Prognostic factors in patients with HR+/HER2 breast cancer | CMAR – Dove Medical Press

Introduction

Advances in screening and treatment paradigms for breast cancer has led to an overall decline in mortality rate in the past decade.1 The survival rate depends on stage of breast cancer at diagnosis, among other factors.2 The five-year survival rate for patients diagnosed with Stage IV breast cancer is 22%, for Stage III is 72% and Stage II is >90%.3 Clinical decision-making in breast cancer management relies on determination of receptor status, as therapies have been developed that specifically benefit patients depending on hormone receptor (HR) and human epidermal growth factor (HER2) receptor status.46 HR+/HER2 status is the most common molecular subtype, accounting for two-thirds of US female breast cancer cases.79

In addition to advancements in treatment options over time, prognosis of breast cancer is influenced by factors that indicate growth, invasion, and metastatic potential of disease, thereby informing disease course and clinical outcome.4 The HR+/HER2 subtype has been associated with improved survival compared with other subtypes in the metastatic setting, also indicating some prognostic relationship between survival and receptor status.4,10 Amongst HR+/HER2 subtype, survival is influenced by other disease-related factors such as tumor grade, site of the metastasis (eg bone, liver, lung, or brain), prior therapy, as well as patient-related factors (eg age, race).11,12

Although several studies have identified prognostic factors associated with survival, especially in the early breast cancer setting,1315 it remains unclear to what extent these factors impact prognosis in advanced breast cancer. Currently, there is no comprehensive summary assessing the collective available evidence and the strength of evidence for these prognostic factors among patients with HR+/HER2 advanced breast cancer that can aid clinical decision-making. Therefore, we conducted a systematic literature review (SLR) based on a pre-specified protocol to identify the prognostic factors associated with survival endpoints in patients with HR+/HER2 advanced breast cancer and qualitatively assess the evidence and its strength and consistency.

A SLR was conducted and reported in accordance with guidelines established by the Centre for Reviews and Dissemination (CRD),16 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement,17 and Cochrane guidebook.18 Comprehensive searches were conducted in major electronic databases (MEDLINE, EMBASE, and Cochrane Controlled Register of Trials) to identify primary research studies published between January 1, 2010 and November 15, 2018. These were supplemented by searches of relevant conference proceedings (American Society of Clinical Oncology, European Society for Medical Oncology, European Cancer Organization, European Cancer Summit, Improving Care and Knowledge through Translational Research Breast Cancer Conference, The International Consensus Conference for Advanced Breast Cancer, San Antonio Breast Cancer Symposium, and American Association for Cancer Research) held in the two prior years to identify abstracts of interest. The primary publications related to the conference abstracts were searched. Relevant SLRs published recently were cross-checked to find additional studies. The search strategy was designed to include an extensive list of search terms (including MeSH/Emtree terms and natural language terms) which were broadly grouped into: 1) HR+/HER2- breast cancer, 2) advanced disease stage, 3) prognostic factors, 4) outcomesincluding tumor response, also referred to as objective response or clinical benefit, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS). Disease terms included a combination of terms to identify advanced stage breast cancer in combination with terms specific to HR+/HER2- status.

Patients with HR+/HER2- advanced breast cancer were the population of interest for this SLR. However, there were limited studies that included this patient population exclusively. Besides, the proportion of patients with HR+/HER2- subtype widely varied across studies. Hence we decided to exclude studies where <50% of patients were either HR+ or HER2. Since the proportion of patients with advanced/metastatic breast cancer also varied across studies, we included studies where 80% of patients were diagnosed with advanced breast cancer. These eligibility criteria allowed for inclusion of studies with the population of interest, thus striking a balance between validity and generalizability of the review. Observational studies with sample size of 300 patients and RCTs with sample size of 300 patients were eligible for inclusion. Editorials, letters, commentaries, reviews, invitro-studies, and non-English publications were excluded. Since prognostic and predictive terms are used, sometimes incorrectly as interchangeable in literature,19 we excluded studies that reported the interaction p-value between a factor and treatment indicative of predictive association.

After removing duplicates, two reviewers independently screened abstracts and full-texts for eligibility. Disagreements were resolved by consensus or by a third reviewer. A single reviewer extracted all data, and a separate reviewer independently validated extracted data.

Strength of evidence was determined in terms of consistency of evidence, directionality of association, use of multivariable analyses, and strength of association based on effect size. If >50% of studies that assessed an association found it to be significant, then evidence was considered consistent. Similarly, if the direction of association was the same in >50% of studies that demonstrated a significant association, then directionality of association was deemed consistent. For example, negative progesterone receptor status was associated with worse survival in 100% of studies that reported a significant relationship. Based on hazard ratios (HR) calculated in univariate and multivariate analyses, the strength of associations was categorized as strong (HR3), moderate (HR=1.52.9), or weak (HR<1.5).20

Prognostic factors satisfying all the following criteria were deemed to have the strongest evidence of association with OS or PFS: i) consistency of evidence; ii) consistency in the direction of association; iii) at least >5 studies demonstrating a significant association. For example, circulating tumor cell (CTC) count showed the strongest evidence of association with OS in nine out of 10 studies (ie, achieved consistency based on >50% studies with a significant association) and showed consistency in direction of association as well as strength of association based on effect size. The Quality In Prognosis Studies (QUIPS) risk of bias assessment tool was used to assess study quality.21 Based on our understanding of the literature base and variability expected in the patient population and study design, we did not plan to conduct a meta-analysis of the relationship between prognostic factors and survival endpoints.

The PRISMA flow diagram summarizes the review (Figure 1). Overall, the SLR included 72 full-text articles and seven conference abstracts (Table 1).10,2298 The studies identified included retrospective data analyses (71%), prospective cohort studies (16.5%), studies with both retrospective and prospective data collections (2.5%), randomized controlled trials (RCTs) or clinical trials (7.5%), and post-hoc analyses of RCTs (2.5%). OS was the most commonly assessed endpoint (n=67), followed by PFS (n=33), while BCSS (n=5) and tumor response (n=3) were assessed less frequently. The majority of studies were conducted in Europe (n=38), followed by North America (n=15), Asia (n=18), Northern Africa (n=1), the Middle East (n=1), and five studies were multinational. One study did not report study location.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for study selection.

The median age of patients in the included studies ranged between 4468 years; age was not reported in 12 studies.28,31,55,66,8487,93,97 In 22 studies, the entire study population was HR+ and HER2, while in eight studies the proportion of patients with HR+ and/or HER2 status was between 8099%, and the remaining 49 studies included patients with HR+ and/or HER2 status ranging between 5079%.

Patients with breast cancer positive for progesterone, estrogen, or both receptors were deemed HR positive. The relationship between PR status and OS (n=10), PFS (n=2), and tumor response (n=1) was evaluated, with a significant association reported in 80% (n=8), 50% (n=1), and 100% (n=1) of studies, respectively.26,38,45,56,66,72,73,92,98 The association of PR status with BCSS was assessed in one study, and it did not report any significant relationship.40 Patients with negative PR status compared with positive were moderately associated with worse OS. The evidence was insufficient to assess the strength of association between PFS/tumor response and PR status.

The type of tumor grading system used was reported in only four studies that assessed OS. Two studies used the Scarff Bloom Richardson grading,52,88 one utilized the modied BloomRichardson grading,96 and the other study employed the Elston-Ellis modification of Scarff-Bloom-Richardson grading system.82

The relationship between tumor grade and OS (n=21), PFS (n=4), BCSS (n=3), and tumor response (n=1) was evaluated, with a significant association reported in 62% (n=13), 75% (n=3), 100% (n=1), and 100% (n=1) of studies, respectively.26,28,29,38,42,55,66,73,78,81,82,85,88,90 Survival was worse in patients with poorly to moderately differentiated tumors compared with well-differentiated tumors. Consistency in evidence and directionality of association was observed for all survival endpoints. Overall, the effect size of the association between tumor grade and survival endpoints was moderate.

