Prognostic factors
Patient age
Axillary lymph node status
Histological subtypes (e.g. tubular, mucinous, papillary)
Tumour size
Histological grade
Lymphatic/vascular invasion
HER2 gene amplification and/or overexpression
Oestrogen receptor/progesterone receptor status
Response to neoadjuvant therapy
Predictive factors
Oestrogen receptor (RE) and progesterone receptor (PR) status
HER2 gene amplification and/or overexpression
Additional factors (potentially prognostic and/or predictive)
Multigene expression profile (e.g. Oncotype DX)
BRCA1/2 gene mutation
Bone marrow micrometastases
p53 gene analysis
Cathepsin D level
Lymph node involvement is the most important single prognostic factor in BC, as discussed in Sect. 13.2. The vast majority of patients with lymph node metastases are candidates to adjuvant systemic therapy. However, determining which lymph node-negative patients should receive adjuvant therapy is challenging, particularly because the majority are cured by local treatment (surgery +/− radiotherapy). The benefit from adjuvant treatment for patients who are at risk of relapse may be minimal, with significant costs and toxicities. Thus, additional prognostic and predictive factors should be used to decide which lymph node-negative patients may benefit from adjuvant treatment.
Tumour size is a well-recognised independent prognostic factor and predictor of axillary node involvement, being a large tumour associated with higher probability of lymph node involvement and worse prognosis.
All cases of invasive BC are evaluated for ER and PR status that, as already underlined, have both predictive and prognostic value. In fact, ER and/or PR positivity is associated with reduced mortality compared to women with ER- and/or PR-negative disease; the presence of hormone receptors is a powerful predictive factor for the likelihood of benefit from adjuvant hormonal therapy. A tumour is defined positive for ER/PR when the percentage of tumour cells stained positively by immunohistochemistry is >1 %.
HER2 oncogene is amplified and/or overexpressed in approximately 20 % of BC and is a strong predictor of relapse and worse overall survival, particularly in node-positive patients. Moreover HER2 positivity predicts response to trastuzumab. Amplification and/or overexpression of the HER2 is routinely evaluated, using immunohistochemistry and/or fluorescence in situ hybridisation (FISH), respectively, even if variability across the laboratories involved in this determination remains a major issue with both methodologies (see Sect. 13.2).
Additional established prognostic factors include patient’s age, tumour grade, and lymphovascular invasion. Certain histological subtypes of BC are generally associated with a favourable prognosis, such as tubular, mucinous and papillary carcinoma. The proliferation rate of the tumour as determined by the mitotic count is also an important prognostic factor, but this information is usually used to determine the tumour grade. The prognostic relevance of proliferative index expressed by Ki67 value is controversial, and its determination is problematic because of absence of standardised method of evaluation and interpretation.
Oncotype Dx is a diagnostic test that estimates the likelihood of disease recurrence in women with newly diagnosed, early-stage, lymph node-negative, ER-positive BC by analysis of a panel of 21 genes. Moreover, this test helps define whether chemotherapy should or should not be added to hormonal therapy (see Sect. 13.3).
The Oncotype DX gene panel was validated in a large, independent, multicenter clinical trial of adjuvant tamoxifen treatment (NSABP B-14 study). In this study, patients with low or intermediate risk had a significant benefit from the use of adjuvant tamoxifen, whereas the high-risk group did not. Moreover, in a retrospective subset analysis of the NSABP B-20 study (a randomised trial of adjuvant chemotherapy with CMF-like regimens), patients in the high-risk recurrence score strata significantly benefited from adjuvant chemotherapy, whereas the intermediate- and low-risk groups did not achieve statistical significance.
Oncotype DX has also been evaluated in a pilot retrospective study in patients with lymph node-positive, ER-positive disease. Similar to observations in lymph node-negative disease, the pilot study indicated little (if any) benefit from anthracycline-based (but not containing a taxane) adjuvant chemotherapy for patients with low risk of recurrence, whereas patients with high risk of recurrence had a significant impact from adjuvant therapy.
Response to neoadjuvant chemo- and hormonal therapy has been shown to be a strong prognostic factor and has the added benefit of providing a short-term endpoint for the rapid evaluation of treatment protocols. Determining patient response to neoadjuvant therapy is best achieved using pathological evaluation of the posttreatment specimen.
Factors not routinely used in clinical practice, although may have prognostic impact, are detection of bone marrow micrometastases at the time of diagnosis, p53 gene analysis, markers of invasion (e.g. levels of the proteolytic enzyme cathepsin D), markers of angiogenesis (e.g. microvessel density as detected by immunohistochemistry) and so on.
