Systemic therapy

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Request’) indicative of a strong recommendation (using GRADE methods) by the source guideline authors. The source recommendation was accepted with minor stylistic changes, but with no changes to the meaning or tone of the source recommendation.

Assessment of markers (ER, PR and HER2) #2 (Recommendation)

Assess the ER, PR and HER2 status of all invasive breast cancers using standardised and quality-assured immunohistochemical techniques and report the results quantitatively. Ensure receptor status test results are available and recorded at the preoperative and postoperative multidisciplinary team meetings when systemic treatment is discussed.

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). This recommendation was adopted from three source recommendations based on a systematic review of the evidence conducted to September 2017. Although all three source recommendations used wording (‘Assess’) indicative of a strong recommendation (using GRADE methods) by the source guideline authors, the NICE evidence review indicates that these recommendations are based on expert consensus due to a lack of evidence. The source recommendations were combined into one recommendation.

HER2 testing (Practice Point)

Perform in situ hybridisation testing for HER2 status on core biopsy material if neoadjuvant systemic therapy is being considered, noting that receptor status between core and surgical specimens may be different.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

Gene expression profiling (Practice Point)

If considering the use of tumour gene expression profiling tests to inform decisions about the use of adjuvant chemotherapy for patients with breast cancer, be aware that the clinical utility of these tests has not yet been established. Discuss with the patient the potential benefits (reduced adverse events due to avoiding chemotherapy) and potential harm (breast cancer recurrence that might have been prevented) of using these.

How this guidance was developed

Although international recommendations regarding the use of gene expression profiling tests were identified, these were considered less relevant to the Australian health care context than the findings of multiple recent systematic reviews of the clinical evidence undertaken by the Australian government using GRADE methods. This practice point was developed based on eight recent systematic reviews: one for Mammaprint, six for OncotypeDx and one for Prosigna. Importantly, these systematic reviews focused on the impact of using gene expression profiling tests for those women in whom the benefit of adding chemotherapy to endocrine therapy is unclear. These systematic reviews found: RCT evidence (the MINDACT trial) that the use of Mammaprint is associated with poorer overall survival outcomes for women who avoid the use of chemotherapy on the basis of the Mammaprint test results; inconclusive RCT evidence (the TAILORx trial) that the use of OncotypeDx is non-inferior or superior to current clinical practice (consideration of clinical and histopathological information); and insufficient evidence (no RCT) to determine the relative performance of Prosigna.

Assessment of markers after neoadjuvant therapy (Practice Point)

Repeat receptor status testing on any residual disease after neoadjuvant systemic therapy.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

Systemic therapy planning considerations – Multidisciplinary assessment (Recommendation)

Consider adjuvant systemic therapy after surgery for patients with invasive breast cancer, individualising treatment based on a multidisciplinary assessment of prognostic and predictive factors and the possible risks and benefits of treatment. Ensure that recommendations for treatment are recorded at a multidisciplinary team meeting.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). Two source recommendations were merged and adapted by noting that the treatment should be individualised rather than ‘according to patient preferences’. Both source recommendations were based on a systematic review conducted to September 2017 and used wording (‘Consider’) indicative of a ‘conditional’ recommendation and wording (‘Ensure’) indicative of a ‘strong’ recommendation (using GRADE methods) by the source guideline authors.

Systemic therapy planning considerations – Prognostic tools and markers (Recommendation)

In patients with breast cancer consider use of the PREDICT tool to estimate prognosis and the absolute benefits of adjuvant systemic therapy, recognising that the PREDICT tool is less accurate in some women and has not been validated in men or in an Australian population. Ki67 should be used in conjunction with other clinicopathological variables and should not be used alone in any patient to make treatment decisions.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted in September 2017 and used wording reflecting a strong recommendation (using GRADE methods) by the source guideline authors. The source recommendation was adapted by making it less directive, by replacing 'use' with 'consider' to reflect the Australian context, and by expanding the patient population from 'women' to 'all patients'.

Systemic therapy planning considerations – Premenopausal women (Recommendation)

Offer temporary ovarian suppression with a gonadotrophin releasing hormone (GnRH) agonist such as goserelin during chemotherapy to all premenopausal breast cancer patients undergoing chemotherapy who are interested in preventing early menopause and/or preserving fertility. Commence goserelin at least one week prior to the commencement of chemotherapy.

How this guidance was developed

This recommendation was adopted from the AIOM 2017 guidelines (Italy). The source recommendation was based on a systematic review of the evidence conducted to January 2016 and was graded ‘strong’ (using GRADE methods) by the source guideline authors. The source recommendation was accepted with minor stylistic changes, but with no changes to the meaning or tone.

Systemic therapy planning considerations – Pregnancy avoidance (Practice Point)

Advise women with breast cancer who are receiving chemotherapy, anti-HER2 therapy, or tamoxifen, to avoid pregnancy as these therapies are potentially teratogenic. 

