Study In Advanced Breast Cancer Research Articles

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in < 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of < 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between < 40 and ≥ 50 y groups were performed. Results: Pts < 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were < 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ < 40y pts. The median time to recurrence was < 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( < 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of >2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both < 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-11.

Abstract P4-07-51: Impact of the Theralink CLIA protein/phosphoprotein assay on treatment selection in routine clinical practice: a prospective observational study in advanced breast cancer

Abstract Background: The Theralink Reverse Phase Protein Array-based (RPPA) CLIA assay is a novel molecular assay developed to assist physicians in therapy selection for patients diagnosed with advanced/recurrent breast cancer. The assay was specifically designed to quantitatively measure protein activation/phosphorylation of 32 FDA-approved and Phase III drug targets and pathway-linked downstream substrates, providing functional information on actionable oncogenic drivers in individual tumors. Given the recent commercialization of the Theralink assay (TLA), knowledge gaps exist regarding its use in routine clinical practice and the impact of the test on clinical decision-making in real world practice. The primary objective of this analysis was to assess how the TLA has been integrated in therapy selection for breast cancer patients with a focus on understanding its target population, the rationale for patient selection by the treating physician, and the utilization of the molecule information generated by the assay as part of the therapeutic decision-making process. Findings from this study will help optimize patient selection and maximize the clinical impact of the test as a tool for advancing precision oncology. Methods: We prospectively collected data from 124 women with advanced breast cancer whose tumors were profiled using the Breast Cancer TLA from February, 2021 to May, 2022. All patients were confirmed as actively managed for advanced/recurrent breast cancer. Eight μm FFPE sections (n=5) from a recently collected tissue biopsy were used to isolate tumor epithelia via Laser Capture Microdissection and to generate RPPA-based molecular profiles. Clinical management and therapy selection information for 68 patients was gathered via surveys completed by treating physicians. Results: Median age of the 124 participants was 53 years (range 26-82) and 111 (89.5%) patients had stage IV disease. The cohort included 66 hormone receptors positive (of which 5 were HER2+), 51 triple negative, and 7 HR-/HER2+ breast cancers. The TLA yielded molecular information for all specimens and profiles were generated on average in 11 days. One or more targets were highly activated (highly actionable) in 91 patients (73.4%) and moderately activated (partially actionable) in 29 patents; only 4 patients had no actionable target (3.2%). Previous treatment information was available for 118 (95.2%) patients. The TLA was requested to assist with the selection of first-line treatment in 36 patients (of which 24 had previously received neoadjuvant treatment), second-line treatment in 35 patients and third- or subsequential-lines of treatment in 47 patients. Clinicians provided feedback on the use of the assay for 68 patients included in the study. The survey revealed that the TLA impacted treatment selection in 50 (73.5%) cases and was used to either expand options beyond standard of care (30 cases), refine/re-prioritize available treatments (11 cases), narrow treatment from a plethora of options (2 cases) or a combination of the three (7 cases). When TLA data were used for treatment selection, physicians defined the assay highly and moderately beneficial for patient management in 15 and 27 cases, respectively. Conclusion: Our study suggests the TLA yields useful information for selecting treatment for breast cancer patients with advanced/recurrent disease. In this prospective analysis, the assay identified actionable targets in more than 90% of patients, which is significantly higher than what has previously been reported for genomic profiling alone. Overall, physicians found the information yielded by the assay useful for selecting treatment. The inclusion of the TLA in oncology may offer important insights for advancing precision medicine for breast cancer patients. Citation Format: Kris Weinberg, Mariaelena Pierobon, Edik Blais, Justin Davis, Joyce O’Shaughnessy, Emanuel F. Petricoin. Impact of the Theralink CLIA protein/phosphoprotein assay on treatment selection in routine clinical practice: a prospective observational study in advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-51.

Exploring the Effects of Early Censoring and Analysis of Clinical Trial Survival Data on Effectiveness and Cost-effectiveness Estimation through a Case Study in Advanced Breast Cancer.

Interim analyses of clinical trial data are frequently used to provide evidence to obtain marketing authorization for new drugs. However, results from such analyses may not reflect true estimates of relative effectiveness when trial follow-up is complete. Survival results, available at 2 time points from a breast cancer clinical trial, were compared to test the hypothesis that using immature data and a widely used right-censoring rule leads to biased survival estimates. Kaplan-Meier progression-free and overall survival data from 2 published CLEOPATRA trial reports (2012 and 2014) were digitized. Overlaying these results highlighted divergent trends. Parametric functions were fitted to both data sets but did not indicate consistent patterns that could be used as a basis for long-term extrapolation. Heavy censoring of patients in the early data cut coincides with sudden changes in hazard trends and survival patterns, supporting the hypothesis of censoring bias. This challenges the validity of estimates of clinical benefit (progression-free survival and overall survival) based on extrapolation of results from interim analyses of trial data, using a commonly employed censoring rule.

