Recommendations from the European Breast Cancer Guidelines

Should a threshold of 10% or more vs. 1% or more of cells showing oestrogen receptor positivity be used for providing endocrine therapy in women with invasive breast cancer?

Recommendation

The recommendation tailored for patient/individual is currently under development. Please find below the recommendation already issued for healthcare professionals.

In women with invasive breast cancer, the ECIBC Guidelines Development Group suggests administration of adjuvant endocrine therapy if 1% or greater of tumour cells show oestrogen receptor positivity rather than applying a threshold of 10% tumour cell oestrogen receptor positivity (conditional recommendation, very low certainty in the evidence).

Recommendation strength

  •   Strong recommendation against the intervention
  • Conditional recommendation against the intervention
  •   Conditional recommendation for either the intervention or the comparison
  •   Conditional recommendation for the intervention
  •   Strong recommendation for the intervention

A recommendation can be strong or conditional.

When a recommendation is strong, most women will want to follow it. When a recommendation is conditional, the majority of women want to follow it but may need more discussion with their healthcare professional first.

Justification

The justification for the recommendation tailored for patient/individual is currently under development. Please find below the justification for the recommendation already issued for healthcare professionals.
 

Overall justification

The GDG agreed by consensus that the limited very low quality evidence reviewed favours the current practice, using an oestrogen receptor (ER) threshold of 1% positivity.

Detailed justification

Desirable Effects:
The GDG judged that the desirable anticipated effects of a change in ER positivity threshold from current practice of 1% to 10% were trivial.

Undesirable Effects:
The GDG judged that there were moderate undesirable effects due to uncertainty in the data regarding thresholds, and the potential that patients with ER positivity between 1 and 10% would not be treated with the endocrine therapy.

Certainty of evidence:
The GDG notes that the data included was very indirect and very low quality. Furthermore, it notes that interpretation of ER positivity thresholds based on data from the Honma study is limited due to the method of statistical analysis, involving cumulative hazard ratios at different thresholds, not a separate hazard ratio at each level of positivity.

Considerations

Subgroup

None considered.

Implementation

The comparison is already current practice, therefore no implementation considerations were identified.

Monitoring and Evaluation

The GDG suggests monitoring low (1-9%) and high (10% and above) ER positivity in relation to patient outcomes to better assess ER thresholds for treatment.

Research Priorities

1. New research using ideally modern ER immunohistochemical techniques on tumor tissue primarily fixed in 10% neutral buffered formalin .
2. The GDG suggests additional observational studies to provide evidence on the current threshold used in practice, ideally using modern immunohistochemical techniques.

Evidence

Download the evidence profile

Assessment

Background

The hormone receptor status (oestrogen receptor (ER) and/or progesterone receptor (PR) status) of an invasive breast carcinoma is a strong predictive marker of likely tumour response to endocrine therapy (Fitzgibbons, 2000, Gown, 2008). Approximately 80% of invasive breast carcinomas are hormone receptor positive (Rhodes, 2000). The majority of hormone receptor positive breast tumours are ER positive. A small percentage of ER negative tumours are PR positive and may benefit from endocrine therapy but there is uncertainty about the benefits of endocrine therapy in these patients and if this response depends on the level of PR positivity.

All invasive breast carcinomas are tested for ER status as standard of care. Many centres/countries also test tumours for PR status as a routine. Some centres test ER negative tumours only for PR status.
The optimal method tumour testing for hormone receptor status is by immunohistochemistry on formalin- fixed, paraffin-embedded tissue using monoclonal antibodies (Harvey, 1999, Mohsin, 2004, Nofech-Mozes, 2012, Ellis, 2016) . ER and PR testing is usually performed on the core biopsy specimen which facilitates early treatment planning, in particular identification of patients who may be candidates for neoadjuvant therapy. ER and PR studies may be repeated on the operative excision specimen and there is a strong correlation with the results obtained on core biopsy.

It is recommended that ER and PR testing is carried out according to a quality assured testing protocol that complies with recommended test validation and internal and external quality assurance procedures (Hammond, 2010).

Historically different methods of scoring ER and PR status were used including assessment of strength and percentage of tumour cell positivity on IHC staining.