How this guidance was developed

This practice point was developed using an expert consensus process. Development of the practice point was informed by a source recommendation in the JBCS 2016 guidelines (Japan) that was not graded by the source guideline authors and based on a non-systematic review of the evidence (the date of the review was not reported).

Systemic therapy planning considerations – Pregnant women #1(Recommendation)

In pregnant women with breast cancer, chemotherapy can be considered after 14 weeks of gestation. 

How this guidance was developed

This recommendation was adapted from the KCE 2013 guideline (Belgium). The source recommendation was based on a systematic review of the evidence conducted to January 2010 and was graded ‘weak' (using GRADE methods) by the source guideline authors. The source recommendation was accepted with minor stylistic changes, but with no changes to the meaning or tone of the source recommendation.

Systemic therapy planning considerations – Pregnant women #2 (Practice Point)

The dosage of chemotherapeutic agents should be the same for pregnant women as compared to non-pregnant women. A lower pre-pregnant weight should not be used. 

How this guidance was developed

This practice point was developed using an expert consensus process. Development of the practice point was informed by a source recommendation in the ESGC 2010 guidelines (US) that was not graded by the source guideline authors and was based on a non-systematic review of the evidence (the date of the review was not reported). Strongly directive language was used for this PP because of the serious impact to the woman of receiving a potentially sub-therapeutic dose of a chemotherapeutic agent.

Systemic therapy – Breastfeeding (Practice Point)

Breastfeeding is not recommended during chemotherapy or endocrine therapy.

How this guidance was developed

This practice point was developed using an expert consensus process. Development of the practice point was informed by a source recommendation in the ESGC 2010 guidelines (US) that was not graded by the source guideline authors and was based on a non-systematic review of the evidence (the date of the review was not reported) and is also informed by a recent Academy of Breastfeeding Medicine (US) Clinical Protocol (2020).

Chemotherapy

Adjuvant chemotherapy – Indications #1 (Recommendation)

Consider adjuvant chemotherapy for all patients with breast cancer whose disease is at high risk of recurrence and has a subtype likely to respond to adjuvant chemotherapy (e.g. triple negative; HER2-postive; luminal B).

How this guidance was developed

This recommendation was adapted from the NCCP 2015 guidelines (Ireland). The source recommendation was based on a systematic review of the evidence conducted to September 2014 and was graded 'A' (using SIGN methods) by the source guideline authors. The source recommendation was adapted to remove reference to ‘moderate risk of recurrence’ as the evidence in favour of chemotherapy in this group of patients is not as clear as for patients with a high risk of recurrence. Reference to the likely responsiveness of the cancer based on its biology was also added.

Adjuvant chemotherapy – Indications #2 (Recommendation)

The choice of neoadjuvant or adjuvant chemotherapy should be determined by a patient’s comorbidities, physical function, and degree of frailty, and not by gene mutation status or age alone.

How this guidance was developed

This recommendation was adapted from the CA 2014 guidelines (Australia). The source recommendation was based on a systematic review of the evidence conducted to April 2012 and was graded 'C' (using NHMRC methods) by the source guideline authors.  The source recommendation was adapted by expanding the patient population from ‘women’ to ‘all patients’, by replacing ‘BRCA1/2 status’ with 'gene mutation status’, and by including age as a factor. 

Adjuvant chemotherapy – Timing and sequencing (Recommendation)

Ideally adjuvant chemotherapy should commence within 4 to 6 weeks of the date of surgery. If adjuvant chemotherapy and radiation therapy are indicated, the chemotherapy should be given first.

How this guidance was developed

This recommendation was adapted from three source recommendations. The period within which adjuvant chemotherapy should commence is based on a recommendation in the RACP 2017 guidelines (Australia) which was based on a systematic review of the evidence conducted in April 2014 and was graded ‘C' (using NHMRC methods) by the source guideline authors, and a recommendation in the ESMO 2019 guidelines (evidence review methods not stated), graded ‘strong’ (using ESMO methods. These two source recommendations were merged and adapted by removing the aspect of care related to patients with high-risk disease.

The second sentence from this recommendation was adopted from the KCE 2013 guidelines (Belgium). The KCE source recommendation was based on a systematic review of the evidence conducted to January 2010 and was graded ‘strong’ (using GRADE methods) by the source guideline authors. Further development of the recommendation included specification of the timing as ‘4-6 weeks from the date of surgery’. In accordance with this timing, a more recent recommendation by ESMO (2019) graded ('A') has indicated that adjuvant treatment should preferably start within 3-6 weeks after surgery.

Adjuvant chemotherapy – Combination with endocrine therapy (Practice Point)

Chemotherapy can be given concurrently with the gonadotropin-releasing hormone (GnRH) agonist goserelin but not with tamoxifen.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process, with reference to findings from two RCTs: the POEMS clinical trial (goserelin for ovarian protection during breast cancer adjuvant chemotherapy) and the SOFT and TEXT clinical trials (tailoring adjuvant endocrine therapy for premenopausal breast cancer).