Relationship between tumor size and OS (n=12) and BCSS (n=2) was evaluated, with a significant association reported in 42% (n=5) and 50% (n=1) of studies, respectively.28,38,81,90,92 No included study assessed the association between tumor size and PFS or tumor response. In four studies, large tumors (>5 cm diameter) were associated with worse survival,28,38,90,92 while one study showed improved OS in patients with T2 tumors (>2 cm and <5 cm) compared with T1 tumors (2 cm).81 Less than 50% of studies that assessed the association between tumor size and OS reported a significant association, although among those, directionality of evidence was consistent in the five studies. Overall, the effect size of the association between tumor size and survival endpoints ranged from weak-to-moderate.

The relationship between lymph node involvement and OS (n=11), PFS (n=1), and BCSS (n=2) was evaluated, with a significant association reported in 36% (n=4), 100% (n=1), and 100% (n=2) of studies, respectively.28,38,40,66,70,90

In two of four studies demonstrating a relationship with OS, N1, N2, and N3 categories were associated with better OS than patients with no lymph node involvement (N0);28,90 these studies involved stage IV de novo metastatic patients from the Surveillance, Epidemiology, and End Results (SEER) registry. The trend, however, was converse in the other two studies, among patients with metastatic disease with no prior diagnosis and another with recurrent disease after breast surgery or neoadjuvant chemotherapy, in which greater lymph node involvement was associated with greater risk of death.38,66 The two studies focusing on BCSS and the one study70 focusing on PFS also reported higher lymph node involvement was associated with greater risk of death.28,90 In summary, the directionality of association was inconsistent across studies assessing OS and lymph node involvement. Overall, the effect size of the association between lymph node involvement and survival endpoints was moderate.

In Gampenrieder et al,42 patients with lobular carcinoma (HR=3.44; 95% CI=1.0711.11; P=0.039) or other type of carcinoma (HR=3.19; 95% CI=1.059.70; P=0.041) were associated with 3-fold greater risk of death compared with ductal carcinoma; similar results were observed for PFS. The effect size of the association between histological type (lobular vs ductal) and survival endpoints was strong. The evidence of association was insufficient as a significant association was reported in only one of five studies with OS and two studies with PFS.

Relationship between CTC count and OS (n=10), PFS (n=10), and BCSS (n=1) was evaluated, with a significant association reported in 90% (n=9), 80% (n=8), and 0% (n=0) of studies, respectively.24,31,32,36,47,51,7476,83 The presence of a higher CTC count (5/7.5 mL whole blood) was consistently associated with poor OS and PFS.

The relationship between Ki67 expression and OS (n=7), PFS (n=4), and tumor response (n=1) was evaluated, with a significant association reported in 86% (n=6), 100% (n=4), and 100% (n=1) of studies, respectively.27,30,45,57,60,66,67,80 Studies did not consistently report the source of the Ki67 (primary or metastatic tumor site). High Ki67 expression was associated with worse OS, PFS, and tumor response. The thresholds for the Ki67 was inconsistent across studies, with a Ki67 index of 14% vs >14% being the most common.

The association of both CTCs and Ki67 with OS and PFS was harmonious with respect to consistency of evidence and directionality of association. Overall, the effect size of the association between these biomarkers and survival endpoints were moderate.

The relationship between de novo mBC and OS (n=5), PFS (n=3), and BCSS (n=1) was evaluated, with a significant association reported in 100% (n=5), 67% (n=2), and 0% (n=0) of studies, respectively.30,33,39,57,62,91 Four studies demonstrated longer OS in patients with mBC at diagnosis compared with recurrent breast cancer;30,39,57,91 while one study reported shorter OS in patients with de novo mBC.62 Similarly, one study showed longer PFS associated with patients with de novo mBC,30 while another study showed a reverse relationship.33

The association of de novo mBC with OS and PFS was consistent with respect to evidence. The directionality of association was consistent with OS but not with PFS. The effect size of the association between de novo mBC and survival endpoints ranged between weak to moderate.

The relationship between number of metastatic sites and OS (n=27), PFS (n=11), and BCSS (n=1) was evaluated, with a significant association reported in 89% (n=24), 55% (n=6), and 100% (n=1) of studies, respectively.10,2830,33,38,39,41,43,44,48,5155,57,59,60,66,69,71,75,79,80,89 Multiple metastases were associated with significantly worse OS and PFS. There were variations in the way comparisons between the number of metastatic sites were made across studies (eg, 1 vs >1; 3 vs >3); however, the multiple vs single site of metastases (ie, >1 vs 1) comparison was the most common. Most studies compared either the number of metastatic sites (eg, >1 vs 1) or types of sites/location of metastasis (eg, lungs vs brain, visceral vs non-visceral) However, three studies10,28,54 compared multiple metastatic sites (visceral, brain, skin, lymph nodes) to bone metastasis and found significantly greater risk of death associated with the former. Consistency in evidence and directionality of association was observed for OS and PFS. The effect size of the association between number of metastatic sites and survival endpoints ranged from moderate to strong, depending on the comparison groups.

Twenty-two of the 34 studies found a significant association between sites of metastasis and OS.10,29,30,32,36,38,39,4244,48,52,54,59,63,69,71,75,7880,89 Sites of metastasis were compared heterogeneously (eg, visceral vs non-visceral, visceral vs bone, hepatic vs no hepatic, brain vs no brain). Liver involvement was the most widely studied (n=1230,32,38,39,43,48,59,63,71,78,79,89), followed by brain/CNS (n=1410,29,30,38,43,48,54,61,63,69,7880,89), visceral (n=1310,30,36,4244,52,54,63,69,75,78,99), bone (n=910,38,48,54,59,63,69,75,78), and lung (n=730,38,63,71,78,79,89). All these studies reported shorter OS associated with the presence of metastasis at these specific sites compared to lack of it (eg, visceral vs non-visceral). Bone metastasis was also often used as the reference category when comparing the effect of other metastatic sites on survival, and was associated with improved prognosis compared to these other sites.10,44,54,69,75,78

Ten of 13 studies reported a significant association with PFS.26,29,30,32,33,36,60,63,76,84 Bone was the most assessed site (n=533,36,63,76,84), followed by liver (n=426,30,32,63), and visceral (n=430,60,63,76). As with OS, the presence of metastasis compared with absence in bone, liver, and visceral sites was associated with worse PFS; visceral sites reported worse PFS when compared with bone.10,78 Only one study reported poor tumor response associated with liver metastases.26

The definition of visceral sites varied across studies, most commonly defined as lung, liver, pericardial/pleural/peritoneal, and brain. Consistency in evidence and directionality of association was observed for OS and PFS. The overall effect size of association with survival was: moderate for liver, brain, and visceral sites; weak for lung; and ranged from weak to moderate for bone.

Time to recurrence or progression to advanced breast cancer was most often defined as the time between date of diagnosis of primary breast cancer, and date of diagnosis of first distant metastasis or recurrence. Disease-free interval (DFI), metastasis-free interval (MFI), and recurrence-free interval (RFI) are other terminology used to describe this. In Zhao et al,70 it was defined as the date from surgery to first recurrence. Eight studies did not report the definition.36,45,49,5254,66,71

The relationship between time to recurrence or progression to advanced breast cancer and OS (n=18) and PFS (n=5) was evaluated, with a significant association reported in 78% (n=14) and 80% (n=4) of studies, respectively.10,29,36,39,45,48,49,5254,60,66,70,71,91 In 13 studies, shorter time to recurrence or progression to advanced breast cancer was associated with worse survival relative to longer time, except in Jung et al,48 where the 15 years vs <1 year MFI was associated with worse OS (HR=1.30; 95% CI=1.021.65; P=0.032). The 2-year time interval was the most commonly studied cut-off point. Four studies showed a shorter time to recurrence or progression to advanced breast cancer (eg, <2 years) was associated with worse PFS.29,54,60,70 Consistency in evidence and directionality of association was observed for OS and PFS. The overall effect size of the association between time to recurrence or progression to advanced breast cancer and survival endpoints was moderate.

Given the patient population had advanced breast cancer, patients were likely to have received prior therapy (except those with de novo mBC) such as surgery, chemotherapy, radiation therapy, hormone therapy to treat early breast cancer. Type of prior therapy, line of prior therapy received in the metastatic setting, or clinical benefit to prior therapy were all grouped under the prior therapy category in this review.