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials.

To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising. At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.

Abstract P2-09-24: Relationship of Capecitabine Response to Thymidine Phosphorylase Expression and Overall Survival in Advanced Breast Cancer

Abstract Background: Capecitabine is an oral fluoropyrimidine carbamate that is metabolised to FU through three enzymatic steps. Thymidine phosphorylase (TP) is involved in the final step of the conversion from 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU. TP is highly expressed in cancer cells compared to normal tissue. By exploiting this difference in TP activity, capecitabine is activated and preferentially converted into 5-FU within tumours. Besides this, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), a known angiogenic factor. While TP expression is predictive of benefit from capecitabine in colorectal cancer (CRC), initial studies in advanced breast cancer (ABC) examining the predictive value of TP and related enzymes have produced mixed results. Furthermore, whether response to capecitabine is associated with any overall survival (OS) benefit has not been studied. Materials and Methods: This retrospective study analysed 92 ABC patients who received at least one cycle of capecitabine for locally advanced or metastatic disease with intention to treat. Best responses to capecitabine (assessed clinically or by imaging) whilst patients were on capecitabine were included for analysis. TP expression was analysed by immunohistochemistry in primary excised samples. Composite TP scoring (including cytoplasm and stroma) was used to define TP status. Chi-squared tests were carried out to find associations between TP and clinical factors. Kaplan Meier survival curves were produced for relapse free survival and OS. The logrank statistic was calculated to test independence of the survival curves by category. Results: On multivariate analysis, when the TP composite factor was added to a Cox regression model for OS using age, ER, grade, nodal status and size, it appeared to act as an independent prognostic factor for OS after first primary (hazard ratio: 0.45, p=0.01). Overall, responses included partial response (PR) in 38% and stable disease (SD) for 3 months or longer in 25% patients. There was no statistically significant correlation for capecitabine response and TP status. Also there was no significant difference in time to first relapse or from first relapse to start of capecitabine stratified by response, showing that response was not intrinsically related to better prognosis or slower growing cancers. However, there was a significantly prolonged OS equivalent for both SD and PR to capecitabine (logrank, p=0.02). Discussion: Most studies in ABC have not found high TP expression alone to predict better response to capecitabine. The results of our study, the largest to date, confirm these findings. A combined approach studying plasma levels of 5'-DFUR along with intra-tumoral TP should be investigated further. Interestingly, the finding of high TP as an independent prognostic factor could be due to deprivation of thymidine needed for proliferation, but this also needs further investigation. By analysing the long term course of breast cancer based on ultimate pattern of response, this study suggests a substantial benefit of capecitabine even though second or third line. It also suggests that if patients achieve SD therapy should continue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-24.

Phase II trial of dolastatin-10 in patients with advanced breast cancer

Phase II multicenter cooperative group study investigated the efficacy and toxicity of the novel anti-microtubule agent dolastatin-10 in patients with advanced breast cancer. Twenty-one patients with measurable metastatic breast cancer were treated with dolastatin-10 at a dose of 400 mcg/m2 by intravenous bolus once every 3 weeks. Patients must have received a total of 1 or 2 prior chemotherapy regimens and have an Eastern Cooperative Oncology Group performance status of 0-2. Patients received this treatment as either a first (n = 11) or second-line (n = 10) chemotherapy for metastatic disease. Eighteen patients (86%) had received a prior anthracycline. The National Cancer Institute provided the dolastatin-10. One out of 21 patients (5%; 95% CI: 0-24%) achieved a partial remission for a duration of 113 days. Four patients maintained stable disease for a median of 87 days. A total of 58 courses of dolastatin-10 were administered. Patients received a median of two cycles of dolastatin-10. Hematologic toxicity was moderate, with 8 patients developing grade 4 neutropenia, and 5 with grade 3 neutropenia; one grade 3 febrile neutropenia was observed. These episodes of grade 3 and 4 neutropenia were experienced on 36% of the treatment cycles. Non-hematologic toxicity was uncommon. While the toxicity profile of dolastatin-10 was acceptable, it had minimal activity in this advanced breast cancer study. We are not pursuing further clinical trials of this agent in the setting of advanced breast cancer.