Anthracyclines and taxanes – Dosage (Recommendation)

The cumulative dose of anthracycline in a two-drug regimen should not exceed 240 mg/m2 for doxorubicin, or 720 mg/m2 for epirubicin.

How this guidance was developed

This recommendation was adapted from the ASCO 2016 guidelines (US). The source recommendation was based on a systematic review of the evidence conducted to July 2015 and was not graded by the source guideline authors. The source recommendation was simplified by removing the detail and the specification of the patient population.

Anthracyclines and taxanes – Cumulative toxicity (Recommendation)

When choosing a chemotherapy regimen, consider the cumulative toxicity when an anthracycline and a taxane are used together.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording ('Consider') indicative of a conditional recommendation (using GRADE methods) by the source guideline authors. The source recommendation was simplified by removing the detail regarding additional topics to be discussed with the patients and linking the recommendation to Table 4 from the NICE guideline, which includes this detail.

Chemotherapy protocols #1 (Recommendation)

For patients in whom an anthracycline-taxane regimen is contraindicated, cyclophosphamide-methotrexate-fluorouracil (CMF) with oral cyclophosphamide is an acceptable chemotherapy alternative. 

How this guidance was developed

This recommendation was adapted from the ASCO 2016 guidelines (US). The source recommendation was based on a systematic review of the evidence conducted to July 2015 and was not graded by the source guideline authors. The source recommendation was simplified by removal of the details of specific chemotherapy regimens.

Chemotherapy protocols #2 (Recommendation)

Refer to eviQ for the preferred adjuvant chemotherapy regimens (including dose-dense regimens and alternatives to doxorubicin-cyclophosphamide x 4). 

How this guidance was developed

This recommendation was adapted from two recommendations in the ASCO 2016 guidelines (US). Each source recommendation was based on a systematic review of the evidence conducted to July 2015 and neither recommendation was graded by the source guideline authors. The overall intention of the source recommendations was retained but the details of the different chemotherapy regimens was removed.

Chemotherapy – Growth factor support (Practice Point)

Treat all patients with growth factor support if dose-dense adjuvant systemic therapy is being prescribed and for other regimens where the risk of febrile neutropenia is higher than 20%.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

Adjuvant chemotherapy for residual disease – HER2-positive breast cancer (Practice Point)

Offer trastuzumab emtansine as additional adjuvant treatment for patients with HER2-positive breast cancer who have residual disease after a neoadjuvant taxane-trastuzumab regimen.

How this guidance was developed

No evidence-based source recommendation was initially identified for this topic, which was considered an important aspect of care. A practice point was therefore developed using an expert consensus process during the initial phases of Guidance development.

However, findings from the KATHERINE trial have since become available and the recommendation is also informed by the more recent ESMO 2019 clinical practice guidelines (Europe) containing a source recommendation (date of evidence review not reported) that was graded ‘C’ (using ESMO methods adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System) by the guideline authors.

Adjuvant chemotherapy for residual disease – Triple negative breast cancer (Practice Point)

For patients with triple negative breast cancer with residual disease after neoadjuvant chemotherapy, consider the addition of capecitabine to a post-neoadjuvant anthracycline-taxane regimen.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process. A source recommendation (date of evidence review not reported) in the recent ESMO 2019 clinical practice guidelines (Europe) which was graded ‘C’ (using ESMO methods adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System), supports this practice point.

Antiemetics and chemotherapy (Practice Point)

Use adequate antiemetics when treating patients with systemic therapy.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

Scalp cooling and chemotherapy (Recommendation)

Consider scalp cooling to reduce the risk of hair loss for patients receiving chemotherapy, noting scalp cooling may be less effective with anthracycline-containing regimens.

How this guidance was developed

This recommendation was adopted from the NCCN 2019 guidelines (US). The source recommendation was based on a systematic review of the evidence conducted in June 2015 and was graded ‘2A’ (using NCCN methods) by the source guideline authors. The source recommendation was accepted with minor stylistic changes such as changing ‘alopecia’ to ‘hair loss’, but with no changes to the meaning or tone of the source recommendation.

Anti-HER2 therapy

Anti-HER2 therapy – Indications #1 (Recommendation)

Offer adjuvant trastuzumab (with or without pertuzumab) for patients with at least T1c, HER2-positive breast cancer (given at 3-week intervals for 1 year) in combination with surgery, chemotherapy, and radiation therapy as appropriate. 

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Offer’) indicative of a strong recommendation (using GRADE methods) by the source guideline authors. The source recommendation was adapted by adding ‘with or without pertuzumab’.

Anti-HER2 therapy – Indications #2 (Recommendation)

Consider trastuzumab in addition to chemotherapy as adjuvant treatment for patients with T1a/T1b HER2-positive breast cancer, taking into account any comorbidities, prognostic features and possible toxicity of chemotherapy. 

