03 Adjuvant Systemic for HER2 Negative Breast Cancer : BC Cancer Agency

Updated 1 February 2012

The BCCA Breast Adjuvant Systemic Policy Guidelines are based on estimated recurrence risk assessed as either "low", "intermediate", "high-risk node negative", "high risk node positive" or "extreme" risk. The estimated 10 yr lower limit of risk of recurrence for each category without any adjuvant systemic therapy is as shown in Table 1.

These risk categories are somewhat arbitrary divisions. Recurrence risk is heterogeneous and continuous with some overlapping risk between these defined risk categories. The high risk node positive category represents a threshold of risk in which consideration of some form of adjuvant chemotherapy is usually justified, even in most estrogen receptor positive cases.

Several adjuvant chemotherapy choices are available: anthracycline alone: AC, CEF, FEC, CAF po (d1 & d8); and anthracycline and taxane based: TAC, FEC-D, AC-T (the latter ideally in a dose-dense or weekly approach). AC and CMF adjuvant chemotherapy have seen declining use, as overall, the reductions in recurrence and mortality risk are superior with newer generation regimens, with approximately 30% and 20% better outcomes, respectively. It should be noted that these are improvements in relative risk reduction, and that absolute risk reduction is a function of estimated relapse risk at the outset, for any individual tumour. Therefore, although newer regimens demonstrate statistical superiority, absolute benefits may be small or very small when the estimated initial 10 year relapse risk is 30-40% or lower. Patient’s age, underlying health, and menopause and hormone receptor status are important additional considerations. Therefore the following recommendations allow a range of options and rely on doctor-patient discussion of risks, benefits, and preferences. A decision aid known as ADJUVANT¹⁷! (http://www.adjuvantonline.com/) might be helpful to estimate risk /benefit of various systemic treatment options for an individual patient with tumour characteristics in the broad risk categories below.

The listed options represent indications for use of these regimens based on long term efficacy in phase III clinical trials of node positive disease (or high risk node negative) for premenopausal and/or postmenopausal groups, or on extrapolation of the same data to other age/menopausal groups and/or for node negative disease with the same estimated risk as node positive disease.

Node Negative Status

Discrimination of risk within node negative disease remains challenging. Tumor size, histological grade and lymphatic vascular invasion (LVI) are the most important prognostic factors. The importance of tumor size and grade in a node negative series⁶ without LVI and no adjuvant systemic therapy (her2/neu status unknown) is shown in Table 4 at bottom, with 10 year observed relapse-free, breast cancer specific and overall survival.

A clinical trial (TailoRx) is currently available in some BCCA centres to test the ability of a multi-gene assay to enhance risk evaluation and systemic therapy in hormone receptor positive, node negative tumours. More details can be obtained from a BCCA Breast Medical Oncologist.

Other Risk Factors
Young age¹⁰ appears to be an independent prognostic factor for both early node negative and node positive disease, with a RR impact on overall survival in the same range as for her2/neu positive status. For the age categories 35 to 39, 30 to 34 and those < 30 years the relative risks compared to age > 40 years are respectively 1.5, 1.7 and 1.8.

Over-expression of human epidermal growth factor receptor 2 (her2/neu) is an important prognostic and predictive factor⁷ and is associated with an increase in relative risk of mortality of approximately 2. The management of her2/neu+ breast cancer is discussed in a separate section. See Adjuvant Trastuzumab Therapy page.

Non-chemotherapy Options for Pre-menopausal Patients

The benefit of ovarian ablation alone in premenopausal, estrogen receptor positive, node positive disease is equal to CMF¹¹. For premenopausal women with estrogen receptor positive breast cancer, who decline a recommendation for chemotherapy, ovarian ablation and tamoxifen can be recommended¹². The value of ovarian ablation over and above chemotherapy and/or tamoxifen in estrogen receptor positive, premenopausal women is unknown and is the subject of current clinical trials. Because of the expense and inconvenience of a prolonged course of chemical therapy to achieve ovarian ablation, surgical ovarian ablation is an alternative for individual patients. In patients known or suspected to have an inherited BRCA mutation, who are undertaking surgical ovarian ablation, this should be done in consultation with a genetic counselor or gynecologic oncology expert, to ensure that appropriate protocols are followed in the operating room and pathology suite.