DECISION-MAKING PROCESS (See also Sect. 13.3). As known, adjuvant treatment of BC is designed to treat micrometastatic disease or BC cells that have escaped the breast and regional lymph nodes but have not yet developed identifiable metastases. The decision to administer adjuvant systemic therapy must take into account not only the individual patient’s risk of relapse but also the absolute benefits of treatment, the potential short-term and long-term complications and the patient’s comorbidities and life expectancy. Depending on the model of risk reduction, adjuvant systemic therapy has been estimated to reduce the mortality rate by 35–70 %.
Not all factors have similar influence on the decision-making process, for their different prognostic/predictive value, as well as the potential overlap of some with others. It is therefore appropriate to divide them into essential and additional factors. Indications and choice of type of adjuvant systemic treatment for invasive BC should be driven by:
The histological characteristics of the tumour, including essential factors such as tumour size (pT) and nodal involvement (pN) and additional factors such as grade and peritumoural lymphovascular invasion (LVI)
The biological characteristics of the tumour, including essential factors such as ER/PR status and HER2 expression and additional factors such as Ki67 and multigene test (Oncotype DX and others), if available
In Table 18.2 are summarised factors that help to decide which kind of adjuvant therapy should be considered. Special groups of general population like young (<40 years old) and very young (<35 years old) women (see Section 15.3) or elderly woman (see Section 15.4) have few different options.
Table 18.2
Factors involved in decision-making process for adjuvant treatment of BC patients
Relative indications for chemotherapy with/without endocrine therapy | Factors not useful for decision | Relative indications for endocrine therapy alone | |
|---|---|---|---|
Biological factors | |||
ER and PR status | Lower ER and PR level | Higher ER and PR level | |
Ki67 | High (>30 %) | Intermediate (16–30 %) | Low (<15 %) |
HER2 expression | 3+ by IHC or FISH positive | ||
Multigene test (if available) | High score | Intermediate score | Low score |
Histological factors | |||
pT | >5 cm | 2.1–5 cm | <2 cm |
Grade | Grade 3 | Grade 2 | Grade 1 |
LVI | Present | Absent | |
pN | 4 or more involved nodes | 1–3 involved nodes | Node negative (pN0) |
Patient’s characteristics | |||
Patient preference | Choice of all available treatments | Avoid chemotherapy-related side effects | |
Patient comorbidity | Intolerance to chemotherapy | ||
PARAMETERS USED TO CHOOSE ADJUVANT THERAPY. The St. Gallen International Consensus Conference gathers a worldwide group of BC experts to provide updates on adjuvant therapy recommendations based on low, intermediate and high risk [1]. They recommend adjuvant chemotherapy for patients with hormone receptor-positive, high-risk disease or hormone receptor-negative, intermediate- or high-risk disease. They also recommend consideration of chemotherapy for patients with hormone receptor-positive, intermediate-risk disease. High-risk disease is defined as four or more positive nodes with any HER2 status or one to three positive nodes and HER2 positive. Low-risk group includes patients with age greater than 35, tumour size less than or equal to 2 cm, grade 1, no lymphovascular invasion and HER2-negative status (Table 18.3).
Table 18.3
St. Gallen systemic adjuvant therapy recommendations
Risk category | Associated features | Adjuvant therapy options |
|---|---|---|
Low risk | Node negative, ER/PR positive, T <1 cm, grade 1, no LVI, HER2 negative, age >35 (all listed factors) | None |
Endocrine only | ||
Consider multigene test (Oncotype DX) | ||
Intermediate risk | Node negative and at least one of the following: T > 2 cm, grade >1, LVI, age < 35, HER2 positive | Endocrine only (ER/PR+) |
CT followed by endocrine (ER/PR+) | ||
Node positive (one to three nodes) and HER2 negative | Consider multigene test (if node negative and ER/PR+) | |
CT (ER/PR-) | ||
High risk | Node positive (one to three nodes) and HER2 positive | CT followed by endocrine (ER/PR+) |
CT | ||
Node positive (> four nodes) |
The National Comprehensive Cancer Network (NCCN) gathers experts to create practice guidelines in oncology, which are available to all practitioners [2]. The NCCN guidelines consider some factor like grading and Ki67 as non-important factors to decide adjuvant treatment of BC patients and state that ER and PR status should be evaluated on every BC to guide the decision to use hormonal therapy, whereas HER2 overexpression should be evaluated on every BC to select patients who have to be treated with trastuzumab. NCCN guidelines recommend adjuvant chemotherapy for patients with lymph node involvement, hormone receptor-negative BC and tumour size greater than 1 cm and for those with hormone receptor and HER2-positive disease and tumour size greater than 1 cm.