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Consider’) indicative of a conditional recommendation (using GRADE methods) by the source guideline authors as the evidence shows that only a small number of people with breast cancer will benefit from this treatment. The source recommendation was accepted with no changes.

Anti-HER2 therapy – Combination with chemotherapy (Recommendation)

Ideally adjuvant trastuzumab (with or without pertuzumab) should be given concurrently with taxane-based regimens but should not be given concurrently with anthracyclines. 

How this guidance was developed

This recommendation was adapted from the NCCP 2015 guidelines (Ireland). The source recommendation was based on a systematic review of the evidence conducted to September 2014 and was graded ‘A’ (using SIGN methods) by the source guideline authors. The source recommendation was adapted by adding ‘with or without pertuzumab’.

Anti-HER2 therapy – Combination with neratinib (Practice Point)

Consider adding neratinib to high risk ER-positive/HER2-positive patients who complete one year of trastuzumab and remain disease-free.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

Anti-HER2 therapy – Cardiac monitoring (Recommendation)

In patients receiving trastuzumab, consider monitoring cardiac function during treatment (e.g. every 3 months) and follow-up. Early referral to a cardiologist should be considered in cases of deterioration in cardiac function.

How this guidance was developed

This recommendation was adapted from the KCE 2013 guidelines (Belgium). The source recommendation was based on a systematic review of the evidence conducted to January 2010 and was graded ‘strong’ (using SIGN methods) by the source guideline authors. The source recommendation was adapted by adding ‘Early referral to a cardiologist should be considered in cases of deterioration in cardiac function’. The additional text in the ESMO (2020) guidelines that ‘the effectiveness of this strategy in patients with low cardiovascular risk and no early evidence of left ventricle dysfunction’ and ‘the closer monitoring of high-risk patients’ is highlighted.

This recommendation is supported by more recent guidelines developed by ESMO (2020) on the management of cardiac disease in cancer patients, although the relevant recommendation indicates that frequency of monitoring may depend on patients’ baseline cardiovascular risk.

Cardiac dysfunction during treatment

Surveillance during treatment – Patients at increased risk of cardiac dysfunction (Recommendation)

Consider routine surveillance, preferably with an echocardiogram, of asymptomatic patients considered to be at increased risk of developing cardiac dysfunction. Frequency of surveillance should be determined by patient baseline and future risk of cardiotoxicity.

How this guidance was developed

This recommendation was adopted from the ASCO 2017 clinical practice guideline on cardiac dysfunction (US). The source recommendation is based on a systematic review of the evidence conducted to February 2016 and was graded ‘moderate’ (using ASCO methods) by the source guideline authors.

The source recommendation references the high-risk patients which are indicated to include those patients with the following treatments:

• High-dose anthracyclines (equivalent to ≥250 mg/m2 of doxorubicin or ≥600 mg/m2 of epirubicin
• Radiation with the heart in the treatment field at a dose of 30 Gray or more
• A combination of anthracyclines and radiation, even at lower dosages
• A combination of anthracycline followed by trastuzumab
• Low-dose anthracycline and other CV risk factors
• Trastuzumab and other CV risk factors.

More detailed indications for the monitoring of cardiac safety during treatment in patients receiving anthracyclines and anti-HER2 treatments, are provided in the ESMO (2020) guidelines for the management of cardiac disease throughout oncological treatment.

Cardiac dysfunction – Symptomatic (Recommendation)

In patients with clinical signs or symptoms of cardiac dysfunction during routine clinical assessment throughout treatment, the following approaches are recommended:
i. Echocardiogram for diagnostic workup
ii. Cardiac MRI can be performed if echocardiogram is not available or is not technically feasible (e.g. poor image quality). Alternatively, gated heart pool scan can be considered
iii. Serum cardiac biomarkers (troponins, natriuretic peptides) as an adjunct to imaging and clinical assessment
iv. Refer to a cardiologist based on clinical context and findings.

Consider deferral or cessation of cardiotoxic treatment where clinically indicated, in collaboration with a cardiologist.

How this guidance was developed

This recommendation was adapted from the ASCO 2017 clinical practice guideline on oncological cardiac dysfunction (US). The source recommendation is based on a systematic review of the evidence conducted to February 2016 and the various elements were graded ‘moderate’ or ‘strong’ (using ASCO methods). There is a strong preference for use of echocardiogram and it was noted that a cardiac MRI should only be considered in consultation with a cardiologist, as it is used in the evaluation of cardiac function, not as a screening tool.

Support for these approaches and more detailed indications for the monitoring of cardiac safety during treatment in patients receiving anthracyclines and anti-HER2 treatments, are provided in the ESMO 2020 guidelines for the management of cardiac disease throughout oncological treatment.

Endocrine therapy

Adjuvant endocrine therapy – Indications #1 (Recommendation)

Adjuvant endocrine therapy should be considered in all patients with ER-positive cancer, defined as ER immunohistochemistry (IHC) staining ≥1%. Discuss the benefits and risks of endocrine therapy with patients whose cancers contain low levels of ER-positive cells (1%-10% weakly positive cells by IHC).