Twenty-seven of 35 studies found a significant relationship between OS and prior therapy.10,25,28,30,33,34,38,44,49,52,54,55,57,58,60,66,71,72,76,79,80,8891,94 Prior therapy was either adjuvant or neoadjuvant chemotherapy or hormonal therapy in 19 studies that assessed OS.10,29,30,32,33,38,41,42,44,45,54,57,58,60,66,71,80,91,92 Lack of 1st-line hormonal therapy in patients with advanced breast cancer was also associated with worse survival compared with receiving hormonal therapy.80 Furthermore, the absence of hormonal maintenance therapy in the advanced setting was associated with worse OS in three studies.38,58,80 Two studies reported that adjuvant hormonal therapy use was associated with shorter survival compared with lack of use.33,54 Lobbezoo et al54 reported shorter survival was associated with receipt of initial chemotherapy compared with initial hormonal therapy in the metastatic setting.

Surgery was the prior therapy in ten studies that assessed OS.25,28,38,41,55,58,8890,94 Seven studies showed that receipt of surgery, compared with lack of surgery or best supportive care, resulted in significantly longer survival; five of these studies included de novo mBC patients28,55,89,90,94 and in the remaining two studies, surgery was conducted in early stage breast cancer.38,88

Prior radiotherapy was received in six studies that evaluated OS.38,41,66,79,82,89 First-line radiotherapy (yes vs no) was significantly associated with longer survival for mBC;38 however, the association was not uniform for 1st-line chemotherapy (multiagent vs none/singleagent); Li 2017 38 reported improved OS, while Xie et al33 reported worse OS.

Longer treatment durations in the advanced setting were associated with improved OS, while greater lines of treatment were associated with worse OS.66,76 Four studies demonstrated that the presence of clinical benefit or response to a specific treatment was associated with better OS.38,52,57,72

Fifteen studies assessed the association of PFS with line/type of prior therapy; 13 showed a significant relationship.23,27,29,30,32,33,38,47,54,58,60,70,76,84 Eleven of the 15 studies reported adjuvant or neoadjuvant chemotherapy or hormonal therapy,23,27,29,30,32,33,38,42,54,58,60 while four studies reported chemotherapy as prior treatment.47,70,76,84

Four studies compared multiple vs single lines of treatment and found that increasing treatment line in the metastatic setting correlated with worse prognosis.27,32,33,76 In two studies that included de novo patients, prognostic relevance was shown for surgery vs no surgery as prior therapy and found improved BCSS in patients undergoing breast-conserving surgery/mastectomy.55,90

There was substantial heterogeneity in reporting of type/class of therapy received. In general, patients receiving interventions (surgery/radiotherapy/systemic therapy), responding to treatments, or receiving fewer lines of treatment in the metastatic setting were likely to have better prognosis. Consistency in evidence and directionality of association was observed for OS, PFS, and BCSS. The effect size of the association between prior therapy attributes and survival endpoints was moderate.

Relationship between age and OS (n=37), PFS (n=7), and BCSS (n=3) was evaluated, with significant association reported in 46% (n=17), 29% (n=2), and 67% (n=2) of studies, respectively.10,28,30,33,36,38,43,48,55,57,58,62,69,78,84,85,9092 Among studies that found a significant association, increasing age was associated with worse OS, PFS, or BCSS. The time-point at which age data was collected in the study (whether age at diagnosis or at treatment initiation) was not reported in the majority of included studies. Among studies that did report, age at diagnosis was the most common. In three studies, increasing age was associated with worse OS.57,62,69 Age groups compared across studies varied widely (eg, >50 vs 50 years, >65, or 5064 vs 1849 years). Among the different age group comparisons, age 50 years was the most common cut-off point, reported in six studies.10,54,55,78,90,91 Less than 50% of studies found a significant association between age and OS as well as PFS, however, the directionality of association was consistent (ie, increasing age was associated with shorter survival). The effect size of the association between age and survival endpoints varied widely across studies, ranging from weak to strong.

Relationship between race and OS (n=13) and BCSS (n=3) was evaluated, with a significant association reported in 54% (n=7) and 100% (n=3) of studies, respectively.22,28,38,55,73,78,90 Poorer OS or BCSS was observed in blacks compared with whites. One study reported that better OS was observed for patients of other races vs whites (HR=0.59; 95% CI=0.440.78; P<0.001).38 One study evaluated but did not report a significant association between race and PFS.33 Consistency in evidence and directionality of association was observed between race and OS as well as BCSS. The effect size of the association between race and survival endpoints was weak.

Relationship between performance status and OS (n=14) and PFS (n=8) was evaluated, with a significant association reported in 79% (n=11) and 50% (n=4) of studies, respectively. ECOG scale was used in all but two studies; one study employed the World Health Organization (WHO) performance status scale,51 and one did not define the performance status scale.59 Comparison of different ECOG statuses varied across studies; most studies compared ECOG levels 2 vs 01, three studies compared 1 vs 0, while one study compared 3 vs 02.33,34,37,42,51,63,71,80 All studies found poor performance status or limitations in daily activity to be significantly associated with worse OS or PFS. Consistency in evidence and directionality of association was observed between performance status and OS. Less than 50% of studies found a significant association between PFS and performance status, however, the directionality of association was consistent. The effect size of the association between performance status and survival endpoints was moderate.

Table 2 summarizes the strength of evidence between prognostic factors and survival endpoints. Figure 2 shows the number of studies that reported better, worse, or no association between the prognostic factors and OS (Figure 2A) and PFS (Figure 2B).

Table 2 Strength of Evidence Assessment

Figure 2 Association between selected prognostic factors and OS (A), and PFS (B).

Abbreviations: BCSS, breast cancer-specific survival; CTC, circulating tumor cell; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PFS, progression-free survival; PR, progesterone receptor.

Associations between OS and PR status, tumor grade, CTC count, Ki67 level, de novo mBC, number and sites of metastases, time to recurrence or progression to advanced breast cancer, race, and prior therapy attributes were consistent (>50% of studies found a significant association). However, the evidence was limited (<50% of studies reported a significant association) for tumor size, histological type, lymph node involvement, and age. The direction of association was consistent for all the prognostic factors summarized in this study except for lymph node involvement. Based on effect size, strength of association with OS was moderate (HR=1.52.9) for PR status, tumor grade, Ki67 level, number and sites of metastases, time to recurrence or progression to advanced breast cancer, performance status, and prior therapy attributes, and weak (HR<1.5) for de novo metastatic breast cancer and race.

After applying the strongest evidence criteria, disease-related factors such as PR status, tumor grade, CTC count, Ki67 level, number and sites of metastases, and time to recurrence or progression to advanced breast cancer, performance status, prior therapy attributes, and race were found to have the strongest evidence of an association with OS.

Associations between PFS and tumor grade, CTC count, Ki67 level, number and sites of metastases, time to disease recurrence or progression to advanced breast cancer, and prior therapy attributes were consistent. However, the evidence was limited for PR status, lymph node involvement, histological type, performance status, age, and race; no data were reported for association between PFS and tumor size or marital status. The direction of association was consistent for all the prognostic factors, except for de novo metastatic breast cancer.

Since fewer studies assessed PFS than OS, evidence on prognostic factors related to PFS was limited. Thus, high CTC count, number and sites of metastases, and prior therapy attributes in the early or metastatic setting were the only four prognostic factors with the strongest evidence of an association with worse PFS. Similarly, there was limited information for the other endpoints.

There were many other variables assessed in the included studies. However, these were reported sparsely and we could not assess strength of evidence for them. They consisted of many genetic/biomarkers factors, for example, estrogen receptor gene (ESR1) mutation status,68 ligand binding domain (LBD) status,97 CA 153 level,51,70 alkaline phosphatase level,79 serum C-reactive protein level (CRP),79 lactic acid dehydrogenase (LDH) level,51,59,79 along with other demographic-related factors like marital status,55 income level,55 menopausal status,59 and education status.55 A high level summary can be found in Table 3.

The overall risk of bias was considered high for three studies, moderate for 22 studies, and low for the remaining 47 studies (Figure 3). Studies that failed to report exclusion criteria, definition of survival endpoints, or did not perform multivariate analysis to account for confounding were deemed high risk of bias.

