriers), progesterone receptor negative (62.5% for BRCA1+ carriers and 31.3% for BRCA2+ carriers vs. 29.5%), nucleus grade III (45.3% for carriers vs. 29.5% for non-carriers), or a higher Ki-67 index (Ki-67 index >20) (89.5% vs. 61.8%) than non-carriers. In addition, carriers underwent chemotherapy more frequently than non-carriers (62.5% vs. 42.4%). Cancer stage, tumor size, HER2 status, presence of lymphatic invasion, and rates of positive or narrow surgical margins did not differ statistically between the groups studied.
During follow-up, it was found that nine breasts from BRCA1/2+ carriers (15.6%/12.5%) and 35 breasts (6.7%) from non-carriers developed IBTR. When patients who did not undergo radiotherapy were excluded, the IBTR rate remained significantly higher in BRCA1/2+ carriers. The median time to IBTR was 10.2 years for carriers (10.2 years for BRCA1+ and 8.5 years for BRCA2+) and 3.5 years for noncarriers. Carriers were more likely than noncarriers to have various subtypes of recurrent tumors in the ipsilateral breast (66.7% versus 19.4%) that occurred in a different quadrant than the primary tumor (50.0% versus 27.3%). No significant differences in OS, BCSS, or DRFS were observed.
Congress: San Antonio Breast Cancer Symposium (SABCS)
Literature:
- Boughey JC, et al: Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance). GS4-01. 10/12/2022. SABCS 2022.
- Partrige A, et al: Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer: Primary Results from the POSITIVE Trial (IBCSG 48-14 / BIG 8-13). GS4-09. 10/12/2022. SABCS 2022.
- Cittely D, et al: Estradiol represses anti-tumoral immune response to promote progression of ER- brain metastases. GS5-07. 10/12/2022. SABCS 2022.
- Kang I, et al: Rx for Positive Node, Endocrine Responsive Breast Cancer. GS1-04. 10/12/2022. SABCS 2022.
- Kanu N, et al: Clinical implications of tumor heterogeneity single cell genomics. 12/06/2022. SABCS 2022.
- Kondo S, Kumiko K, Misato S, et al: Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery. P1-09-03. 06/12/2022. SABCS 2022.
InFo ONCOLOGY & HEMATOLOGY 2023; 11(1): 28-29.