How this guidance was developed

This recommendation was adapted from the CCO 2014 guidelines (Canada). The source recommendation was based on a systematic review of the evidence conducted to March 2012 and was not graded by the source guideline authors. The source recommendation was adapted by removing the phrase ‘taking into consideration overall disease risk, patient preference and potential adverse effects’. The recommendation was further adapted by adding in the discussions of benefits and risks of endocrine therapy with patients whose cancers contain low levels of ER-positive cells based on the ASCO/CAP guideline update on oestrogen and progesterone receptor testing in breast cancer in 2020, which was based on a systematic review of the evidence to April 2019. The evidence quality was high, and the recommendation was graded ‘strong’ (using ASCO methods). The ASCO/CAP Expert Panel noted that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive.

Adjuvant endocrine therapy – Indications #2 (Recommendation)

Consider adjuvant endocrine therapy in patients with ER-negative but PR-positive tumours, noting that this scenario is extremely unusual, and consideration should be given to repeat confirmatory testing.

How this guidance was developed

This recommendation was adapted from the CCO 2014 guidelines on systemic therapy (Canada). The source recommendation was based on a systematic review of the evidence conducted to March 2012 and was not graded by the source guideline authors. The source recommendation was adapted by making it more directive, replacing 'consensus was not reached' with 'consider' but noting that tumours of this type are rare. The repeat confirmatory testing can be repeat ER testing or repeat ER and PR testing on a different block if available.

Adjuvant endocrine therapy – Timing #1 (Practice Point)

Endocrine therapy should start as soon as appropriate, after completion of chemotherapy and/or radiation therapy (and in some cases will be started prior to chemotherapy).

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process. The wording is informed by that contained in the Optimal Care Pathway for people with breast cancer (in draft 2020).

Adjuvant endocrine therapy – Timing #2 (Recommendation)

In patients with ER-positive tumours who do not commence adjuvant endocrine therapy immediately after surgery or chemotherapy, delayed endocrine therapy is still clinically beneficial. 

How this guidance was developed

This recommendation was adopted from the CCO 2014 guidelines (Canada). The source recommendation was based on a systematic review of the evidence conducted to March 2012 and was not graded by the source guideline authors. The source recommendation was accepted with minor stylistic changes, but with no change to the meaning or tone of the source recommendation.

Primary endocrine therapy without surgery in older patients (Recommendation)

Primary endocrine therapy (endocrine therapy alone without surgery) should only be offered to older patients with ER-positive tumours who have a short-estimated life expectancy (<2–3 years), who are considered unfit for surgery after optimisation of comorbid medical conditions, or who decline surgery. The involvement of a geriatrician is strongly recommended to estimate life expectancy and guide management of reversible comorbidities. It is reasonable to choose tamoxifen, or an aromatase inhibitor based on potential side-effects.

How this guidance was developed

This recommendation was adopted from the SIOG/EUSOMA 2012 guidelines on the management of elderly patients with breast cancer (Europe). The source recommendation was based on a systematic review of the evidence conducted to June 2010 and was not graded by the source guideline authors. The source recommendation was accepted with minor stylistic changes, but with no changes to the meaning or tone of the source recommendation.

Adjuvant endocrine therapy in older patients (Recommendation)

Omission of adjuvant endocrine therapy is an option for older patients with a very low risk tumour (pT1aN0) or those with life-limiting comorbidities.

How this guidance was developed

This recommendation was adapted from the SIOG/EUSOMA 2012 guidelines on the management of elderly patients with breast cancer (Europe). The source recommendation was based on a systematic review of the evidence conducted to June 2010 and was not graded by the source guideline authors. The source recommendation was simplified by removing the details of the treatment regimen and replacing ‘life-threatening comorbidities’ with ‘life-limiting comorbidities’.

Endocrine therapy and bone health – Advice to patients (Practice Point)

Advise patients on the importance of weight-bearing exercise and on adequate calcium intake and vitamin D levels.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered and important aspect of care. This practice point was developed using an expert consensus process.

This practice point informed by the narrative in ESO-ESMO 2017/2020 on the side effects of any endocrine treatment in young women (noting that, in contrast to its effects on bones in premenopausal women, tamoxifen can cause bone loss in premenopausal women); the narrative in the Position statement by the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society and the COSA 2018; and by a recommendation in the CCO/ASCO 2017 clinical practice guideline on the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer.

Initial adjuvant endocrine therapy – Men and premenopausal women (Practice Point)

Offer tamoxifen as the initial adjuvant endocrine therapy for men and premenopausal women with ER-positive invasive breast cancer with low risk of recurrence.