Figure 3 Risk of bias assessment for each domain of QUIPS tool.

This comprehensive SLR was conducted to evaluate the strength and consistency of evidence of prognostic factors associated with survival in patients with HR+/HER2 advanced breast cancer. As commonly observed in oncology literature, OS was the most widely assessed survival endpoint, followed by PFS. The evidence was limited for tumor response (n=3) and BCSS (n=5). Hence, this review focused on prognostic factors associated with OS and PFS.

Higher CTC count, Ki67 level, number of metastases (multiple vs single), and sites of metastases (presence of liver metastases vs absence), prior therapy attributes, negative PR status, higher tumor grade, shorter time to recurrence or progression to advanced breast cancer, poor performance status and race (black vs white) were the prognostic factors with strongest evidence of association with OS and PFS. Previously published studies11,12,24,100,104 have also demonstrated the prognostic relationship between survival endpoints and disease-related factors such as PR status, CTC count, Ki67 level, number and sites of metastasis and treatment-related factors and performance status. Other studies in the literature103,105107 have also reported older age, black race, and unmarried status to be associated with shorter survival rates. Future cohort studies exclusively in HR+/HER2- advanced breast cancer will be beneficial to further validate the collective set of prognostic factors with the strongest evidence.

In the advance disease setting, breast cancer is incurable and the treatment goal is mainly palliative, improving quality-of-life and prolonging survival. Many factors are generally considered in developing treatment plans including patient-related factors like patient preferences, age, menopausal status, co-morbidities, performance status, socioeconomic status, psychological factors, treatment availabilities, and disease-related factors like DFI, previous therapies, tumor burden (number and sites), and any need for rapid disease control.108

This comprehensive review substantiates the importance of these factors in clinical decision-making for HR+/HER2 advanced breast cancer. The directionality of relationship between the prognostic factors and OS and PFS was largely consistent, except for lymph node involvement with OS and de novo metastatic breast cancer with PFS. Another published study109 also reported the divergent association between lymph node involvement and OS. A retrospective cohort study109 reported patients with N1 Stage IV BC had better OS than did those without lymph node metastasis (HR=0.902, 95% CI=0.8250.986, p-value=0.023). One potential explanation could be that the invasion of tumor cell into lymph nodes may have activated an antitumor immune response, which renders beneficial effect on patients with lymph node metastasis.110 Other studies106,111,112 have observed better OS in patients without lymph node metastasis compared to those with lymph node involvement. Similarly, the prognosis of de novo stage IV breast cancer was found to be better than those with recurrent tumors in several studies.4,113,114

Definitions of survival endpoints used across studies varied. The most common definition of OS was the time from diagnosis to death from any cause or last follow-up; many studies calculated the time interval from date of treatment initiation or patient selection. There was overlap in definitions of OS and BCSS. Gong et al55 defined BCSS as time from date of diagnosis to date of death attributed to breast cancer or date of last follow-up, while Yerushalmi et al93 defined BCSS as time from diagnosis of distant metastasis to death or censor date; two other studies did not define BCSS.22,90 It was observed that BCSS was not commonly assessed across included studies.

We observed heterogeneity in the comparison groups for certain prognostic factors for example, different age groups being compared (eg, >50 vs 50, >65, 5064 vs 1849); different cut-off points for Ki67 levels (10%, 14%, 25%, 30%); different prior therapies were compared (initial chemotherapy vs initial endocrine therapy, adjuvant endocrine therapy vs absence of prior therapy); site of metastasis (eg, presence vs absence of liver metastasis, visceral sites vs bone). Due to the differences in categorizations of prognostic factors as well as other factors such as differences in study design and patient population it was not possible to perform meta-analysis or derive a single hazard ratio estimate representing the relationship between the prognostic factors and survival endpoints. Despite inconsistencies in comparators groups, we observed an overall trend in directionality of association for some prognostic factors. For example, tumor size >5 cm diameter, CTC count 5/7.5 mL whole blood, time to recurrence or progression to advanced breast cancer of <2 years, and multiple vs single site of metastases were associated with worse survival.

This review focused on patients with HR+/HER2 advanced breast cancer; however, in 62% of 79 included studies, the proportion of patients with HR+/HER2 breast cancer ranged between 5079%. The results of such studies may not be reflective entirely of patients with HR+/HER2 advanced breast cancer. We observed a dearth of studies investigating the prognostic factors in exclusively patients with HR+/HER2 advanced breast cancer. For studies that included de novo metastatic patients, including in subgroups, baseline characteristics were captured in the metastatic setting. However, for the remaining studies, it was difficult to distinguish whether baseline characteristics were collected at initial diagnosis or when patients progressed to metastatic stage (as this information was not reported).

This review was subject to some limitations. An overall rating for risk of bias (low/moderate/high) was estimated for each study by taking into account the risk levels for the six domains of the QUIPS tool. The cut-off points chosen to derive the overall rating, though based on previously published SLRs, were essentially arbitrary.115117 Other limitations may be the exclusion of non-English studies, though English language studies from across the globe were included, and that studies published before 2010 and after 2018 were not included. Since the studies included in this SLR were published between 20102018, there were no studies that assessed the association between the newer targeted therapies such as CDK4/6 inhibitors, mTOR inhibitor, PI3K inhibitor, or kinase inhibitors, and survival endpoints. The conference abstracts included in this SLR contained limited relevant data and full-text publications related to these abstracts were not available. We found limited evidence on the prognostic value of genetic or tumor biomarkers in patients specifically with HR+/HER2 advanced BC. Some of these studies showed the relationship between tumor markers such as LDH,51,59,79 ALP,79 CEA,51,70 CA,51,70 to be associated with survival. This review did not distinguish the nature of the outcomes assessed (ie, primary or secondary) and therefore findings must be interpreted cautiously. Additionally, there was uncertainty around the power of subgroup analyses data reported in both observational studies and trials.

Strengths of this review include that this is the first SLR, to our knowledge, to comprehensively assess prognostic factors associated with survival in patients with HR+/HER2 advanced breast cancer. This review presents a complete overview of a large number of studies published recently with multivariate robust results that would help account for confounding of other key variables in understanding the association. This review was performed based on best practice guidelines, included supplementary searches of key conference proceedings and cross-referencing of other SLRs, and incorporated a double-blind study selection process, all of which lend to the robustness of this reviews methodology.

The strongest evidence for prognostic factors associated with worse OS included negative PR status, higher tumor grade, higher CTC count (5 vs <5), higher Ki67 levels (>14%), number of metastatic sites (multiple vs single), specific sites of metastases (presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, absence of prior therapy-related attributes (type of therapy, treatment line, response of prior therapy) in early or metastatic setting, poor performance status, and race (black vs white). The strongest evidence for prognostic factors associated with worse PFS included higher CTC count, number and sites of metastases, and prior therapy-related attributes in early or metastatic settings.

Apart from the commonly used markers recommended for routine use (eg, ER, PR, HER2), evaluation of the aforementioned factors shed light on the history and pathophysiology of the breast cancer in a patient, thereby providing a comprehensive clinical picture that may enable clinicians to enhance personalized treatment approaches and supportive care to improve patient outcomes. Identification of these prognostic factors will also guide future research in the HR+/HER2 advanced breast cancer setting.

We thank Michael Friedman for his editorial inputs.

ICON PLC. received funding from Eli Lilly and Company to conduct this review.

Keri Stenger, and Claudia Morato Guimares are employees and shareholders of Eli Lilly and Company. Gebra Cuyn Carter was an employee ofEli Lilly and Company when the review was being conducted. She is a shareholder of Eli Lilly and Company. Shereports personal fees from Exact Sciences.Maitreyee Mohanty, Shivaprasad Singuru, Vanita Tongbram are employees of ICON PLC.Pradeep Basa and Sheena Singh were employees of ICON PLC. when the review was being conducted.Dr. Kuemmel reports personal fees from Eli Lilly and Company, Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, Sonoscope, AstraZeneca, Somatex, MSD, Pfizer, Puma Biotechnology, PFM medical, non-financial support from Roche, Daiichi Sankyo outside the submitted work. Dr. Guarneri reports personal fees from Eli Lilly and Company, Novartis, Roche, MSD, outside the submitted work. Dr Tolaney reports grants and personal fees Eli Lilly and Company, AstraZeneca, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, Bristol-Myers Squibb, Eisai, Nanostring, Puma, Cyclacel, sanofi, Celldex, Odonate, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Anthenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, Mersana Therapeutics, Certara,CytomX, Samsung Bioepsis Inc., Gilead, outside the submitted work.