A randomized neoadjuvant chemotherapy (NC) study in advanced breast cancer (BC): AC vs FEC 60

832 Background: We designed this study to compare the clinical and pathologic response rates of AC [Doxorubicin (D) and Cyclophosphamide (C)] and FEC [Fluorouracil (F), Epirubicin (E) and Cyclophosphamide] as NC in patients (pts) with BC. Methods: Women (n = 100) with operable primary BC with stage III and age ≤ 70 years old (yo) were randomly assigned to receive four cycles of AC (arm A, n = 51 pts) (D = 60 mg/m2; C = 600 mg/m2) every 21 days or four cycles of FEC (arm B, n = 49 pts) (F = 600 mg/m2; E = 60 mg/m2; C = 600 mg/m2) every 28 days between January 2002 and May 2003. Clinical and pathologic tumor responses were assessed by clinical examination and pathologic analyses. The initial tumor size, stage, age, menopausal status and hormonal receptors status were well balanced in both arms. Results: Median initial tumor size was 9,34 and 8,8 cm, stage IIIa was 50% and 48%, stage IIIb was 50% and 52%, median age was 51 yo (range from 28 –70) and 52 yo (range from 33 –69), menopausal status was 42% and 44%, estrogen receptor positive was 62,2% and 60,4%, progesterone receptor positive was 53% and 56% in the arm A and arm B respectively. After four cycles of NC the results were as follows (arm A first): median pathologic tumor size 3,9 vs 3,12 cm, median clinical size reduction 5,95 vs 5,15 cm, downstaging 49% vs 52%, negative nodes (pN0) 30,7% vs 26,5%, pathologic complete response (pCR) 12,1% vs 10,7%, pathologic partial response 75,3% vs 77,1%, stable disease was 7,3% vs 10,2% and progression 4,3% vs 2%. Conclusions: The FEC 60 neoadjuvant regimen is as effective as AC in this population. Randomized trials report complete pathologic responses ranging from 14% to 31%. However, this study could not found these rates. It is believed due to the large mean tumor size verified in our population. Furthermore, the literature shows better pCR in sequential NC regimens containing anthracycline and taxanes, so FEC with a Taxane can be an approach to these patients. No significant financial relationships to disclose.

A randomized neoadjuvant chemotherapy (NC) study in advanced breast cancer (BC): AC vs FEC 60

832 Background: We designed this study to compare the clinical and pathologic response rates of AC [Doxorubicin (D) and Cyclophosphamide (C)] and FEC [Fluorouracil (F), Epirubicin (E) and Cyclophosphamide] as NC in patients (pts) with BC. Methods: Women (n = 100) with operable primary BC with stage III and age ≤ 70 years old (yo) were randomly assigned to receive four cycles of AC (arm A, n = 51 pts) (D = 60 mg/m2; C = 600 mg/m2) every 21 days or four cycles of FEC (arm B, n = 49 pts) (F = 600 mg/m2; E = 60 mg/m2; C = 600 mg/m2) every 28 days between January 2002 and May 2003. Clinical and pathologic tumor responses were assessed by clinical examination and pathologic analyses. The initial tumor size, stage, age, menopausal status and hormonal receptors status were well balanced in both arms. Results: Median initial tumor size was 9,34 and 8,8 cm, stage IIIa was 50% and 48%, stage IIIb was 50% and 52%, median age was 51 yo (range from 28 –70) and 52 yo (range from 33 –69), menopausal status was 42% and 44%, estrogen receptor positive was 62,2% and 60,4%, progesterone receptor positive was 53% and 56% in the arm A and arm B respectively. After four cycles of NC the results were as follows (arm A first): median pathologic tumor size 3,9 vs 3,12 cm, median clinical size reduction 5,95 vs 5,15 cm, downstaging 49% vs 52%, negative nodes (pN0) 30,7% vs 26,5%, pathologic complete response (pCR) 12,1% vs 10,7%, pathologic partial response 75,3% vs 77,1%, stable disease was 7,3% vs 10,2% and progression 4,3% vs 2%. Conclusions: The FEC 60 neoadjuvant regimen is as effective as AC in this population. Randomized trials report complete pathologic responses ranging from 14% to 31%. However, this study could not found these rates. It is believed due to the large mean tumor size verified in our population. Furthermore, the literature shows better pCR in sequential NC regimens containing anthracycline and taxanes, so FEC with a Taxane can be an approach to these patients. No significant financial relationships to disclose.

Strategies for improving quality of life in older patients with metastatic breast cancer.

Given both the increase in the mean age of the population of Western countries and the high incidence of breast cancer beyond the age of 65 years, it is evident that breast cancer in older women will be a very common problem for the medical oncologist. Metastatic breast cancer is still not amenable to a cure; therefore quality of life during therapy is an important issue, which until recently has been poorly investigated. Similarly, despite recent advances in breast cancer therapy, physicians have been reluctant to enrol older patients in clinical trials, and there is a lack of data regarding this population. This review focuses on quality-of-life issues during metastatic breast cancer treatment in geriatric patients, comparing the standard therapeutic options and newer approaches. Although first-line endocrine therapy with tamoxifen remains a standard treatment, the newer third-generation aromatase inhibitors provide similar or better efficacy with fewer adverse effects and a better quality of life. It has been a common belief that chemotherapy impairs quality of life, but recent studies in advanced breast cancer have shown that this therapy has a positive effect on quality of life, at least in responders. Consequently, chemotherapy should not be denied to elderly patients with metastatic breast cancer, provided a prior geriatric assessment is performed to evaluate the risk-benefit ratio. New chemotherapy strategies, such as the taxanes and orally administered chemotherapy, represent a very attractive alternative for a better quality of life in elderly patients with metastatic breast cancer.