Pre-operative anthracycline-based chemotherapy has traditionally been recommended for patients with locally advanced breast cancer, including inflammatory breast cancer¹³. Recent randomized clinical trials support the role of sequential docetaxel after doxorubicin as neoadjuvant treatment for locally advanced^14,15 and for operable breast cancer¹⁶including those with T3,N2,M0 disease.

Pre-operative chemotherapy also confers other advantages of allowing assessment of tumour response to therapy, and allowing time for planning of definitive surgery +/- reconstruction. Locally advanced breast cancer is considered high risk breast cancer and patients should routinely be considered for eligibility in clinical trials at the BC Cancer Agency and should be referred promptly. Urgent referrals to the BCCA for this purpose are made by contacting the medical oncologist on call for breast cancer.

Clinical trials are available for many patients in the indicated categories below. Please check the BCCA website under Clinical Research (link below), or consult a breast medical oncologist for more information.

Table 2: Treatment options: Premenopausal /Peri-menopausal and/or < Age 60

Extreme Risk

High Risk

Intermediate

Low Risk

ER Positive

BRLAACD

BRAJCEF

BRAJFECD

BRAJDAC

Or, BRAJACTG (if above options are unacceptable)

Shorter, less intensive regimens not preferred for Extreme Risk; avoid if possible

Then, adjuvant hormone tx* in all

Node Positive:

BRAJFECD

BRAJDAC

BRAJFEC

BRAJCEF

Shorter, less intensive regimens not preferred for Node+; avoid if possible

Node Negative:

BRAJFEC

BRAJACTG (see notes below)

Or, BRAJAC, BRAJCMF, or BRAJACT (If above options are unacceptable)

Or, BRAJDC, if anthracyclines contra-indicated; compassionate access request needed

Then, adjuvant hormone tx*

adjuvant hormone therapy

+/-

BRAJAC

BRAJFEC

(chemo, if given, to precede hormone therapy)

Or, BRAJDC, if anthracyclines contra-indicated; compassionate access request needed

adjuvant hormone therapy

ER Negative

BRLAACD

BRAJCEF

BRAJFECD

BRAJDAC

Or, BRAJACT(G) if above options are unacceptable

Shorter, less intensive regimens not preferred for Extreme Risk; avoid if possible

Node Positive:

BRAJFECD

BRAJDAC

BRAJFEC

BRAJCEF

BRAJACTG

or BRAJACT

if above are

unacceptable

Shorter, less intensive regimens not preferred for Node+; avoid if possible

Node Negative:

BRAJFEC

BRAJACTG

Or

BRAJAC, BRAJCMF or BRAJACT if above are unacceptable

Or, BRAJDC, if anthracyclines contra-indicated; compassionate access request needed

BRAJACTG

or

BRAJFEC

Or, if above unacceptable:

BRAJAC

BRAJCMF

BRAJACT

Or, BRAJDC, if anthracyclines contra-indicated; compassionate access request needed

* If a premenopausal patient in these risk groups declines recommended chemo, she may be offered BRAJLHRHT, per previous discussion notes.

Individual risk and benefit for any chemotherapy regimen must be considered and discussed with patients.

ER positive tumours may respond less to any chemotherapy. The use of concurrent tamoxifen appears to confound the benefit of any chemotherapy in ER positive tumours, such that a sequential approach should be taken, ie. all chemotherapy should be completed prior to commencing tamoxifen. This has not been clearly demonstrated, or studied, with aromatase inhibitors. Practices vary, but it is reasonable to initiate hormonal therapy in a sequential fashion after chemotherapy and radiation therapy, in the majority of cases, if only to provide reduced chance of side effects and clarity as to the source of any side effects.