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26. Goetz MP, OShaughnessy J, Sledge GW, et al. The benefit of abemaciclib in prognostic subgroups: an exploratory analysis of combined data from the MONARCH 2 and 3 studies. Cancer Res Conf. 2017;78(4 Supplement):1.

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30. Bonotto M, Gerratana L, Di Maio M, et al. Chemotherapy versus endocrine therapy as first-line treatment in patients with luminal-like HER2-negative metastatic breast cancer: a propensity score analysis. Breast. 2017;31:114120. doi:10.1016/j.breast.2016.10.021

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33. Xie J, Hao Y, Li N, et al. Clinical outcomes among HR+/HER2- metastatic breast cancer patients with multiple metastatic sites: a chart review study in the US. Exp Hematol Oncol. 2015;4(1):31. doi:10.1186/s40164-015-0023-0

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Prognostic factors in patients with HR+/HER2 breast cancer | CMAR - Dove Medical Press

Hartford Services – FXDFR DB REDEEM 15/04/2042 USD 25 (HGH) gains 0.15% in Active Trading on August 6 – Equities.com

Last Price$ Last TradeChange$ Change Percent %Open$ Prev Close$ High$ low$ 52 Week High$ 52 Week Low$ Market CapPE RatioVolumeExchange

HGH - Market Data & News

Today, Hartford Financial Services Group Inc. - FXDFR DB REDEEM 15/04/2042 USD 25 Incs (NYSE: HGH) stock gained $0.04, accounting for a 0.15% increase. Hartford Services - FXDFR DB REDEEM 15/04/2042 USD 25 opened at $26.41 before trading between $26.45 and $26.36 throughout Fridays session. The activity saw Hartford Services - FXDFR DB REDEEM 15/04/2042 USD 25s market cap rise to $22,743,822,104 on 59,449 shares -above their 30-day average of 54,179.

Visit Hartford Financial Services Group Inc. - FXDFR DB REDEEM 15/04/2042 USD 25's profile for more information.

The New York Stock Exchange is the worlds largest stock exchange by market value at over $26 trillion. It is also the leader for initial public offerings, with $82 billion raised in 2020, including six of the seven largest technology deals. 63% of SPAC proceeds in 2020 were raised on the NYSE, including the six largest transactions.

To get more information on Hartford Financial Services Group Inc. - FXDFR DB REDEEM 15/04/2042 USD 25 and to follow the company's latest updates, you can visit the company's profile page here: Hartford Financial Services Group Inc. - FXDFR DB REDEEM 15/04/2042 USD 25's Profile. For more news on the financial markets be sure to visit Equities News. Also, don't forget to sign-up for the Daily Fix to receive the best stories to your inbox 5 days a week.

Sources: Chart is provided by TradingView based on 15-minute-delayed prices. All other data is provided by IEX Cloud as of 8:05 pm ET on the day of publication.

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Airport Runway Surveillance Market 2021 Growing Trends and Technology |- Argosai, Bosch Security and Safety Systems, CONTROP, Electro Optical…

The Airport Runway Surveillance Market report offers qualitative and quantitative insights and a detailed analysis of market size & growth rate for all possible segments in the market. The Global Airport Runway Surveillance Industry presents a market overview, product details, classification, and market concentration. The report also provides an in-depth survey of key players in the market which is based on various competitive intelligence parameters like company profiles, product picture and specification, capacity, production, price, cost, revenue, and contact information. The Airport Runway Surveillance Market report provides an in-depth study of SWOT analysis i.e. Strength, Weakness, Opportunities, and Threat to the organization.

Click here to get a Free Sample Copy of the Report: (Flat 25%)

https://www.marketinsightsreports.com/reports/03082684702/global-airport-runway-surveillance-market-growth-2021-2026/inquiry?Mode=XII

Top Companiesin the Global Airport Runway Surveillance Market: Argosai, Bosch Security and Safety Systems, CONTROP, Electro Optical Industries, HGH Infrared Systems, Hitachi Kokusai Electric Inc., Moog, NI, Pavemetrics Systems Inc., Rheinmetall Italia SpA, Stratech Group Limited, Vaisala, Xsight Systems and others.

This report segments the global Airport Runway Surveillance market on the basis ofTypesis:

FOD Detection

Intrusion Detection

Other

On the basis ofApplication, the Global Airport Runway Surveillance market is segmented into:

Personal

Business

Military

The research study evaluates the overall size of the market, by making use of a bottom-up approach, wherein data for different industry verticals, and end-user industries and its applications across various product types have been recorded and predicted during the forecast period. These segments and sub-segments have been documented from the industry specialists and professionals, as well as company representatives, and are outwardly validated by analysing previous years data of these segments and sub-segments for getting an accurate and complete market size.

Influence of The Airport Runway Surveillance Market Report:

-Comprehensive assessment of all opportunities and risk in the Airport Runway Surveillance market.

Airport Runway Surveillance market recent innovations and major events.

-Detailed study of business strategies for growth of the Airport Runway Surveillance market-leading players.

-Conclusive study about the growth plot of Airport Runway Surveillance market for forthcoming years.

-In-depth understanding of Airport Runway Surveillance market-particular drivers, constraints and major micro markets.

-Favourable impression inside vital technological and market latest trends striking the Airport Runway Surveillance market.

For more information of this report:

https://www.marketinsightsreports.com/reports/03082684702/global-airport-runway-surveillance-market-growth-2021-2026?Mode=XII

Table Of Content

Chapter 1 Study Coverage

Chapter 2 Executive Summary

Chapter 3 Hard Adventure Airport Runway Surveillance Market Competitor Landscape by Players

Chapter 4 Hard Adventure Airport Runway Surveillance Market Size by Type and Application

Chapter 5 Global and Regional Analysis

Chapter 6 Company Profiles

Chapter 7 Market Opportunities, Challenges, Risks and Influences Factors Analysis

Chapter 8 Value Chain and Sales Channels Analysis

Chapter 9 Research Findings and Conclusion

Chapter 10 Methodology/Research Approach

Finally, the Airport Runway Surveillance Market report is the believable source for gaining the market research that will exponentially accelerate your business. The report gives the principal locale, economic situations with the item value, benefit, limit, generation, supply, request and market development rate and figure, and so on. Airport Runway Surveillance industry report additionally Presents a new task SWOT examination, speculation attainability investigation, and venture return investigation.

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CanGro is a Cosmetic Brand Refusing to use Growth Hormones – PRNewswire

FORT LAUDERDALE, Fla., Aug. 3, 2021 /PRNewswire/ -- CanGro is an Australian-born sensation that is taking the cosmetic world by storm. Started in 2017, the company has spent the intervening years building a passionate, international customer base thanks, in particular, to the fact that it refuses to compromise on its ingredients. This commitment to quality revolves around the fact that the CanGro brand won't use growth hormones a common ingredient in eyelash products due to the serious risks that come with using the substance on healthy eyes.

CanGro was founded by Belinda Robinson and Felecia Tappenden when the pair of entrepreneurs teamed up to create an eyelash product that enhances eyelashes safely. The founders were already personally aware of the damaging effects that eyelash extensions can have on an individual's native lashes. Additionally, they had experienced the redness and soreness that many of the existing serums had on one's eyes. The goal of their new company was to eliminate the need for extensions altogether. Instead, they aimed to create a product that uses safe, effective ingredients to get the most out of an individual's natural eyelashes.

The focus on safe ingredients is a departure from industry norms. Historically, many lash products both have and continue to use growth hormones like prostaglandins to make their serums more effective. What they fail to point out is that prostaglandins are actually a very strong medical ingredient. According to the National Library of Medicine, as recently as 2016, prostaglandin analogs were still "the front-line medication for the treatment of glaucoma...by lowering intraocular pressure."

