Introduction
Materials and methods
Results
1. Definition of metastatic disease or locoregional recurrence not susceptible to local curative treatment
Is it necessary to determine the intrinsic luminal subtype using gene expression platforms for therapeutic decision-making in luminal MBC?
Can luminal A and B MBC subtypes be differentiated using immunohistochemical techniques?
What are the criteria for defining menopause?
NCCN [100] | Prior bilateral oophorectomy ≥ 60 years < 60 years, and amenorrhea ≥ 12 months in the absence of chemotherapy, tamoxifen, toremifene, or Ovarian suppression, and levels of FSH and estradiol within postmenopausal ranges In case of treatment with tamoxifen or toremifene and age < 60 years, FSH and estradiol plasma levels must be within postmenopausal rangesa |
ASCO [19] | Lack of menstruation in the past 12 months in the absence of chemotherapy Oophorectomy, or Ovarian suppression with LHRH agonists |
NICE [101] | > 45 years with no menstruation in the last 12 months and not taking hormonal contraception, or > 45 years with hysterectomy and menopausal symptomsb |
Should metastatic disease be biopsied at the time of its appearance and should the result guide the therapeutic decision?
LA (%) | LE/RD | |
---|---|---|
90 | 1 | |
Determination of intrinsic luminal subtypes using gene expression should not be the only factor considered in decision-making in luminal MBC. Decisions on the treatment of luminal MBC (HR-positive, HER2-negative) have to be made taking into account biomarker results (ER, PR, HER2) from immunohistochemistry and ISH (expert opinion) | 92 | 5/D |
Menopause is defined based on the following criteria: Age ≥ 60 years or Bilateral oophorectomy or Age < 60 years and ≥ 12 months of amenorrhea in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression, with levels of FSH and estradiol within postmenopausal ranges In case of treatment with tamoxifen or toremifene and age < 60 years, FSH and estradiol plasma levels must be within postmenopausal ranges* [28] | 97 | 5/D |
Premenopausal patients who have received chemotherapy may present anovulation/amenorrhea, without implying a loss of ovarian function. Therefore, FSH and estradiol levels persistently within menopausal ranges with close monitoring for a period of at least 2 years must be demonstrated to assign a post-menopausal status (expert opinion) | 95 | 5/D |
99 | 1/B | |
Whenever clinically possible and technically appropriate, the study of biomarkers (ER, PR, and HER2) in metastatic disease is recommended (at least at the beginning of metastatic disease), as these markers can change in disease progression with respect to the primary tumor, so the most appropriate systemic treatment can be selected (although insufficient evidence is available to suggest that re-evaluation of biomarkers improves prognosis). This procedure should always be carried out if the biomarker status of the primary tumor is unknown and there is no access to it [34‐36] | 99 | 1/B |
When discrepancies are found between ER, PR or HER2 biomarkers in the primary tumor and the metastases, the ER, PR and HER2 status of the metastasis should be used to guide systemic treatment, provided that it is compatible with the setting/clinical judgment. In this case, serial biopsies from various locations are recommended for a better assessment of biomarker progress [35, 37] | 88 | 5/D |
2. Definition of hormone sensitivity and hormone resistance in metastatic luminal disease
What variables can be used to set the definition of hormone sensitivity and hormone resistance in luminal MBC?
Reference | Primary hormone resistance | Secondary hormone resistance | Level of evidence |
---|---|---|---|
European Consensus guidelines [34] | Relapse occurred during the first 2 years of adjuvant HT, or Progressive disease in the first 6 months of HT in MBC | Relapse occurred after the first 2 years of adjuvant HT or in the first year after completion of adjuvant HT Progressive disease occurring after the first 6 months of HT in MBC | 5 |
GINECO study [57] | Relapse during adjuvant HT or in the first 6 months after completion of adjuvant HT Progressive disease in the first 6 months of HT in MBC | Relapse occurring later than 6 months after completion of adjuvant HT, or Progression after 6 months of starting HT in MBC | 2 |
Progressive disease without initial response to treatment | Progressive disease after initial response to treatment | 5 |
Is there evidence for suggesting that a combination of several hormonal drugs can reverse hormone resistance and increase effectiveness compared to single-agent hormone therapy?
Is there evidence for suggesting that HT combined with chemotherapy can reverse hormone resistance and increase effectiveness compared to single-agent hormone therapy?
Is there evidence for supporting the use of HT combined with targeted therapies instead of single-agent hormone therapy to reverse hormone resistance and increase effectiveness in HR-positive, HER2-negative MBC?