In some cases, St. Gallen guidelines differ slightly from NCCN recommendations, being slightly more conservative, and sometime contrasting, for example, a woman with a 1.5-cm, node-negative, grade 1 tumour. ER positive, HER2 negative has an approximate 15 % 10-year risk of recurrence without systemic therapy. The NCCN guidelines would recommend considering adjuvant chemotherapy in addition to hormonal therapy, whereas the St. Gallen guidelines would recommend hormonal therapy only.
MULTIDISCIPLINARY TEAM (MDT). Diagnosis and treatment should be carried out in specialised institutions (Breast Units) caring for a high volume of BC patients, and the care of BC patients should be assigned to a MDT including at least a surgeon, a radiation oncologist, a medical oncologist, a radiologist and a pathologist—all specialised in BC. Patients should be provided with full, preferably written, information about their disease and treatment.
TIMING. It is recommended to start adjuvant chemo- or endocrine therapy (or radiotherapy), within 8 weeks from surgery.
18.2 Adjuvant Endocrine Therapy
Clinical Practice Points
Premenopausal women with ER-positive BC should be treated with tamoxifen (TAM) for at least 5 years, to a total of 10 years, unless there are contraindications or side effects.
Postmenopausal women with ER-positive BC should be considered rather for treatment with aromatase inhibitors (AI) as an alternative to TAM, either upfront AI for 5 years or switch to an AI after 3–3 years of TAM for a total of 5 years.
Postmenopausal women who have completed 5 years of TAM may be considered for extended (5 years) treatment with an AI.
The choice and sequence of adjuvant endocrine agents should consider benefit and side effects of treatment.
18.2.1 Agents
Hormone therapy decreases oestrogens level avoiding growth of dormant cancer cells. In ER-positive early-stage BC, hormone therapy plays a main role in adjuvant treatment, either alone or in combination with chemotherapy. Approved endocrine therapies for adjuvant treatment of BC include tamoxifen and aromatase inhibitors (anastrozole, letrozole, exemestane). Gonadotropin-releasing hormones (GnRH) analogue is an additional agent for premenopausal women (Table 18.4).
Table 18.4
Hormone agents used in BC
Premenopausal | Tamoxifen | 20 mg PO every day |
+/− GnRH analogue: | ||
Leuprorelin or Triptorelin | 3.75 mg IM/SC depot q1mo/11.25 mg IM/SC q3mo | |
Goserelin | 3.6 mg SC depot q1mo/10.8 mg SC q3mo | |
Postmenopausal | Tamoxifen | 20 mg PO every day |
Aromatase inhibitor: | ||
Anastrozole | 1 mg PO every day | |
Letrozole | 2.5 mg PO every day | |
Exemestane | 25 mg PO every day | |
TAMOXIFEN (TAM) is a selective oestrogen receptor modulator that binds to and inhibits oestrogen receptor signalling in the breast [3]. As a receptor antagonist in BC, it is effective in all age groups, both in premenopausal and postmenopausal women. TAM acts also as agonist in other tissues, including bone (resulting in preservation of bone density) and endometrium (leading to an increased risk of endometrial cancer).
Beneficial effects of TAM are greater when taken for at least 5 years. There is little but important evidence that TAM is of additional benefit if taken for more than 5 years. Effects of TAM on outcomes are the following:
1.
Increases 10-year survival from about 70 to 80 % among women without lymph node involvement with an absolute gain of 15.6 %
2.
Increases 10-year survival from about 50 to 60 % among women with lymph node involvement with an absolute gain of 15.5 %
3.
Almost halves the risk of development of cancer in the contralateral breast
Of note, up to 7 % of the white and black populations are poor metabolisers of tamoxifen. Poor metabolisers have been shown in several retrospective studies to have lower disease-free survival and higher recurrence rates than extensive metabolisers. Poor metabolisers also seem to tolerate tamoxifen better, with less severe hot flashes and endocrine-related toxicities.
AROMATASE INHIBITORS (AIs). AIs, in contrast to TAM, act via inhibition of oestrogen synthesis. There are two classes of AIs: nonsteroidal, as anastrozole and letrozole, and steroidal, as exemestane. As AIs have no effect on ovarian oestrogen production, they are effective only in postmenopausal women and should not be used in premenopausal women. Beneficial effects of AIs are the improvement of disease-free and metastatic-free survival rate which appears to be higher than with tamoxifen in postmenopausal women [4].
Beneficial effects of AIs on outcomes are the following.
Absolute gain at 8 years in risk of relapse of 3.9 % if administered upfront.