Cut off levels of IHC staining, applied for categorising a tumour as hormone receptor positive, have changed from 10% to 5% to 1% at the present time (Hammond, 2010). As such, patients with breast tumours that show positive IHC staining for ER and/or PR in at least 1% of tumour cells are considered likely to benefit from endocrine therapy. However, immunohistochemistry has evolved in the last decades. The established retrieval methods, antibodies and detection systems have increased the sensitivity of immunohistochemistry.

Is the problem a priority?
Yes *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Research Evidence
Endocrine therapy may be associated with side effects depending on the drug administered and menopausal status of the patient. Accuracy in predicting likely response to endocrine therapy is clearly important in designing the appropriate treatment regime for individual patients.
Additional Considerations

The GDG prioritised this question for the ECIBC.

How substantial are the desirable anticipated effects?
Trivial *
* Possible answers: ( Trivial , Small , Moderate , Large , Varies , Don't know )
Research Evidence

OutcomesImpact№ of participants
(studies)
Certainty of the evidence
(GRADE)
Recurrence free survival (Honma 2014)(Honma 2014): tamoxifen vs no endocrine treatment on 5 years recurrence-free survival in ER positive cases according to different thresholds. The following adjusted HR (95%CI)) were observed:
• At >0% threshold: 0.633 (0.426; 0.934)
• At 1% threshold: 0.649 (0.431; 0.973)
• At 10% threshold: 0.671 (0.434; 1.039)
• At 33% threshold: 0.555 (0.342; 0.898)
• At 67% threshold: 0.472 (0.272; 0.816).


(1 observational study)1,a
VERY LOW
b,c,d
Recurrence free survival (Yi 2014)(Yi 2014): patients with ER-positive tumours at 1-9% receiving endocrine treatment vs patients with ER-negative tumours (i.e. <1%) who did not receive treatment; no difference was observed (p=0.7) – see Figure 1 below.



e
(1 observational study)2,a
VERY LOW
f,g
Overall survival (Yi 2014) (OS)(Yi 2014): patients with 1-9% ER-positive tumours receiving endocrine treatment had worse survival rates than patients with ER-negative tumours (i.e. <1%) who did not receive treatment (p=0.04) - see Figure 2 below.










h
(1 observational study)2,a
VERY LOW
f,g
Direct response to endocrine therapy (defined according to World Health Organization criteria as complete response, partial response, no change, or progressive disease) (Direct response to endocrine therapy )No studies identified (0 studies)-
Adverse effects of endocrine therapy (Adverse effects)No studies identified (0 studies)-
Health-related quality of lifeNo studies identified (0 studies)-
  1. Honma, N., Horii, R., Iwase, T., Saji, S., Younes, M., Ito, Y., Akiyama, F.. Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast; Dec 2014.
  2. Yi, M., Huo, L., Koenig, K. B., Mittendorf, E. A., Meric-Bernstam, F., Kuerer, H. M., Bedrosian, I., Buzdar, A. U., Symmans, W. F., Crow, J. R., Bender, M., Shah, R. R., Hortobagyi, G. N., Hunt, K. K.. Which threshold for ER positivity? a retrospective study based on 9639 patients. Ann Oncol; May 2014.
  1. Retrospective cohort study
  2. Honma 2014 presented serious risk of bias due to the nature of the study design (retrospective cohort study), which resulted in increased risk of bias in terms of the selection of participants to the study and in terms of the classification of interventions.
  3. Wide confidence intervals. Number of events not reported.
  4. Honma 2014 did not report direct comparisons of thresholds >=1% vs >=10%, but rather conducted subgroup analyses according to different thresholds of the comparison treatment vs no treatment. Treatment effect according to the different subgroups (1-9%; 10-33%; 33-67%) was not reported either. In addition available evidence is exclusively based on a single drug (tamoxifen). The expert group should agree on whether these issues result or not in serious indirectness.
  5. In addition Yi 2014 observed that patients with tumours at 1%–9% ER positivity had worse recurrence-free survival than patients with tumours at ≥10% positivity, when both groups received treatment (p=0.0005), and when neither received treatment (p=0.0003).
  6. Yi 2014 presented serious risk of bias due to confounding: There are important differences between patients with 1-9% positivity (with a more advanced disease, more likely to receive neoadjuvant chemotherapy, and more likely to have HER-2 positive and grade III disease). The Kaplan-Meier curves used to provide the relevant information for this PICO did not adjust for these differences.
  7. Indirect comparison: Yi 2014 did not provide results for patients with 1-9% ER+ on tamoxifen versus no endocrine treatment. Instead, they compared 1-9% ER+ patients who received endocrine treatment vs ER negative patients who did not receive treatment, and also compared 1-9% vs >10% ER+ in subgroups of patients receiving and not receiving endocrine treatment.
  8. In addition Yi 2014 observed that patients with tumours at 1%–9% ER positivity had worse overall survival than patients with tumours at ≥10% positive when both groups received treatment (p<0.0001), and when neither received treatment (p=0.002).