How this guidance was developed

This recommendation was adapted from two source recommendations: a recommendation in the NICE 2018 guidelines (UK) based on a systematic review of the evidence conducted to September 2017 and used wording indicative of a strong recommendation (using GRADE methods) by the source guideline authors and a recommendation in the ESO-ESMO 2017 (Europe) guidelines for young women, and graded ’A’ (using ACCP methods). The recently released ASCO 2020 guideline on the management of male breast cancer is noted. This guideline, based on a systematic review of the evidence to 20 September 2019, indicates that ‘Men with hormone receptor–positive breast cancer who are candidates for adjuvant endocrine therapy should be offered tamoxifen’ (Type: formal consensus; Evidence quality: low; Strength of recommendation: strong).

Ovarian function suppression – Use of GnRH agonist #1 (Recommendation)

For premenopausal women with ER-positive breast cancer at higher risk of recurrence, consider ovarian function suppression with a gonadotrophin releasing hormone (GnRH) agonist in addition to endocrine therapy (tamoxifen or aromatase inhibitors), noting that a GnRH agonist must be used with aromatase inhibitors. 

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). Two source recommendations were merged and simplified by omitting ‘explain to women that ovarian function suppression may be most beneficial for those women who are at sufficient risk of disease recurrence to have been offered chemotherapy’. Both source recommendations were based on a systematic review conducted to September 2017 and used wording ('Consider') indicative of a conditional recommendation (using GRADE methods). This recommendation was further adapted by merging with the ESO-ESMO 2017/2020 recommendation (graded 'A' using ACCP methods) that aromatase inhibitors without ovarian function suppression are contraindicated in young women.

The recently released ASCO 2020 guideline on the management of male breast cancer is noted. This guideline, based on a systematic review of the evidence to 20 September 2019, indicates that ‘Men with hormone receptor-positive breast cancer who are candidates for adjuvant endocrine therapy but have a contraindication to tamoxifen may be offered GnRH and an aromatase inhibitor’ (Type: formal consensus; Evidence quality: low; Strength of recommendation: moderate).

Ovarian function suppression – Use of GnRH agonist #2 (Recommendation)

If a gonadotropin-releasing hormone (GnRH) agonist is used in premenopausal women, it should be given on a monthly basis to optimise ovarian suppression. 

How this guidance was developed

This recommendation was adopted from the ESO-ESMO 2017 guidelines for young women (Europe). The source recommendation was based on a review of the evidence (date not reported) and was graded ‘B’ (using ACCP methods) by the source guideline authors. The updated ESO-ESMO 2020 recommendations on this topic indicate the strength of the recommendation to be ‘Expert opinion’ (a different grading system was used). As the recommendation is based on the 2017 source recommendation, the allocation of ‘recommendation’ rather than ‘practice point’ remains.

Initial adjuvant endocrine therapy – Postmenopausal women (Recommendation)

Offer an aromatase inhibitor as the initial adjuvant endocrine therapy for postmenopausal women with lobular cancer or ER-positive breast cancer who are at intermediate or high risk of recurrence. Offer tamoxifen or aromatase inhibitors to postmenopausal women who are at low risk of recurrence. Offer tamoxifen if aromatase inhibitors are not tolerated or are contraindicated.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to July 2008 and used wording (‘Offer’) indicative of a strong recommendation (using GRADE methods) by the source guideline authors. The source recommendation was adapted with the addition of ‘lobular cancer’. Also, there was some concern that the source recommendation does not reflect that many researchers and guidelines (e.g. CCO 2014; ASCO 2018) recommend that adjuvant endocrine therapy in postmenopausal women with ER-positive early breast cancer should include an aromatase inhibitor (AI). Studies consistently demonstrate the use of an AI alone or sequentially after tamoxifen therapy, compared with tamoxifen alone, reduces the risk of recurrence and improves disease-free survival rate. However, it is also noted that the absolute gain in breast cancer endpoints is generally small and that these gains are higher for patients with higher-risk cancer.

The guidelines also note that tamoxifen alone may be appropriate in some patients. It is generally recognised that the risk-to-benefit ratio of using tamoxifen and AIs must be taken into account.

The source recommendation was therefore adapted to incorporate the option for AIs as the initial therapy in postmenopausal women at low as well as intermediate or high risk of recurrence.

Endocrine therapy with tamoxifen – Duration of therapy (Recommendation)

Consider extending the duration of tamoxifen therapy beyond 5 years for premenopausal or postmenopausal women with ER-positive breast cancer.

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Consider’) indicative of a conditional recommendation (using GRADE methods) by the source guideline authors. Consideration of extending the duration of extended therapy to 10 years for premenopausal women at higher risk of recurrence is noted in the ESO-ESMO 2017/2020 guidelines for young women with breast cancer recommendation graded 'A' (using ACCP methods), as well as the ASCO 2018 updated guidelines.

