Hormone Positive Metastatic Breast Cancer Research Articles

Estimation of Progression Free Survival (PFS) in Patients with Hormone Positive Metastatic Breast Cancer in Cohort of Egyptian Patients (Retrospective Cohort Study)

Background Breast cancer (BC) is the second most common cancer in the world and the most frequent cancer among women with approximately 1.7 million new cancer cases diagnosed yearly. It is the most common female malignancy accounting for 22.9% and 37.7% of all female cancers worldwide and in Egypt, respectively. BC in Egypt carries an unfavorable prognosis with 29% mortality and 3.7:1 incidence to mortality ratio. Aim of the Work to assess progression free survival (PFS) in patient with hormone positive metastatic breast cancer and prognostic factors affecting it in series of Egyptian patients treated in Ain Shams University hospitals and Maadi Medical Armed Forces Complex. Patients and Methods This retrospective cohort study was conducted in Clinical Oncology Department, Ain Shams University Hospitals and Medical Oncology Department, Maadi Medical Armed Forces Complex from January 2019 till December 2020. Progression free survival was estimated for all patients. Age of the studied patients ranged from 32 to 85 years with mean age of 58 years, 77.9% of the patients with MBC were postmenopausal, 22.9% of patients had positive family history. Most of our patients were IDC (95%) while only 5% were ILC, hormonal and molecular status among studied groups showed ER +ve in 100% of patients. Results Regarding to progesteron receptor (PR) status, 8.7% of patients were negative and 91.3% were positive. Ninety percent had HER2 overexpression. In 240 breast cancers, proliferative index Ki-67 was low in 84.6%. High levels were seen in 15.4% of cases. Progression free survival ranged from 1 to 66 months with median of 15 months. There are statistically significant relations of progression free survival with menopausal status, family history, HER2 overexpression, proliferative index Ki67, onset of metastasis evolution, site of metastasis, 1st line of treatment for metastasis, type of hormonal treatment for metastasis and ovarian ablation for premenopausal MBC patients. Conclusion There are statistically significant relations of PFS with 1st line of treatment of metastasis, as we find that Patients who received hormonal treatment only was significantly higher PFS (median PFS 17 months) compared to patients whose received both hormonal therapy and chemotherapy (median PFS 15 months) and patients whose received chemotherapy only (median PFS 5 months).

Efficacy of cyclin-dependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: a single institutional study from India.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown marked benefit in the treatment of hormone positive metastatic breast cancer (HR+ MBC). There are limited real-world studies with palbociclib and ribociclib. Here we report our experience with CDK4/6 inhibitors in these groups of patients. Patients with HR+ MBC who have received either palbociclib or ribociclib during the course of their treatment from January 2017 to January 2022 were included in the study. The baseline demographic features, treatment details and toxicity were recorded. Patients who received at least 1 month of therapy were included in the survival analysis. A total of 144 patients received CDK4/6 inhibitors during the time period. The median age of the population was 53 (30-80) years. Ninety-eight (71.4%) patients presented with de novo metastatic disease. The most common site of metastasis was to the skeleton (74.2%). Most patients (75%) received palbociclib as their therapy. At a median follow-up of 20.2 months, the median progression free survival (PFS) of the whole population was 16.5 (95% confidence interval (95% CI): 11.6-25.5) months and the median overall survival (OS) was 29.7 (95% CI: 21.7-44.6) months. The presence of liver metastases, low progesterone receptor positivity (Allred score < 6) and prior systemic treatment were poor prognostic factors for both PFS and OS in multivariate analysis. Drug was discontinued for only 2.1% of the patient population. Use of CDK4/6 inhibitors has led to improvement in PFS and OS in patients with HR+ MBC and it is well tolerated. The presence of liver metastases and low progesterone receptor positivity (Allred score < 6) and prior treatment are poor prognostic factors.