While this powerful growth hormone created results for those seeking longer lashes, the problem came from the numerous side effects that could take place when a strong ingredient of that nature was used near healthy eyes. According to Tappenden, prostaglandins have been linked to a number of issues, including:

This hefty list of undesirable side effects inspired Tappenden and Robinson to launch CanGro with a vision for safe products that create luscious lashes. They spent months raising funds, conducting research, testing the product (on humans, not just animals), and generally ensuring that they were creating something that was both safe and effective.

The outcome of this effort was Long Lashes. The high-quality eyelash enhancer is Australian-made, gentle enough to be used on sensitive eyes, and utilizes ingredients that are vegan, gluten-free, and cruelty-free.

In the years since its launch, CanGro's cosmetics line has grown quickly as has its customer base. The ability to deliver genuine results without the need for harsh ingredients like growth hormones has been a difference-maker for countless individuals. This has fueled CanGro's exponential growth as the brand has quickly become a premier cosmetic option both on its home turf of Australia as well as around the globe.

About CanGro: CanGro was launched in 2017 as a cosmetic company that offers safe and effective alternatives to many of the harsher products on the market. Since its inception, the brand has developed a robust catalog of products and has sold them to an international audience that includes New Zealand, Europe, Saudi Arabia, Israel, Hong Kong, Taiwan, Canada, and the US.

Please direct inquiries to:Marsha Houck(954) 525-8433[emailprotected]

SOURCE CanGro

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Everything You Need to Know About Beauty Sleep! – Femina

Image: Shutterstock Every time you have a big event coming up for which you need to look your best, be it a party or a wedding, you mustve heard someone recommend that you need your beauty sleep to be fresh and glowing for the day. Commonly, being well-rested has many overall benefits, not just for your everyday life but also for your prolonged well-being.

However, how much truth is there to the term beauty sleep? Is it just a catchy term that people use to promote good, long sleep, or does proper sleep actually have beauty benefits to it? Well, turns out, there have been studies that prove that getting a good rest at night actually better your appearance.Read on to know more about beauty sleep...

1. What Is Beauty Sleep?2. Benefits of Beauty Sleep3. How To Achieve Beauty Sleep?4. FAQs

Did you know that humans have different stages of sleep? There is a stage when you are not so much in a deep sleep and this is when you usually get your dreams. Whereas, the other stage is when you are fast asleep and all your body functions slow down. This is the stage where the actual restoration of your body happens.

When we enter deep sleep, the cortisol (stress hormone) goes down and the growth hormones go up. These growth hormones start their work and repair the damage done to our body during the day and restore our skin and body. This means that your skin can look amazing even before you start your daily care routine in the morning.

Tip: The average time you should sleep to get a good beauty rest is 7-9 hours.

Your skin health significantly gets worse when you are not sleeping properly. Skin is exposed to a bunch of harmful stressors throughout the day, when you go to sleep your hormones start working and the skin starts healing. When you dont get enough sleep, the skin doesnt get enough time to heal. When your skin faces some damage, a few consecutive nights of good sleep can help in the repair.

Tip: Drink eight glasses of water during the daytime, so your body can hydrate better when youre asleep.

A lot of times when you dont sleep properly, or are beyond exhausted, you get deep dark circles under your eyes or your eyes start puffing up. These are almost impossible to hide, and why take the effort at all, if you can just get rid of them with a good nights sleep. Ensure you sleep for eight hours every day, and wake up with your perfect eyes.

Tip: Try using a few pillows under your head as you sleep on your back. The elevation improves blood flow and prevents blood from pooling under your eyes.

There are a lot of reasons as to why our skin starts to show the signs of old age even at a young age. A simple solution to avoid this is having a proper sleep schedule. While sleeping, the blood flows to the epidermis increases, which increases the formation of collagen. This prevents the skin from sagging and getting wrinkles. So, the more sleep you get, the more collagen is formed, making it less likely to wrinkle.

Tip: Sleep with a memory foam pillow as the flexibility of the foam doesnt compress your skin as much.

Hormonal and stress-related acne is very common among young women, and the daily breakouts can honestly be quite irritating. Poor sleep can lead to increased stressed and also hormonal imbalance. Sleeping properly every night can aid in regulating your hormones and manage your stress, which would reduce the breakouts.

Tip: Clean your pillowcase weekly to get rid of bacteria that could harm your skin.

When your sleep is restricted, you develop higher levels of ghrelin. Ghrelin is also called the hunger hormone. It is the hormone that stimulates your appetite and makes you hungrier all the time. Sleeping regulates your metabolism, when you dont sleep properly, your metabolism slows down and it can get harder for you to lose weight.

Tip: Have a light meal before you go to bed. Heavy meals at night can increase your weight gain.

Washing your face is obviously a very important thing to do, and you should ideally do it multiple times in a day. However, doing it right before you sleep is optimal. In the span of the day, your face collects a lot of dirt, bacteria and even produces oil, and there is obviously also a chance that you have some make upon. Cleansing your face right before you sleep helps in getting rid of all these and prevents them from transferring to your pillowcases.

Tip: Wash your face at night to prevent breakouts.

There are a lot of times when we feel particularly snacky at midnight, at times like these it is best to avoid the ones with high salt levels like a bag of chips and instead go for healthier options. Salty midnight snacks are responsible for inflammation and puffy eyes in the morning. They can also give you stomach aches and increase the time it takes for you to fall asleep.

Tip: If you feel hungry at night, try eating a fruit or snack on nuts.

For many people, sleep doesnt come very easily. You may be stressed or just overthinking about things. It is very helpful if you create an environment that completely relaxes you and aids you in better sleep. Make sure your bedding is comfortable, the temperature in your room is to your liking. Maybe put on some relaxing music or white noise, if that helps you.

Tip: It is always better to sleep in pitch darkness. If you dont like it that way, only keep one dim light on.

Drinking alcohol close to your bedtime has a lot of disadvantages. Firstly, it reduces the quality of your rest. Additionally, it also dilates your blood vessels which would cause your eyes and face to swell up more in the morning. An evening drink may seem relaxing at the moment, but it can add to your stress levels later and also cause insomnia in many. So, it is best to avoid nighttime drinking.

Tip: Try to drink water, tea, or warm milk before sleeping.

Apart from cleaning your pillowcases, regularly cleaning your bedsheets is also equally important. Cleaning and changing them regularly helps in getting rid of any acne-causing bacteria and take care of your complexion. Use a mild detergent and use a fabric sanitizer to get rid of germs, dirt, and bacteria.

Tip: Try to wash your sheets weekly, or at most two weeks if you dont have the time.

Also Read:Everything You Should Know About Using Vitamin C For Your Skin

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Everything You Need to Know About Beauty Sleep! - Femina

Global Hormone Replacement Therapeutics Market 2021 Industry Segmentation, CAGR Status, Leading Trends, Forecast to 2027 KhelPanda – KhelPanda

The Global Hormone Replacement Therapeutics Market from 2021 to 2027 research focuses on the global examination of current market developments. MarketQuest.biz objective is to provide customers with a complete view of the market and to assist them in formulating growth plans. The Hormone Replacement Therapeutics provides a prediction for the years 2021-2027 based on a thorough and professional study.

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It focuses on market elements such as major drivers, opportunities, limiting factors, and issues in the global market. Company strategists will benefit from this study since it will help them achieve effective expansion in both global and regional markets. The research provides details on the many types of

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The following are the important participants identified in the Hormone Replacement Therapeutics report:

The major geographical areas covered in this study are

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This report can be customized to meet the clients requirements. Please connect with our sales team (sales@marketquest.biz), who will ensure that you get a report that suits your needs. You can also get in touch with our executives on +1-201-465-4211 to share your research requirements.