The main benefit of adjuvant chemotherapy occurs in the first 3-5 years after therapy, by reference to the EBCTCG analyses. The relapse risk is highest in this timeframe for ER negative tumours, whereas the risk for relapse of ER positive tumours extends out well beyond 5 years. Some trials of taxanes added to anthracyclines have suggested very limited benefit to the taxane if the tumour is ER positive. However, other trials have suggested that addition of taxanes is beneficial despite ER status. It is likely that ER positive tumours generally benefit less from chemotherapy compared to ER negative tumours, but that more aggressive ER positive tumours, with high grade, over-expression of HER2, or significant lymphatic or lymph node spread, do benefit sufficiently to warrant consideration of multi-agent chemotherapy. A number of studies jointly suggest that, when Paclitaxel is chosen for adjuvant therapy, it may be more efficacious to administer it on a dose-dense or weekly protocol.^{18, 19, 22} For this reason, BRAJACT, given at standard 3 weekly intervals, is not generally a preferred regimen, unless individual patient circumstances dictate that this regimen is the most safe and feasible treatment selection for a patient. If a patient is unable to use G-CSF, to allow use of BRAJACTG, consideration could be given to using paclitaxel weekly for 12 weeks, rather than 3-weekly, in discussion with a medical oncologist.

If a patient is not felt to be fit for anthracycline chemotherapy due to cardiac concerns, CMFpo or the adjuvant taxane only regimen Docetaxel Cyclophosphamide (UBRAJDC--CAP request required) may be considered for substitution in any patient where chemotherapy is otherwise recommended.

Best adjuvant therapy practices for elderly women with breast cancer are more difficult to discern from the available literature, as elderly women are under-represented in clinical trials of adjuvant chemotherapy. This relates to multiple factors, including the higher frequency of lower risk, ER positive tumours in this age group; the more frequent presence of significant co-morbidities in elderly age groups, which increases risk of other causes of death, as well as risks of chemotherapy; and clinical trial design, in some instances. In general, meta-analyses suggest that older women do benefit from adjuvant chemotherapy, but that 1) a survival benefit has only so far been demonstrated with the use of adjuvant anthracycline regimens; 2) benefit is greater with more intensive chemotherapy regimens; 3) survival benefit may not be present, or may be hard to demonstrate for ER positive tumours, especially if node negative; 4) risk of chemotherapy related significant morbidity and mortality is slightly higher in elderly women. The age groups included in recent adjuvant chemotherapy trials has varied. For example, in the comparison of Docetaxel AC vs FAC, women as old as 70 were included, but the median age was 49. In the PACS-01 trial, comparing FEC x 6 vs FEC x 3 then Docetaxel x 3, women as old as 67 were enrolled, and the median age was 50. In the CALGB 93-44 trial, comparing AC at different doses, with and without paclitaxel, 13% of patients were older than 60. In CALGB 9741, comparing AC-T to dose dense AC-T, only 2-3% of patients in each arm were 70 or older. By extrapolation from available data, it would appear that older women do stand to benefit from adjuvant chemotherapy, but this type of therapy must be selected carefully, with attention to tumour risk and the fitness of the individual patient for more aggressive therapy.

10 Year Relapse-Free Survival (RFS), Breast Cancer Specific Survival (BCSS),Overall Survival (OS) in a Population-based Cohort⁶ of Lymphatic and Vascular Invasion Negative, Histological Grades 1 to 3, T1-2,N0 Breast Cancers untreated with Adjuvant Systemic Therapies

		0-1 cm				1.1-2.0 cm			2.1-5 cm
		G1	G2		G3	G1	G2	G3	G1	G2	G3
# patients (n=)		105		210	115	72	284	151	19	109	122
RFS:	10 year	88%	84%		74%	89%	74%	71%	73%	63%	69%
BCCS	10 year	93%	94%		88%	97%	91%	84%	88%	76%	75%
OS	10 year	77%	83%		75%	81%	80%	75%	74%	66%	84%

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