Sequential anticancer therapy in a patient with metachronous primary uterine cancer and breast cancer

Breast cancer (BC) is a heterogeneous disease characterized by the presence or absence of membrane receptor overexpression on tumor cells that correlates with the disease prognosis. Understanding of the patterns and mechanisms of tumor progression gained through clinical experience of managing BC patients is important. The treatment strategy depends on the hormone receptor status of the tumor, the HER2 / neu expression, and the proliferative activity level. A clinical case of advanced luminal A breast cancer is reported, and the rationale for sequential treatment strategy is provided taking into account the clinical situation and clinical course of the disease. Adequate endocrine therapy for hormone-positive metastatic BC provides long-term tumor control like in this case, as well as a high quality of life over the entire course of sequential treatment with anticancer drugs.

Real-world Indian scenario of CDK4/6 inhibitors (palbociclib and ribociclib) with endocrine therapy in upfront hormone positive metastatic breast cancer.

e13028 Background: CDK4/6 inhibitors (CDKi), in combination with endocrine therapy (ET), has become the standard of care in the treatment of hormone positive (HR+)/ HER2 neu negative metastatic breast cancer (MBC) patients. We evaluated clinical outcomes and toxicity in MBC patients, who have received ET with two CDKi, namely palbociclib and ribociclib. Methods: This is an ambispective, single institutional analysis of de-novo HR+ MBC patients treated with CDKi (palbociclib 125 mg and ribociclib 600 mg once a day for 21 days /28 days cycle) from November 2016- October 2020 at AIIMS, New Delhi, India. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was response rate and toxicity. A total of 157 female patients were recruited in this study however the response and toxicity data were available in 120 cases. All premenopausal women received ovarian suppression or ovarian ablation. Results: A total of 120 patients were included in this study with a median age of 57 years (35-75) and 93 (77.5%) cases were postmenopausal. Twenty-three (19.1%) patients had a bone-only disease, 49 (40.9%) had bone and visceral disease and 48 (40%) had only visceral disease. In this study 91 (75.9%) patients received palbociclib and 29 (24.2%) received ribociclib. The median PFS was 18 months (4-36). Twenty four (20%) patients achieved a complete response, 69 (57.5%) patients attained partial response, 18(15%) patients had stable disease and 9 (7.5%) had disease progression. Grade 3–4 neutropenia, thrombocytopenia, and anaemia were observed in 18(15%), 8 (6.7%), and 4 (3.3%) cases respectively. None of the patients developed febrile neutropenia. Cutaneous, renal, hepatic, and gastrointestinal toxicity was observed in 1,1,3,4 cases respectively. Prolonged QTc was observed in one case. Grade 3 fatigue was observed in 7 cases. Dose interruption/delay (mean dose delay of 7 days), dose modification, and drug discontinuation were observed in 24 (20%), 12 (10%), and 10 (8.3%) of cases respectively. Conclusions: This is one of the largest real-world Indian data on CDK4/6 inhibitors on upfront HR+ MBC. Side effects are less than published literature with similar efficacy. Neutropenia was the most common side effect which was managed by brief dose interruption.

Fulvestrant in the treatment of luminal metastatic breast cancer: the balance of effectiveness and safety