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Global Hormone Replacement Therapeutics Market 2021 Industry Segmentation, CAGR Status, Leading Trends, Forecast to 2027 KhelPanda - KhelPanda

Global Growth Hormone-inhibiting Hormone Market 2021 Development Status Novartis, Pfizer, Ispen The Manomet Current – The Manomet Current

MarketQuest.biz research on the former Global Growth Hormone-inhibiting Hormone Market and existing forecasts for something like the economic development and trends to better grasp these market models in the years 2021 to 2027. The report presents Growth Hormone-inhibiting Hormone sales for 202127 predicated upon that background for 2020 with the year forecasted for 2027. In the expected period, the accumulated trend of increase (CAGR) was also reported.

A unique approach was developed to examine the expansion of the international market Growth Hormone-inhibiting Hormone and the determination of the industry plays a vital role in development opportunities. This is a combination of primary and secondary research that assists analysts to deliver their results reliably and precisely.

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Types segmented in the report are:

Applications in the report are:

In their international markets study Growth Hormone-inhibiting Hormone, analysts discuss multiple sources, namely details about corporate internet, company financial reports, documents of Moment please, transaction reports, official documents, and state institutes.

The market included geographical areas the report is based on important industries, covering geographical regions

It gives an improved efficiency to the variable declaration that influences or tries to control worldwide monetary construction.

The key players covered in the global market report:

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The above research creates a competitive atmosphere for the market. This study shows a regulatory environment Growth Hormone-inhibiting Hormone. Major economic participants will be selected for a better understanding of customer factors and categorized them. Some of the elements reported by the major companies in this study include the company description, current status, economic environment, and SWOT.

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Global Growth Hormone-inhibiting Hormone Market 2021 Development Status Novartis, Pfizer, Ispen The Manomet Current - The Manomet Current

From your diet to sleep habits doc shares 5 hacks to grow taller… – The Sun

WE'VE all envied our friends who are just that little bit taller than us - but one doctor has now revealed how you could soar to their heights.

Whether it's your diet, or making sure you get good quality sleep, Dr Mike Varshavski says there are some actions you can take that will help.

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Posting to TikTok Dr Mike highlighted the five things you should be focusing on to grow as tall as possible.

He explained: "Make sure you get enough protein, make sure you're eating your veggies and fruits. I know that it sounds like your grandma talking but it's true.

"You need to get enough sleep, because when you sleep well you actually get a lot of growth hormone release.

"When I say a lot, I mean the right amount.

"On top of that you need to make sure you're exercising, it makes you process food differently, it makes your muscles grow and all of those things will contribute to your physical appearance - including your height."

The post has been watched more than 270,000 times and has been liked more than 50,000 times.

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Dr Mike's 5 tips to help you grow taller

Dr Mike explained the five things you need to do to grow the tallest you can be

Other doctors have previously shared their tips on how you can grow taller.

Dr Brian Boxer Walchersaid many people tend to look to their parents when it comes to their appearance, with them putting down their height and other aesthetics such as eye and hair colour, down to genetics.

But he said just 60 per cent of height is passed on through genetics.

Dr Walcher said: That means that 40 per cent are things you can do.

The expert said he is 6ft 2inches but his parents measured in at 5ft 7inches and 5ft 5inches.

He agreed with Dr Mike and said that sleep is one of the best things you can do to get taller.

He also revealed drinking cows milk and lifting weights were other great ways to grow taller, with good poster another tool in the arsenal of height.

In order to improve posture and prevent pain we should be sitting with our knees, hips and elbows at 90 degree angles with our spine in a neutral position and our shoulder blades set gently back and down away from our ears, with our feetcomfortably on the floor.

But if this all sounds too much like hard work, then one TikTok doctor said you can pay 60,000 for surgery to get taller.

Doctor Shahab Mahboubian uses "magnetic nails" to perform height-lengthening surgery, which he has been practising for over ten years.

The 45-year-old, who lives in California charges patients 56,000 ($75,000) for lengthening of femurs and 61,000 ($85,000) for lengthening of tibias.

Those who want maximum results could shell out a whopping 112,000 ($155,000) to have their bones "cut" through.

The orthopaedic surgeon highlights that it will take three to four months for patients to walk unassisted and six to eight months after surgery until they can take part in sports.

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From your diet to sleep habits doc shares 5 hacks to grow taller... - The Sun

Best Supplements for Working Out, According to Experts | Eat This Not That – Eat This, Not That

Everyone's looking for an edge. Whether you're an Olympic athlete or weekend tennis player, everyone wants something that'll provide a boost during exercise or competition. It takes more than pushing yourself physically to build your body or improve your performance; you need to supply your body with nutrients that'll maximize your effort.

Even if you eat enough carbohydrates, the chief macronutrient for energy to fuel endurance, and even if you eat a healthy diet (do you, really?), you probably don't get enough of the good stuff that'll make your body hum when you're huffing and puffing. Dietary supplements can fill those gaps.

We asked nutritionists and fitness experts for their must-have supplements for exercise and sports. Be forewarned: there are a lot of opinions out there and few iron-clad clinical studies supporting the claims. But you can do your own research to figure out what's worth a try for the goals you have in mind. This review of Dietary Supplements for Exercise and Athletic Performance from the National Institutes of Health, will help the next time you're considering buying, say, deer antler velvet, a Chinese supplement purported to have growth factors for building muscle.

And remember that dietary supplements are not regulated by the Food & Drug Administration as drugs. Many manufacturers make claims that may not be entirely true. What's more, because they are not rigorously controlled as pharmaceuticals, dietary supplements can contain ingredients that may interact with your prescription medicines. Talk with your doctor before taking any new dietary supplements and review our story on Popular Supplements with Hidden Dangers.

Protein is the building block of muscle. If you're doing vigorous exercise or resistance training, you are breaking down your muscle fibers and need protein to repair and rebuild them stronger than they were before, says certified sports nutritionist Hope Prenner, a National Academy of Sports Medicine Certified Personal Trainer on staff at BucketListTummy.com. "I strongly recommend supplementing with protein powder and creatine monohydrate, a natural substance found in muscle cells that is the first form of energy that the body burns through during strenuous exercise," she says.

READ MORE:The Best and Worst Protein Powders to Buy

Polyphenols are micronutrients found in fruits and vegetables. One of the most effective of these phytonutrients is ellagitannin, which has been shown to reduce delayed onset muscle soreness (DOMS) that typically starts a day or two after a workout.

Ellagitannins are found in pomegranate extract, which is a key ingredient in Beachbody super trainer Autumn Calabrese's go-to post-workout drink Recover, a plant-based protein and polyphenol powder. "I feel good knowing I'm getting a high-quality source of vegan protein and phytonutrients to combat exercise-induced muscle soreness, speed recovery and restore my strength so I can do it all over again the next day," says Calabrese, author of Lose Weight Like Crazy Even If You Have a Crazy Life.

"Recover helps me stay consistent with my routine. At almost 41, I'm the fittest I've ever been." A serving of Recover contains 20 grams of pea protein; that's just about the maximum amount your body can use at one time to support muscle protein synthesis, according to a study in the Journal of the International Society of Sports Nutrition.

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Exercise itself helps build bone. The forces you exert on your bones when exercising cause bones to become denser. But vitamin D is also essential for good bone health because our bodies do not effectively absorb calcium without it. "Supplementing with vitamin D is a good idea for athletes because it promotes bone health, which all athletes rely on for good performance," says Diana Gariglio-Clelland, RD, a nutritionist on staff at NextLuxury.com, and a certified diabetes education specialist. "It's estimated that over 40% of Americans are vitamin D deficient, so vitamin D is a worthwhile supplement to invest in for overall health." And it is well-researched in terms of benefits, something that can't be said of all dietary supplements, she says.

For more, check outThe #1 Best Vitamin D Supplement to Take, Says Dietitian.

The BCAAs valine, leucine, and isoleucine are essential amino acids your body gets from the proteins in dairy, meat, and legumes. For you chemistry buffs out there, "branched-chain" refers to their chemical structure. BCAA supplements are popular with weightlifters because they may enhance muscle growth and help prevent DOMS (delayed-onset muscle soreness). "One of the most important things to look for when choosing a BCAA supplement is the ratio of leucine to isoleucine and valine," says Jay Cowin, a certified sports nutrition advisor (CSNA) and the nutritionist/director of formulations for ASYSTEM.