Additional Considerations

In addition Yi 2014 (Yi et al., 2014) observed that:
a) patients with tumours at 1%–9% ER positivity had worse recurrence-free survival than did patients with tumours at ≥10% positivity when both groups received treatment (p=0.0005), and when neither received treatment (p=0.0003), and;
b)·patients with tumours at 1%–9% ER positivity had worse overall survival than did patients with tumours at ≥10% positive when both groups received treatment (p<0.0001), and when neither received treatment (p=0.002).

The GDG notes that a trivial difference between receptor status and endocrine treatment between 1% and 10% thresholds was observed in the Honma 2014 study(Honma et al., 2014). Due to the measurement of cumulative threshold in the Honma study, the GDG notes that interpretation of the hazard ratio between 1 and 10% is limited. The GDG also considered that a small number of patients were included in the Honma 2014 study that had ER positivity values >0% and ≤67%(Honma et al., 2014). The GDG judged by consensus that there are no desirable effects of the intervention.

How substantial are the undesirable anticipated effects?
Moderate *
* Possible answers: ( Large , Moderate , Small , Trivial , Varies , Don't know )
Research Evidence

OutcomesImpact№ of participants
(studies)
Certainty of the evidence
(GRADE)
Recurrence free survival (Honma 2014)(Honma 2014): tamoxifen vs no endocrine treatment on 5 years recurrence-free survival in ER positive cases according to different thresholds. The following adjusted HR (95%CI)) were observed:
• At >0% threshold: 0.633 (0.426; 0.934)
• At 1% threshold: 0.649 (0.431; 0.973)
• At 10% threshold: 0.671 (0.434; 1.039)
• At 33% threshold: 0.555 (0.342; 0.898)
• At 67% threshold: 0.472 (0.272; 0.816).


(1 observational study)1,a
VERY LOW
b,c,d
Recurrence free survival (Yi 2014)(Yi 2014): patients with ER-positive tumours at 1-9% receiving endocrine treatment vs patients with ER-negative tumours (i.e. <1%) who did not receive treatment; no difference was observed (p=0.7) – see Figure 1 below.



e
(1 observational study)2,a
VERY LOW
f,g
Overall survival (Yi 2014) (OS)(Yi 2014): patients with 1-9% ER-positive tumours receiving endocrine treatment had worse survival rates than patients with ER-negative tumours (i.e. <1%) who did not receive treatment (p=0.04) - see Figure 2 below.