The review presents the results of studies of fulvestrant in metastatic breast cancer (MBC). Hormone therapy is an effective method of treating hormone-positive metastatic breast cancer even in the presence of visceral metastases in the absence of a visceral crisis and without detected resistance to endocrine therapy. During the COVID-19 pandemic, hormone therapy is safer for patients with hormone-positive MBC than chemotherapy, since it does not lead to immunosuppression. Fulvestrant is a “pure antiestrogen”, it has a greater affinity for estrogen receptors than tamoxifen. Fulvestrant is both a competitive antagonist and a selective estrogen receptor degrader (SERD), this mechanism of action provides complete blocking of the estrogen signaling pathway. In the phase III CONFIRM study, the optimal dose of fulvestrate was determined to be 500 mg once every 28 days, with a loading dose of 500 mg on day 15 of the first month of therapy. In the FALCON phase III study (n = 462), which included postmenopausal MBC patients who had not previously received any endocrine therapy, fulvestrant 500 mg was compared with the aromatase inhibitor anastrozole. Significant improvement in PFS was achieved with fulvestrant therapy compared to anastrozole: 16.6 months in the fulvestrant group versus 13.8 months with anastrozole [OR = 0.797; 95% CI 0.637–0.999; p = 0.0486]. A subgroup analysis showed that patients without visceral metastases can benefit most from taking fulvestrant. In all studies fulvestrant 500 mg has demonstrated a good toxicity profile, so it is being studied as a component of combined endocrine therapy. In the PALOMA-3 study the combination of fulvestrant with palbociclib (CDK4/6 inhibitor) demonstrated a median PFS 9.5 months, compared with monotherapy with fulvestrant – 4.6 months (HR = 0.46, p &lt; 0.0001). In the MONALEESA-3 study, the median PFS in patients receiving ribociclib with fulvestrant was significantly higher compared to those taking placebo with fulvestrant: 20.5 months and 12.8 months, respectively (HR = 0.593; 95% CI: 0.480–0.732; p &lt; 0.001). In the MONARCH-2 study the combination of fulvestrant and abemaciclib was studied in the second line of therapy, the median PFS was 16.4 months in the group of fulvestrant and abemaciclib, and 9.3 months in the group of fulvestrant and placebo (HR = 0.553; 95% CI 0.449-0.681; p &lt; 0.0001). Fulvestrant has a satisfactory toxicity profile, does not require supporting therapy, and is included in the clinical recommendations for monotherapy and combination therapy.

Palbociclib in hormone positive metastatic breast cancer: A real world multicenter Indian experience.

e13057 Background: Palbociclib, a selective CDK4/6 inhibitor, in combination with hormonal therapy has become the standard of care in the treatment of hormonal positive (HR+) metastatic breast cancer (MBC). There is limited efficacy and safety data in Indian patients. Methods: This is a multicenter retrospective study of real world experience of patients with HR+, Her 2 neu negative MBC who received Palbociclib in 5 centers of south India between Oct 2016 and Aug 2019. Endpoints were overall response rate (ORR), progression free survival (PFS) and toxicity. Results: 133 patients received Palbociclib; 83 (62.4%) in the first line setting (hormone naïve MBC) and 50 (37.6%) in the second line (MBC progressed on at least one line of hormonal therapy). Median age was 56 years (range 48-76). All patients started with 125mg/day. In the 83 first line patients, 46 (55.4%) had denovo MBC, 37 (44.6%) had post-adjuvant relapse. 38 (45.8%) had bone only and 45 (54.2%) had visceral metastases. Letrozole was the companion drug in 76%, Fulvestrant in 18%, Exemestane in 6%. 5 (6%) patients achieved complete response (CR), 54 (65%) partial response (PR), 12 (14.5%) stable disease (SD) and 12 (14.5%) had progressive disease (PD). ORR was 71%. At a median followup of 18 months, the median PFS was not reached (maximum ongoing followup 38 months). The median PFS in the denovo metastatic disease versus relapsed disease was not reached versus 18 months (p = 0.021). The median PFS was significantly better in bone only versus visceral metastases (not reached versus 28 months, p = 0.007). In the 50 second line patients, 15 (30%) had bone only and 35 (70%) had visceral metastases. Companion drug was Fulvestrant in 64%, Letrozole in 20%, Exemestane in 16%. 60% received prior chemotherapy. Best response was CR 3 (6%), PR 23 (46%), SD 4 (8%), PD 17 (34%), not assessed 3 (6%). ORR was 52%. The median PFS was 14 months. PFS in bone only versus visceral disease was 14 months versus 13 months (p = 0.382). Neutropenia was present in 75.2%, thrombocytopenia in 19.5%, anaemia in 18%. Neutropenia was grade 1 in 26%, grade 2 in 51%, grade 3 in 23%; with no febrile neutropenia. 30% had dose delays and 8.2% had dose reduction. Conclusions: Palbociclib has resulted in similar efficacy and safety in Indian patients as the PALOMA trials. Neutropenia was the commonest side effect, which was uncomplicated and easily managed with dose delays. Using CDK4/6 inhibitors with hormonal therapy has become the standard of care in HR+ MBC Indian patients.