12 Multiple courses of high-dose alkylating therapy with autologous stem cell support

Since the introduction of autologous blood progenitor cell transplantation, (APCT) bone marrow suppression is no longer dose-limiting after high-dose therapy. We have developed a high-dose chemotherapy regimen ‘CTC', that includes cyclophosphamide (6g/m²), thiotepa (480mg/m²) and carboplatin (1600mg/m²) administered over four days. This regimen has been shown to be well-tolerated in over 80 (first) courses and multiple courses could be feasible. 28 patients received 2 courses of CTC, CTC-2 beginning on day 28 after the first APCT. One patient died of sepsis, one developed reversible veno-occlusive disease (VOD). Eleven patients received 3 subsequent courses of CTC. There were three toxic deaths: 1 × sepsis, 1 × VOD, 1 × hemolytic uremic syndrome (HUS). Two other patients developed reversible VOD, one had reversible HUS. While two closely spaced CTC courses are feasible, three subsequent courses are associated with frequent unacceptable organ toxicity. Preliminary data of a phase I/II study in advanced breast cancer suggest that three tightly spaced ‘tiny CTC' courses—containing 2/3 of the doses of each of the agents in a standard CTC course—may be well tolerated and are not associated with excess organ toxicity.

Clues to the mechanisms of endocrine resistance from clinical studies in advanced breast cancer

Clues to the mechanisms of endocrine resistance from clinical studies in advanced breast cancer

Treating the relapsed patient.

At the present time, clinicians managing patients with metastatic breast cancer face a challenging problem. Therapeutic strategies that include chemotherapy, hormonal therapy, and combination approaches have been based almost exclusively on published experience from clinical trials that antedate common adjuvant systemic therapy use. In fact, most studies in advanced breast cancer excluded patients with any prior hormonal or chemotherapy use as part of the study design. Thus, although the majority of breast cancer patients who develop metastatic disease may have received prior adjuvant chemotherapy and/or hormonal therapy, few prospective trials have evaluated therapeutic approaches for this population.

Aromatase inhibitors in human breast cancer

SynopsisThe results of a phase I/II study in advanced breast cancer in postmenopausal women of the aromatase inhibitors 4-hydroxyandrostenedione (40HA), miconazole and CGS16949A are described. 40HA, a steroidal compound which is an irreversible inhibitor of aromatase, has been administered to 131 patients by weekly (500 mg) or fortnightly (250 mg) i.m. injections, and daily (500 mg) by mouth. The overall response rate (complete regression (CR) and partial regression (PR)) was 33%; all three dose schedules had similar clinical efficacy. Oestradiol levels were suppressed to a mean of 37–45% of pretreatment values with oral and with weekly i.m. 40HA; suppression was marginally suboptimal with 250 mg i.m. fortnightly. 40HA was well tolerated, especially when administered by fortnightly injections; this dose schedule is to be preferred to weekly injections.Significant oestradiol suppression and clinical responses did not occur with the imidazole antifungal, miconazole, which was administered to twenty-two patients at doses of 500–1000 mg daily. The non-steroidal aromatase inhibitor, CGS16949A, induced comparable oestradiol suppression to 40HA at doses of 0.6–4 mg daily; 0.6 mg daily appears to be suboptimal. Five of thirty-one patients treated had objective responses, and disease stabilised for at least six months in nine patients. Some suppression of aldosterone occurred with doses of 2 and 4 mg daily, but clinical toxicity of the compound was minor.

The French fac vs FEC study in advanced breast cancer

The French fac vs FEC study in advanced breast cancer

Corticosteroids for elderly patients with breast cancer.

Ninety-one assessable elderly women (greater than 65 years) with advanced breast cancer were treated with prednisolone 15 mg (or cortisone 75 mg) daily after primary endocrine treatment (estrogens, androgens or tamoxifen). Thirteen (14%) achieved an objective regression, and 19 (21%) others showed no change for greater than or equal to six months. Hence, 32 patients (35%) had control of disease for about one year. Responses were mainly in soft tissue and skeletal lesions and were independent of response to prior endocrine treatment. Toxicity was low. Low-dose corticosteroid treatment is of value in controlling advanced breast cancer in elderly women.