h
(1 observational study)2,a
VERY LOW
f,g
Direct response to endocrine therapy (defined according to World Health Organization criteria as complete response, partial response, no change, or progressive disease) (Direct response to endocrine therapy )No studies identified (0 studies)-
Adverse effects of endocrine therapy (Adverse effects)No studies identified (0 studies)-
Health-related quality of lifeNo studies identified (0 studies)-
  1. Honma, N., Horii, R., Iwase, T., Saji, S., Younes, M., Ito, Y., Akiyama, F.. Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast; Dec 2014.
  2. Yi, M., Huo, L., Koenig, K. B., Mittendorf, E. A., Meric-Bernstam, F., Kuerer, H. M., Bedrosian, I., Buzdar, A. U., Symmans, W. F., Crow, J. R., Bender, M., Shah, R. R., Hortobagyi, G. N., Hunt, K. K.. Which threshold for ER positivity? a retrospective study based on 9639 patients. Ann Oncol; May 2014.
  1. Retrospective cohort study
  2. Honma 2014 presented serious risk of bias due to the nature of the study design (retrospective cohort study), which resulted in increased risk of bias in terms of the selection of participants to the study and in terms of the classification of interventions.
  3. Wide confidence intervals. Number of events not reported.
  4. Honma 2014 did not report direct comparisons of thresholds >=1% vs >=10%, but rather conducted subgroup analyses according to different thresholds of the comparison treatment vs no treatment. Treatment effect according to the different subgroups (1-9%; 10-33%; 33-67%) was not reported either. In addition available evidence is exclusively based on a single drug (tamoxifen). The expert group should agree on whether these issues result or not in serious indirectness.
  5. In addition Yi 2014 observed that patients with tumours at 1%–9% ER positivity had worse recurrence-free survival than patients with tumours at ≥10% positivity, when both groups received treatment (p=0.0005), and when neither received treatment (p=0.0003).
  6. Yi 2014 presented serious risk of bias due to confounding: There are important differences between patients with 1-9% positivity (with a more advanced disease, more likely to receive neoadjuvant chemotherapy, and more likely to have HER-2 positive and grade III disease). The Kaplan-Meier curves used to provide the relevant information for this PICO did not adjust for these differences.
  7. Indirect comparison: Yi 2014 did not provide results for patients with 1-9% ER+ on tamoxifen versus no endocrine treatment. Instead, they compared 1-9% ER+ patients who received endocrine treatment vs ER negative patients who did not receive treatment, and also compared 1-9% vs >10% ER+ in subgroups of patients receiving and not receiving endocrine treatment.
  8. In addition Yi 2014 observed that patients with tumours at 1%–9% ER positivity had worse overall survival than patients with tumours at ≥10% positive when both groups received treatment (p<0.0001), and when neither received treatment (p=0.002).





Additional Considerations

The GDG notes that the Honma study data demonstrates that the group between 0 and 10% positivity benefits from treatment, however, that there is significant uncertainty in the evidence(Honma et al., 2014). As agreement was not reached by consensus, voting was conducted by members of the GDG without COI: 11 members voted ‘moderate undesirable effects’, 5 members voted ‘large undesirable effects’, 3 members voted ‘don’t know’, 2 members voted ‘small undesirable effects and 1 member abstained from voting.

What is the overall certainty of the evidence of effects?
Very low *
* Possible answers: ( Very low , Low , Moderate , High , No included studies )
Additional Considerations

The GDG notes that the data included was very low quality and very indirect. Furthermore, it notes that interpretation of ER positivity thresholds based on data from the Honma study is limited due to the method of statistical analysis, involving cumulative percentages at different thresholds, not a separate hazard ratio at each level of positivity. It was also mentioned that some extend of indirectness might be caused by possible technical weaknesses of the study. Since the included patients had surgery between the early 80s and 90s fixation might have been not optimal for immunohistochemistry. Nowadays 6-72 h fixation in 10% buffered formalin is recommended. It is not described in the publication how fixation was performed or if immunohistochemistry was performed on tissue primarily used for frozen section analysis that was fixed in a second step at least in some patients. Fixation is crucial for the immunoreactivity of the tissue. Furthermore the description of the immunohistochemistry technique lacks relevant information (pre-treatment, detection systems) needed to assess if the used technique is as sensitive as current protocols. Additionally, the GDG noted additional indirectness due to technical weaknesses of the study.

Is there important uncertainty about or variability in how much people value the main outcomes?
Possibly important uncertainty or variability *
* Possible answers: ( Important uncertainty or variability , Possibly important uncertainty or variability , Probably no important uncertainty or variability , No important uncertainty or variability , No known undesirable outcomes )
Additional Considerations

The GDG notes that there is uncertainty on whether treatment is effective through each threshold. The GDG notes that the side effects of endocrine therapy are significant and there may therefore be variability in the way women value this outcome.

The GDG agreed by consensus that there is possibly important uncertainty or variability.