NICE (2018) note that the low quality of evidence for extended duration (longer than 5 years versus fewer than 5 years) of tamoxifen therapy among postmenopausal women meant that the committee were only able to make a weak recommendation. Further, in Table 2 in the NICE (2018) guidelines, “in postmenopausal women who have taken tamoxifen for 5 years, switching to an aromatase inhibitor (AI) may be more effective at reducing recurrence than continuing with tamoxifen”. The supporting evidence review indicated that there was good evidence that switching to an AI after 5 years of tamoxifen improved disease-free survival compared with postmenopausal women who had only received tamoxifen for 5 years, with the benefits being greater in those women who had a greater risk of disease recurrence. Similarly, in the systematic evidence review by ASCO (2018) for the guideline update on use of AIs, a survival benefit for extended therapy for women who received 10 years of tamoxifen compared with 5 years, and for women who receive 5 years of AI therapy after 5 years of tamoxifen, was noted. The recently released ASCO 2020 guideline on the management of male breast cancer is noted. This guideline, based on a systematic review of the evidence to 20 September 2019, indicates that ‘Men who have completed five years of tamoxifen, have tolerated therapy, and still have a high risk of recurrence, may be offered an additional five years of tamoxifen therapy’ (Type: formal consensus; Evidence quality: low; Strength of recommendation: strong).

Endocrine therapy with aromatase inhibitors – Duration of therapy #1 (Recommendation)

Offer extended therapy (total duration of endocrine therapy of more than 5 years) with an aromatase inhibitor for postmenopausal women with ER-positive breast cancer who are at intermediate or high risk of late recurrence and who have been taking tamoxifen for 2 to 5 years.

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Offer’) indicative of a strong recommendation (using GRADE methods) by the source guideline authors. The source recommendation was accepted with no changes.

For noting: In response to stakeholder feedback on the NICE (2018) phrase ‘Offer extended therapy (total duration of endocrine therapy of more than five years)…’ as being too vague, NICE (2018) noted that there is evidence suggesting that 7-8 years is enough, and that 10 years may not be needed; however the evidence review focused on a comparison of durations longer than 5 years against 5 years of endocrine therapy. NICE (2018) further noted that there were no clear results based on the durations of the included studies, so the committee did not think it possible to make recommendations on the absolute duration of therapy or the endpoint.

The inclusion of ‘who have been taking aromatase inhibitors for 2 to 5 years’ in the NICE (2018) source recommendation reflects that many patients receiving tamoxifen switch to an AI after 2-3 years.

For noting: In response to feedback during the stakeholder consultation that there should be ‘a statement on use of extended endocrine therapy in postmenopausal women who have been taking an AI for 5 years’, NICE (2018) indicated that there was insufficient evidence to do so.

The ASCO 2018 focused-update guideline on use of AIs and the relevant recommendation on extended AI therapy is also noted.

Endocrine therapy with aromatase inhibitors – Duration of therapy #2 (Recommendation)

Consider extended therapy (total duration of endocrine therapy of more than 5 years) with an aromatase inhibitor for postmenopausal women with ER-positive breast cancer who are at low risk of late recurrence and who have been taking tamoxifen for 2 to 5 years.

How this guidance was developed

This recommendation was adopted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording (‘Consider’) indicative of a conditional recommendation (using GRADE methods) by the source guideline authors. The source recommendation was accepted with no changes.

The inclusion of ‘who have been taking aromatase inhibitors for 2 to 5 years’ in the NICE 2018 source recommendation reflects that many patients receiving tamoxifen switch to an AI after 2-3 years. 

For noting: In response to feedback during the stakeholder consultation by NICE that there should be ‘a statement on use of extended endocrine therapy in postmenopausal women who have been taking an AI for 5 years’, NICE (2018) indicated that there was insufficient evidence to do so.

The ASCO 2018 focused-update guideline on use of AIs and the relevant recommendation on extended AI therapy is also noted.

Endocrine therapy with aromatase inhibitors – Duration of therapy #3 (Recommendation)

Be aware that alternative strategies for extending aromatase inhibitor therapy beyond 5 years, depending on risk of recurrence and tolerance of therapy, include: continuous therapy to 7.5 years, therapy up to 10 years with a 3-month break each year, and continuous therapy for up to 10 years.

How this guidance was developed

This practice point was developed using an expert consensus process. It is informed by the ASCO 2018 guidelines recommendation (based on a systematic review of the evidence) to not exceed 10 years of total adjuvant endocrine therapy treatment, and by the findings from two trials (ABCSG 16 (no difference in disease-free survival of 10 vs. 7 years of extended therapy with AIs) and the SOLE trial of intermittent vs. continuous extended AI therapy up to a total of 10 years). It is noted that in the evidence reviews by ASCO 2018 and NICE 2018, none of the studies to date has noted a survival benefit of extended AI therapy.

Further, in the ASCO (2018) evidence review, at least 5 of the 6 included trials examining extended AI duration, participants had received prior adjuvant tamoxifen therapy.