"I recommend a supplement that uses a 2:1:1 since leucine plays the most important role in muscle protein synthesis while isoleucine helps process leucine. Valine helps reduce fatigue during your workout." The supplements are available in capsule or powder form. Cowin prefers the powder because it acts faster and delivers higher doses than BCAA capsules.

Arginine (L-arginine) is an amino acid that's often used to treat peripheral artery disease and erectile dysfunction because it affects nitric oxide production, relaxing blood vessels, and improving blood flow. But it's an exercise supplement, too. "It stimulates growth hormone to help grow muscle, build strength, and aid in recovery from vigorous workouts," says Cowin. "It's a precursor to creatine for natural performance enhancement." Cowin points out that arginine and other supplements often contain added ingredients like electrolytes, sweeteners, and gluten, which may cause negative reactions if you are sensitive to these additives. Check ingredient labels before buying.

Beetroot powder is made from the beet plant, a terrific source of nutrients like folate, manganese, potassium, iron, vitamin C, and fiber. "Beet root can help increase blood flow to help oxygenate exercisers' hard-working muscles," says Lauren Manaker, MS, RDN, a member of our Eat This, Not That! Medical Expert Board and a licensed dietitian for Zhou Nutrition, which makes Zhou Beet Complete, beetroot powder.

Studies have shown that beetroot powder can improve athletic performance by helping the mitochondria, the "energy engines" in your cells to work more efficiently during intense exercise. The key ingredient in beetroot is nitrate: a substance that helps your body produce nitric oxide, which dilates blood vessels, improves blood flow, and lowers blood pressure.

In addition, "the antioxidants in beet root may help combat the oxidative stress that may occur during a strenuous workout," says Manaker, who serves as an executive committee member of the Women's Health Dietetic Practice Group of the Academy of Nutrition and Dietetics. "I recommend beetroot as an addition to a dietary regimen for those who exercise vigorously." You can read more about the potential for nitric oxide to boost resistance exercise in this study in The Journal of Strength Conditioning Research involving bench pressing at 60% of recreational athletes' one repetition maximum.

Jamie Hickey, NASM, a certified trainer, nutritionist, and founder of Truism Fitness recommends quercetin supplements. "Quercetin (a flavonoid found in apples, tea, berries and red wine) is a well-studied antioxidant that can work to increase your endurance and act as an appetite suppressant," he says. "A variety of studies have found that quercetin supplementation increases exercise tolerance and muscle loss while decreasing markers of muscle degradation." One double-blind clinical trial of 60 male athletes in the International Journal of Preventive Medicine found that those who received quercetin capsules improved their lean body mass, basal metabolic rate, and total energy expenditure.

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Best Supplements for Working Out, According to Experts | Eat This Not That - Eat This, Not That

Cracking the code of food labels and meat scores – Madison.com

Standing among your many options at the grocery store can be overwhelming. With so many labels to choose from, knowing what they mean can make all the difference when it comes time to choose the right product with the desired flavor and texture for your recipe thats also in line with the grazing and feed practices you support.

Annika Charter-Williams of Charter Beef in Shepherd, Montana says of labeling and educating consumers, For me, as a producer, it is of utmost importance that our ranch, and honestly the whole agricultural industry, is transparent about the practices it employs. I think there is a lot of distrust about our food system and where our food comes from. Consumers have started making it very apparent they care about that knowledge.

She adds that buying locally gives the consumer a better opportunity to talk to the rancher about their practices and see it for themselves, solidifying the trust between the customer and the producer.

Our cattle, like most cattle, are on the range most of their lives, Charter-Williams says. Charter Beef employs holistic range practices and rotational grazing. This essentially means that most of our ranching decisions are based first on how we take care of our soil and our grasslands while taking care of the animals that live off of it.

De-mystifying the labels

Antibiotic-free means no antibiotics for disease prevention has been administered. Animals raised with antibiotics contributes to the public health concern of antibiotic resistance. Also, Charter-Williams explains that, when animals are young and become sick, if a rancher wants to stay true to their practices, the sick cattle should be removed from the feeding stock so that they arent sold for beef, but rather used for breeding purposes instead.

Hormone-free means no added growth hormones have been used in raising the cattle.

Grass-fed refers to cattle consuming grass. All cattle eat grass and forage during their lives. Consumers should look for labels certifying a 100% grass-fed diet to ensure that no grain had ever been eaten. According to Charter-Williams, the benefit of buying grass-fed meat means that pasture-raised cattle and the wide-open spaces they enjoy yields a healthier herd, translating to better-quality meat.

Cattle often receive supplemental grain feed or are finished on a fully grain-based diet. Consuming grains results in marbling and tenderness in the meat as the cows gain weight more quickly and reliably.

Grass-finished means the cattle receive a grass or forage diet their entire lives. Finished means that the cow is physically mature in skeleton, muscle and fatty tissue on the outside of the muscle as well as inside for marbling. Much of the beefs flavor and tenderness come from the fat content.

Charter-Williams shares how she raises their cows: We produce grass-fed, grass-finished beef. We also produce grass-fed, grain-finished beef. We found our consumers want both options and are the happiest with their choices when they know who we are and what we do.

Natural is defined by the U.S. Department of Agriculture as a product that does not contain artificial flavors, colorings, chemical preservatives or other synthetic ingredients. The beef must be minimally processed so it is not fundamentally altered. The label must also expand the term natural with no artificial ingredients; minimally processed.

Non-GMO Project Verified means the cattle were not fed a diet containing genetically engineered crops.

Organic or USDA certified organic is a product label for beef from cattle that was fed 100% organic feed and forage. This includes non-GMO feed, but the cattle are not required to be grass-fed or grass-finished. Antibiotics and hormones must never be administered. The cattle are raised in natural conditions accommodating their natural behavior such as the ability to graze on pasture.

Charter-Williams, who sells directly to the consumer, says of the importance of consumers understanding labeling and knowing their producer, Some ranches might not be able to avoid using GMO feed or antibiotics to save a sick calf or cow for a prosperous ranching operation. To me, the most important thing is for our ranch, or any ranch, to be open about practices and educate consumers why we do what we do. That is the beauty about direct marketing our beef.

How does your meat score?

Grades of beef are categorized by the U.S. Department of Agriculture into eightlevels of beef quality: prime, choice, select, standard, commercial, utility, cutter and canner. Choice and select grades are the most commonly sold options in grocery stores, though prime can be procured at finer meat counters. The meat quality is based on the degree of marbling, or the flecks of fat within the meat, and maturity of the cow, but they are not the only factors that determine flavor and tenderness. Diet, exercise, breed and aging also play a role in meat quality.

The fat found on the outside of the meat is not considered marbling and therefore not a factor when choosing grade. Only a quarter-inch of fat should remain after trimming and before cooking. The fat on grass-fed beef will have a yellow hue which indicates higher levels of carotenoids and beta-carotene ingested from the grass. Because grass-fed cattle graze a large portion of the day, their meat will naturally contain less marbling, though many feel it has a richer, deeper beef flavor. The grades below are based on beef from cattle raised on grain-based diets.

Prime beef is produced from young, well-fed cattle. It has abundant marbling interspersed with lean meat. Often sold with a premium price tag, prime is most commonly found in finer restaurants and specialty butcher shops. Prime roasts and steaks are excellent for dry heat cooking such as broiling, roasting or grilling.

Choice beef is high-quality but has less marbling than prime. Choice roasts and steaks from the loin and rib will be very tender, juicy and flavorful and suitable for dry cooking methods such as grilling. Many of the less tender cuts should be cooked to a medium-rare doneness or braised or simmered with liquid in a tightly covered pan to bring out the flavor and add moisture and tenderness.

Select beef is very uniform in quality and typically leaner than prime or choice. Because it has less marbling, it may lack the juiciness and flavor of the higher grades, though it can still be very tender. Only the tender cuts such as rib-eyes or tenderloin should be cooked with dry heat. Other cuts benefit from marination before cooking or braising to obtain optimal tenderness and flavor.

Standard and commercial grades of beef may be sold as ungraded, but utility, cutter and canner grades of beef are seldom, if ever, sold in a retail setting, but are used instead to make processed products.

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Cracking the code of food labels and meat scores - Madison.com