LA (%) | LE/RD | |
---|---|---|
Negativization (< 1%) of hormone receptors in metastatic cells should be considered as hormone resistance, so ER, PR and HER2 of a new metastasis should be determined whenever possible before making therapeutic decisions (expert opinion) | 95 | 5 |
A high level of hormone receptors makes hormone sensitivity more likely. However, there is no accurate cutoff point or score that indicates hormone resistance, so any tumor with ER ≥ 1% can theoretically be hormone sensitive (expert opinion) | 93 | 5 |
The only unequivocal criterion of hormone resistance is progression during a hormonal intervention. Progressive disease during the first 6 months of HT for MB or during the first 2 years of (neo-)adjuvant HT is evidence of resistance to hormone therapy, so the line of treatment must be changed [19, 50] | 97 | 2 |
93 | 2/B | |
In the context of disease relapse after adjuvant treatment, progression occurring during the first 2 years of adjuvant treatment can be considered as primary or refractory hormone resistance [34] | 97 | 5 |
In the context of MBC, progression in the first 6 months of HT can be considered primary hormone resistance [34] | 97 | 5 |
Insufficient evidence was found to answer this question. However, in the context of relapse during or after adjuvant treatment, relapse occurring later than 2 years after starting treatment and within 1 year after completion could be considered secondary hormone resistance [34] | 95 | 5 |
In the context of metastatic disease, progressive disease after an initial benefit with HT within the first 6 months of treatment is considered secondary hormone resistance [34] | 92 | 5 |
97 | 1/A | |
95 | 1/B | |
93 | 3/C | |
In patients with HR-positive, HER2-negative advanced breast cancer, the use of a combination of TH and chemotherapy is recommended. Sequential administration is recommended, with HT being the preferred option in first line and in successive lines until the emergence of resistance. The use of chemotherapy as a first option is preferable in a critical situation of visceral disease requiring a quick response [19, 34, 56] | 99 | 2/C |
In postmenopausal patients, cyclin-dependent kinase inhibitors ribociclib and palbociclib in combination with an NSAI are recommended as a treatment option in first-line HT. Palbociclib is also recommended in second line in combination with fulvestrant after failure on first-line therapy (palbociclib is also indicated in premenopausal* patients in combination with an NSAI or fulvestrant with an LHRH analog) [38, 66‐69, 74] | 97 | 1/A |
In postmenopausal patients, the combination of exemestane with everolimus is recommended in the absence of symptomatic visceral disease after failure of an NSAI. The use of mTOR inhibitors is not recommended in patients who have not previously received an NSAI or in cases of MBC de novo or those who have relapsed after more than 1 year after the end of adjuvant treatment [19, 34] | 97 | 2/B |
89 | 2/B | |
95 | 2/B |
3. Therapeutic decision-making
Can the menopausal status influence the selection of first-line treatment? Should ovarian function be suppressed in first-line treatment?
What are the criteria for tumor “aggressiveness” in luminal MBC that would indicate the need for chemotherapy?
Are serum biomarkers useful?
LA (%) | LE/RD | |
---|---|---|
Menopausal status should not be taken into account when deciding whether to use chemotherapy or HT in patients with ER-positive, HER2-negative MBC [79] | 89 | 5/D |
90 | 5/D | |
96 | 2/B | |
In premenopausal patients with ER-positive MBC who have never received HT or who relapse after 12 months since completing adjuvant HT, ovarian suppression or ablation should be recommended in combination with tamoxifen or AI ± cyclin inhibitors as first-line treatment, provided that there is no visceral crisis [55] | 97 | 1/A |
In premenopausal patients with ER-positive MBC who relapse during adjuvant HT or in the 12 months after completion of adjuvant HT, ovarian ablation could be combined with an AI or fulvestrant, as in postmenopausal patients, although the evidence is still inadequate [78] | 93 | 3/C |
Suggested criteria for tumor “aggressiveness” in luminal MBC that would indicate the need for treatment with chemotherapy are as follows: Rapidly progressing or very symptomatic disease Disease compromising a vital organ or imminent risk to life Disease with demonstrated endocrine resistance, even after previous treatment with targeted therapies (mTOR or cyclin inhibitors, for example) casting doubt on the possible response to HT (expert opinion) | 99 | 5/D |
Serum markers may not be used as the sole criterion for defining progression (resistance) or for starting, stopping or changing HT. However, progressive and sustained elevation (two determinations more than 1 month apart) of CA 15. 3 and/or CEA could be useful in unmeasurable disease to raise suspicion of progression (resistance) and to request imaging tests to confirm progression (evaluation of PET/CT) (expert opinion) | 97 | 5/D |
In the event of a sustained elevation of serum marker CA15.3 and/or CEA during HT, imaging studies should be requested to document any progression/hormone resistance. At this stage, PET/CT is more sensitive than conventional methods, especially in the evaluation of pathological axillary, supraclavicular, internal mammary chain, and mediastinal lymphadenopathies [56, 85] | 90 | 3/C |
99 | 2/C |