Fatigue, alopecia and stomatitis among patients with breast cancer receiving cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis

ABSTRACTBackground: Cyclin-dependent kinase (CDK) inhibitors emerge as efficacious agents in hormone positive metastatic breast cancer with more acceptable toxicity profiles than cytotoxic chemotherapy. However, some adverse effects such as fatigue, alopecia and stomatitis, vastly concern patients.Methods: The search was conducted in PubMed, American Society of Clinical Oncology meeting library, European Society for Medical Oncology meeting abstract, and the San Antonio meeting abstract databases. We identified phase 2 or 3 trials recruiting patients with breast cancer, randomized to receive hormonal treatment plus either CDK4/6 inhibitors or placebo. We considered studies providing incidence of fatigue, alopecia and stomatitis relevant.Results: One thousand records were screened. 34 studies were considered relevant. Four studies were found to be eligible for meta-analysis with a total of 2007 patients. The relative risk for all grade fatigue was 1.34 [95% CI: 1.17–1.54, p < 0.0001], for all grade alopecia was 2.14 [95% CI: 1.23–3.73, p = 0.007], and for all grade stomatitis 4.87 [95% CI: 2.11–11.24, p = 0.0002]. In addition, the relative risk for high grade fatigue was 2.40 [95% CI: 1.10–5.26, p = 0.03].Conclusion: CDK4/6 inhibitors were associated with an increased risk of fatigue, alopecia and stomatitis. Further studies with self-reported questionnaires may elucidate the impact of the increased risk of these selected adverse effects on the patients’ quality of life.

Abstract P5-14-06: Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer

Abstract Introduction: A significant proportion of breast cancer (BC) patients show primary or acquired resistance to endocrine therapy (ET). The cross-talk between estrogen receptor and other growth factor receptor (GFR) families is suggested to play a crucial role in the development of endocrine resistance and dual targeting of these pathways can potentially reverse endocrine resistance. Lapatinib (Lap) is an oral, dual inhibitor of EGFR/HER2 and preclinical studies have demonstrated combination of Lap and ET to be effective in setting of endocrine resistance. Aims: 1) To evaluate if Lap can restore efficacy of aromatase inhibitor (AI) or fulvestrant(F) in metastatic BC, 2) Study blood/tissue response biomarkers. Methods: Eligible patients with HER2 negative (IHC and FISH) hormone positive metastatic BC who had progression of disease while on AI or Fulvestrant (+/-AI), or developed metastatic disease on adjuvant AI were enrolled on an IRB approved phase II study. Study treatment included continuation of same dose and schedule ET on which last progression was noted with the addition of Lapatinib 1500 mg PO/QD. Patients could have unlimited prior ET. The study end points included clinical benefit rate (CBR) at 16wks (CBR16), CBR at 24 wks (CBR24) and PFS. Correlative studies included blood markers (HER2/ECD, CTC, CTC HER2 phenotyping) and tumor next generation sequencing (NGS) (315 cancer-related genes, Foundation Medicine, Inc). Results: Between 2009 and 2014, thirty-two patients were enrolled. Median age: 61.5 yrs, median number of prior endocrine regimens: 2 (range 1-4), 72% had visceral disease, 28% had bone only disease, 67% were considered to be responsive to the last ET. For 28 patients evaluable for efficacy the ET was AI =29%, F= 32%, AI+F=39%. The CBR16 was 25% (7/28) and the CBR24 was 14%(4/28). Median PFS for the entire cohort was 2.1 mths and the median PFS for patients with CB at 16 weeks was 7.4 mths. 12% of patients had Grade 3/4 AE (Diarrhea: 6%, Vomiting: 6%, Rash: 3%). Serum HER2/ECD was elevated in 43%, &amp;gt;1 CTC detected in 57%, HER2 positive CTC noted in 18%. HER2/ECD and HER2 positive CTC did not correlate with CBR16. Tumor NGS done on partial sample set (n=7, patients without early progression) demonstrate PI3K pathway activating mutations in 55% (4/7) of patients (PIK3CA mutations=3, AKT3 amplification &amp; PTEN homozygous deletion=1). No ESR1 alterations were observed. All 4 patients with PIK3CA pathway mutations demonstrate CB at 16 wks, and 3/4 demonstrate CB at 24 wks. Conclusion: Addition of Lap restored sensitivity to ET (AI/Fulvestrant) in 25% of patients with HER 2 negative BC. Response was independent of HER 2 positive CTC and HER2/ECD levels. Genomic profiling suggests a relationship between PIK3CA mutation and benefit from this approach. NGS of the entire study cohort is in process and will be reported. HER2-negative breast cancers harboring PIK3CA mutations may rely more on GFR/PI3K signaling than on estrogen for growth; thus, blocking GFR signaling with lap might restore hormonal sensitivity. A randomized study of lap + ET in selected patients with HER2 negative BC is warranted and biomarker results from this study may help identify subgroups that should be targeted in a larger study. Citation Format: Sharma P, Kimler BF, Ward C, Wang K, Ali S, Balasubramanian S, O'Dea AP, Madhusudhana S, Baccaray S, Fabian CJ, Schmitt SB, Godwin AK, Khan QJ. Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-06.