Overall, the guideline panel for ASCO (2018) highlighted three ‘preferred options’ for extended duration endocrine therapy for postmenopausal patients:

• 10 years with an AI
• 2-3 years of tamoxifen followed by 7-8 years with an AI
• 5 years of tamoxifen followed by 5 years with an AI.

Postmenopausal patients may also continue tamoxifen for 10 years if they cannot tolerate an AI or prefer tamoxifen over an AI.

ASCO (2018) considered that the data supporting these different regimes should provide reassurance to patients and clinicians that minor degrees of non-adherence during the course of extended therapy likely does not impact on clinical outcomes among average-risk patients. 

Bone-modifying agents and bone health

Bone Mineral Density Assessment (Recommendation)

Consider imaging with dual energy x-ray (DEXA) to measure bone mineral density in patients with breast cancer treated with chemotherapy and/or endocrine therapy. 

How this guidance was developed

This recommendation was adapted from the ACS/ASCO 2016 guidelines (US). The source recommendation was based on a systematic review of the evidence conducted to April 2015 and was not graded by the source guideline authors. The source recommendation was simplified by removing details of the treatment regimens, and by making the recommendation less directive by replacing ‘refer’ to ‘consider’ as a DEXA scan is not recommended for all patients treated with chemotherapy and/or endocrine therapy and to reflect the Australian health care context (MBS items). This recommendation was also informed by several other source recommendations on this topic across guidelines, noting inconsistency across guidelines as to who should have the scans and the frequency of scans. An algorithm for determining who should receive a DEXA, as referred to by NICE and several other guidelines, is noted.

Treatment-induced bone loss – Management (Practice Point)

Consider the use of zoledronic acid or denosumab for the management of treatment-induced bone loss in patients with breast cancer.

How this guidance was developed

This recommendation was initially developed as a practice point due to the lack of evidence-based source recommendation at the commencement of the Guidance development process. It was subsequently adapted from a source recommendation in the ESMO 2019 clinical practice guidelines (date and method of evidence review not indicated), which was graded ’A’. The recommendation was expanded to include denosumab as well as the bisphosphonate zoledronic acid, as supported by the evidence that it reduces clinical fractures.

The recently released ASCO 2020 guideline on the management of male breast cancer is noted. This guideline, based on a systematic review of the evidence to 20 September 2019, indicates that ‘Men with early-stage breast cancer should not be treated with bone-modifying agents to prevent recurrence but could still receive these agents to prevent or treat osteoporosis’ (Type: formal consensus; Evidence quality: low; Strength of recommendation: moderate).

Bone-modifying agents – Treatment considerations (Practice Point)

Before commencing treatment with a bone-modifying agent (denosumab or zoledronic acid) discuss the benefits, common and rare side effects, risks (including unknown harms to future offspring) and regulatory status of the treatments.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). The source recommendation was based on a systematic review of the evidence conducted to September 2017 and used wording indicative of the need for shared decision-making by the source guideline authors. The source recommendation was adapted by including denosumab as well as the bisphosphonate zoledronic acid, and expanding the topics for discussion.

Bone-modifying agents – Dental care (Practice Point)

Refer all patients to a dentist for preventative and ongoing dental care before commencing treatment with a bone-modifying agent.

How this guidance was developed

No evidence-based source recommendation was identified for this topic, which was considered an important aspect of care. This practice point was developed using an expert consensus process.

This practice point is informed by a recommendation (not graded, based on a systematic review of the evidence) in the CCO/ASCO 2017 clinical practice guideline on the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer.

Adjuvant bisphosphonate treatment – Premenopausal women (Recommendation)

Consider the use of zoledronic acid as adjuvant therapy for premenopausal women receiving ovarian suppression. 

How this guidance was developed

This recommendation was adapted from the ESO-ESMO 2017 guidelines for young women (Europe). The source recommendation was based on a review of the evidence (date of review not indicated, considered by the expert panel in November 2016) and was graded ‘B’ (using ACCP methods). The source recommendation was adapted by making stylistic changes by, removing some of the detail. The recommendation and level of evidence has remained unchanged in the ESO-ESMO 2020 update.

The recommendation is supported by a recommendation in the CCO/ASCO 2017 clinical practice guideline on the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer.

It is noted that zoledronic acid is not TGA-approved for this indication.

Adjuvant bisphosphonate treatment – Postmenopausal women (Recommendation)

Consider the use of zoledronic acid as adjuvant therapy for postmenopausal women with breast cancer with a moderate to high risk of recurrence.

How this guidance was developed

This recommendation was adapted from the NICE 2018 guidelines (UK). Two source recommendations on bisphosphonate use were merged. Both source recommendations were based on a systematic review conducted to September 2017: one used wording (‘Offer’) indicative of a strong recommendation and the other used wording (‘Consider’) indicative of a conditional recommendation (using GRADE methods). The source recommendations were adapted by removing reference to sodium clodronate as this is no longer available in Australia, and by making the recommendation less directive due to the merging of the two source recommendations. It is noted that zoledronic acid is not TGA-approved for this indication.