Absolute gain at 6 years in risk of relapse of 3.6 % if administered for 2–3 years after 2–3 years of TAM (switch strategy).
Reduction in risk of recurrence when used as extended adjuvant therapy after 5 years of TAM as well as improved overall survival in the lymph node-positive BC patients.
Reduction in risk of contralateral BC by a further 40–50 % when given instead of or after TAM.
AIs may be more effective than TAM in HER2-positive BC.
None of the head-to-head comparison trials between AIs and TAM has yielded an improvement in overall survival.
18.2.2 Schemes of Endocrine Therapy
The choice of treatment should be made after discussion between clinician and patient about the risks and benefits of each option. Factors to consider when making the choice include whether the woman has received TAM before, the side-effect profiles of the individual drugs and the recurrence score (Table 18.5).
Table 18.5
Adjuvant endocrine therapy for women with hormone receptor-positive BC
Pre- or perimenopausal |
TAM for an initial duration of 5 years |
Adjuvant ovarian ablation/suppression in addition to TAM may be offered to women with ER-positive early invasive BC |
After 5 years, women could receive additional therapy based on menopausal status |
If women are pre- or perimenopausal or if menopausal status is unknown or cannot be determined, they should be offered continued TAM for a total duration of 10 years (in selected cases) |
If women have become definitively postmenopausal, they should be offered to switch to 5-year treatment with an AI |
Postmenopausal |
AIs for a duration of 5 years (no data available for a greater duration) |
TAM for an initial duration of 5 years, then switch to an AI for up to 5 years, for a total duration of up to 10 year |
TAM for a duration of 2–3 years and switch to an AI for up to 5 years |
Tamoxifen for a duration of 10 years (in selected cases) |
Appropriate sequence of endocrine therapy |
Intolerance – women who are postmenopausal and are intolerant of either TAM or an AI should be offered the alternative type of adjuvant endocrine therapy |
If women have received an AI but discontinued treatment at less than 5 years, they may be offered TAM for a total of 5 years |
If women have received TAM for 2–3 years, they should be offered switching to an AI for up to 5–10 years |
In premenopausal women, TAM is offered for an initial duration of 5 years. After 5 years, ASCO suggests women not at low risk should receive additional therapy based on reassessment of the menopausal status. If women are pre- or perimenopausal or if menopausal status is unknown or cannot be determined, they should be offered continued TAM for a total duration of 10 years [5]. If women have become definitively postmenopausal, they should be offered continued TAM for a total duration of 10 years or switching to up to 5 years of an AI for a total duration of up to 10 years of adjuvant endocrine therapy [6]. Adjuvant ovarian ablation/suppression can be offered in addition to TAM to premenopausal women with ER-positive early invasive BC. The benefit of ovarian suppression is not clear, and this treatment represents a therapeutic option mainly in young premenopausal women [7].
In postmenopausal women, AIs represent the first therapeutic choice, both upfront and for 2–3 years after 2–3 years of TAM (switch strategy). TAM should be considered when therapy with AIs is contraindicated. Extended therapy with AIs after 5 years of TAM represents a therapeutic option mainly in high-risk BC patients.
18.2.3 Side Effects of Endocrine Therapy
Table 18.6 presents a review of hormonal agents with their mechanism of action, side effect and main risks.
Table 18.6
Mechanism of action, side effects and specific toxicity of hormonal agents used for the treatment of BC, with their mechanism of action, side effects and main risks
Agent | Mechanism | Side effects | Risks |
|---|---|---|---|
Oestrogen receptor modulator or suppressor | |||
Tamoxifen (TAM) | Selective oestrogen receptor modulator (SERM) | Fatigue, hot flashes, vaginal discharge, rapid change in mood, headache, skin rash, nausea and fluid retention/weight gain | Thromboembolic events, uterine cancer and cataracts |
(Nolvadex®) | |||
Aromatase inhibitors (AIs) | |||
Letrozole | Nonsteroidal: inhibits the synthesis of oestrogen via vreversible competition for the aromatase enzyme | Joint stiffness, bone and joint pain, nausea, headache and fluid retention/weight gain | Osteoporosis |
(Femara®) | |||
Anastrozole | |||
(Arimidex®) | |||
Exemestane | Steroidal: forms a permanent and deactivating bond with the aromatase enzyme | ||
(Aromasin®) | |||
GnRH analogues | |||
Goserelin | Blocks ovarian production of oestrogen | Hot flashes and menopause symptoms | |
(Zoladex®) | |||
Triptorelin | |||
(Decapeptyl®) | |||
Leuprorelin | |||
SIDE EFFECTS OF TAM
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