Does the balance between desirable and undesirable effects favor the intervention or the comparison?
Probably favors the comparison *
* Possible answers: ( Favors the comparison , Probably favors the comparison , Does not favor either the intervention or the comparison , Probably favors the intervention , Favors the intervention , Varies , Don't know )
Research Evidence
No studies identified comparing the impact on adverse effects of using a threshold of 1% or more vs. 10% or more of cells showing oestrogen receptor positivity for the provision of endocrine therapy in women with invasive breast cancer
Additional Considerations

The GDG notes that due to the very low certainty in the evidence, the balance probably favours the comparison. The GDG agreed by consensus that the balance probably favours the comparison.

How large are the resource requirements (costs)?
Don't know *
* Possible answers: ( Large costs , Moderate costs , Negligible costs and savings , Moderate savings , Large savings , Varies , Don't know )
What is the certainty of the evidence of resource requirements (costs)?
No included studies *
* Possible answers: ( Very low , Low , Moderate , High , No included studies )
Does the cost-effectiveness of the intervention favor the intervention or the comparison?
No included studies *
* Possible answers: ( Favors the comparison , Probably favors the comparison , Does not favor either the intervention or the comparison , Probably favors the intervention , Favors the intervention , Varies , No included studies )
Research Evidence
A specific bibliographic search on cost-effectiveness was undertaken, however, no relevant studies were identified.
What would be the impact on health equity?
Probably no impact *
* Possible answers: ( Reduced , Probably reduced , Probably no impact , Probably increased , Increased , Varies , Don't know )
Additional Considerations

The GDG agreed by consensus that there would probably be no impact on health equity.

Is the intervention acceptable to key stakeholders?
Yes *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Additional Considerations

The GDG agreed by consensus that the intervention would be acceptable to key stakeholders.

Is the intervention feasible to implement?
Yes *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Additional Considerations

The GDG agreed by consensus that the intervention would be feasible to implement.


References summary

  • Yi, M., Huo, L., Koenig, K. B., Mittendorf, E. A., Meric-Bernstam, F., Kuerer, H. M., Bedrosian, I., Buzdar, A. U., Symmans, W. F., Crow, J. R., Bender, M., Shah, R. R., Hortobagyi, G. N., Hunt, K. K., [Which threshold for ER positivity? a retrospective study based on 9639 patients] Ann Oncol; 2014
  • Hammond, M. E. et al., [American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer] J Clin Oncol; 2010
  • Fitzgibbons, PL, [Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999] Arch Pathol Lab Med; 2000
  • Gown, AM, [Current issues in ER and HER2 testing by IHC in breast cancer] Mod Pathol; 2008
  • Ellis, IO, [Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological reporting of breast cancer. Cancer datasets and tissue pathways] Royal College of Pathologists UK.; 2016
  • Mohsin, SK, [Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study] Mod Pathol; 2004
  • Honma, N., Horii, R., Iwase, T., Saji, S., Younes, M., Ito, Y., Akiyama, F., [Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy] Breast; 2014
  • Rhodes, A, [Frequency of oestrogen and progesterone receptor positivity by immunohistochemical analysis in 7016 breast carcinomas: correlation with patient age, assay sensitivity, threshold value, and mammographic screening] J Clin Pathol; 2000
  • Harvey, J. M. Clark G. M. Osborne C. K. & Allred D. C., [Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer] J Clin Oncol; 1999
  • Nofech-Mozes, S, [Systematic review on hormone receptor testing in breast cancer.] Appl Immunohistochem Mol Morphol; 2012

Bibliography

Evidence of effects
  • Honma, N., Horii, R., Iwase, T., Saji, S., Younes, M., Ito, Y., Akiyama, F.. Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast; Dec 2014.
  • Yi, M., Huo, L., Koenig, K. B., Mittendorf, E. A., Meric-Bernstam, F., Kuerer, H. M., Bedrosian, I., Buzdar, A. U., Symmans, W. F., Crow, J. R., Bender, M., Shah, R. R., Hortobagyi, G. N., Hunt, K. K.. Which threshold for ER positivity? a retrospective study based on 9639 patients. Ann Oncol; May 2014.
Acceptability
No evidence included
 
Economic Evidence
No relevant economic evaluations were identified.
 
Values and preferences
No evidence included