Abstract P6-09-07: The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L)

Abstract Background: For patients with HER-2/hormone positive MBC, the addition of lapatinib to letrozole is associated improvements in tumour response rates and a prolongation of progression free survival. However, moderate to severe diarrhea (≥ grade 2) is a potentially serious toxicity which can lead to dose reductions, delays, hospitalizations and even the premature discontinuation of treatment. Patient care could substantially be improved if these diarrhea events could be accurately predicted through the use of validated and easy-to-use mathematical models. In this study, the development of a repeated measures model to predict the risk of ≥ grade 2 diarrhea prior to each month of L-L therapy is described. Methods Data from 111 patients who received the L-L combination as part of a clinical trial were reviewed [Johnston, 2009]. Generalized estimating equations (GEE) were used to develop the final risk model using a backwards elimination process. Internal validation of the final regression coefficients was done using nonparametric bootstrapping. A risk scoring algorithm (range 0-250) was then derived from the final model coefficients. A receiver operating characteristic curve (ROC) analysis was then undertaken to measure the predictive accuracy of the final scoring algorithm. Results: Presence of skin and lung metastases at baseline, cumulative lapatinib dose and Hg level (nadir) were identified as being important predictors for ≥ grade 2 diarrhea. There was also a negative association between time on therapy and risk of diarrhea where a higher frequency was observed in the first few months. The ROC analysis indicated good predictive accuracy with an area under the curve of 0.80 (95%CI: 0.72 – 0.88). Prior to each new month of therapy, patients with risk scores &amp;gt; 125 units would be considered at high risk for developing ≥ grade 2 diarrhea. Conclusions: Risk of ≥ grade 2 diarrhea is associated with cumulative lapatinib exposure, disease related factors as well as Hg level. The planned external validation and eventual clinical application of this prediction tool will be an important source of risk information for the practicing oncologist and can enhance patient care by optimizing preventative therapies earlier in a proactive manner. Citation Format: George Dranitsaris, Mario E Locouture. The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-07.

Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer

ObjectiveWe investigated the efficacy of maintenance hormone therapy (MHT), which was given to hormone positive metastatic breast cancer (MBC) patients in non-progression status to the previous chemotherapy. MethodsThis study retrospectively analyzed 76 MBC patients who had been treated with MHT from 2006 to 2010 at a single institute. ResultsFor the 76 patients reviewed, the median progression free survival (PFS) to MHT was 14.4 months (95% CI, 11.6–17.3). Prolonged PFS was associated with less previous palliative chemotherapy, fewer metastatic sites, and the absence of visceral metastasis in univariate analysis. Multivariate analysis showed that only the number of previous palliative chemotherapy (HR 1.73, 95% CI, 1.00–2.98; P = 0.04) remained as a significant variable. MHT was generally well tolerated. ConclusionsMHT showed considerable efficacy and tolerability in this study. Further randomized prospective study is warranted.

Healthcare costs in postmenopausal women with hormone-positive metastatic breast cancer

Objectives:This study examines costs for postmenopausal women with hormone receptor positive (HR+) metastatic breast cancer (mBC).Methods:Data were obtained from the IHCIS National Managed Care Benchmark Database from 1/1/2001 to 6/30/2006. Women aged 55–63 years were selected for the study if they met the inclusion criteria, including diagnoses for breast cancer and metastases, and at least two fills for a hormone medication. Patients were followed from the onset of metastases until the earliest date of disenrollment from the health plan or 6/30/2006. Patient characteristics were examined at time of initial diagnoses of metastases, while costs were examined post-diagnosis of metastases and prior to receipt of chemotherapy (pre-chemotherapy initiation period) and from the date of initial receipt of chemotherapy until end of data collection (post-chemotherapy initiation period). Costs were adjusted to account for censoring of the data.Results:The study population consisted of 1,266 women; mean (SD) age was 59.05 (2.57) years. Pre-chemotherapy initiation, unadjusted inpatient, outpatient, and drug costs were $4,392, $47,731, and $5,511, while these costs were $4,590, $57,820, and $38,936 per year, respectively, post-chemotherapy initiation. After adjusting for censoring of data, total medical costs were estimated to be $55,555 and $70,587 in the first 12 months and 18 months, respectively in the pre-chemotherapy initiation period. Post-chemotherapy initiation period, 12-month and 18-month adjusted total medical costs were estimated to be $87,638 and $130,738.Limitations:The use of an administrative claims database necessitates a reliance upon diagnostic codes, age restrictions, and medication use, rather than formal assessments to identify patients with post-hormonal women with breast cancer. Furthermore, such populations of insured patients may not be generalizable to the population as a whole.Conclusions:These findings suggest that healthcare resource use and costs – especially in the outpatient setting – are high among women with HR+ metastatic breast cancer.

Indian experience with diethylstilbestrol in hormone-positive metastatic breast cancer after failure of standard hormone therapy.

e11502 Background: Blocking estrogen receptor or production is standard of care for hormone receptor positive advanced breast cancer patients. A paradoxical approach of using estrogens in such patients has been used for the last 5-6 decades. The mechanism of action of diethylstilbestrol (DES) focuses on induction of apoptosis. Methods: Fifteen cases of hormone receptor positive advanced breast cancer were treated with DES after failure of standard hormonal chemotherapy. Median age was 55 years. Median time before starting DES for metastatic disease was 2.5 years. Median lines of chemotherapy received before starting DES was two. All patients had received aromatase inhibitors, tamoxifen. Ten patients had also received fulvestrant. Nine patients had liver, nine had bone, six had lymph node, four had lung, and two had skin metastasis. Results: 5 mg BID dose of DES was started. After a period of median 6 month therapy, there were four partial responses, six patients had stable disease, and five had progressive disease. Reduction in serum markers CA15.3 and CEA was seen in eight patients. The therapy was well tolerated. There was mild elevation of liver enzymes – SGOT and SGPT in four cases. There were no other untoward toxicity. Conclusions: In post menopausal hormone receptor positive cases of advanced breast cancer, after failure of standard hormone therapy, DES offers safe, cheap, and effective palliative treatment. No significant financial relationships to disclose.