Adjuvant therapy

Adjuvant therapy unequivocally provides a significant and prolonged improvement in survival. It is based on the principle that breast cancer is, for many women, a systemic disease at the time of diagnosis with undetectable dormant micrometastases. These micrometastases may develop into clinically relevant metastases years after primary diagnosis. Characteristics of the primary tumor that may predict the risk of metastatic disease in individual women include:

  • the involvement (and number) of lymph nodes in the axilla

  • high histological grade of the primary tumor

  • large tumor size

  • other biological factors: estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor 2 receptor (HER2) status.

Endocrine therapy


Adjuvant endocrine therapy has a key role in the treatment of hormone receptor-positive early breast cancer either alone or in combination with chemotherapy.
Tamoxifen is a selective estrogen receptor modulator (SERM) that has effects both as an estrogen agonist and antagonist depending on the tissue and receptor type. It binds competitively with 17-β-estradiol at the receptor site, producing a nuclear complex that decreases DNA synthesis, causing cells to remain in the G0 and G1 phases of the cell cycle. As a prodrug, it is metabolized in the liver by the cytochrome P450 isoform CYP2 D6 and CYP3a4 into active metabolites, such as 4-hydroxytamoxifen and endoxifen, which have 30–100 times greater affinity for the ER than tamoxifen itself. Tamoxifen has been approved for the treatment of ER-positive breast cancer since the 1980s. Two large-scale trials (aTTom and ATLAS) have shown that 10 years of treatment is superior to 5 years in terms of both recurrence and mortality. How 10 years of tamoxifen compares with 5 years of standard-of-care aromatase inhibitor (AI) therapy in postmenopausal women is unknown. However, many clinicians believe that this evidence could be extended to prolong treatment with AIs beyond 5 years, particularly in patients with a higher risk of relapse. Discussions with patients about extended adjuvant therapy must include both the benefits and potential harms. Tamoxifen has partial estrogen agonist activity, which may cause gynecologic symptoms, such as vaginal bleeding and endometrial polyps, and an increase in endometrial thickness. There is a small but definite 2.5-fold increase in the risk of endometrial cancer; however, this equates to only 1 case in every 1000 women treated for 5 years. The relative risk of thromboembolic disease (deep vein thrombosis and pulmonary emboli) is also slightly increased at 1.6, and is more commonly seen in women over 50 years of age or with a predisposition to venous thrombosis (in which case tamoxifen should be avoided). Patients with a variant form of the CYP2D6 gene, which is involved in tamoxifen metabolism, may not receive full benefit from tamoxifen because metabolism into its active metabolites (e.g. endoxifen) is too slow. The use of selective serotonin reuptake inhibitors may decrease the effectiveness of tamoxifen by competing with the CYP2D6 enzyme. Patients may also experience vasomotor symptoms, such as hot flashes. Aromatase inhibitors. In postmenopausal women, estrogen is produced by the aromatization of adrenal androgens by the aromatase enzyme system, which is found mainly in subcutaneous fat but also in muscle, liver and skin. AIs include steroidal (e.g. exemestane) and non-steroidal compounds (e.g. anastrozole and letrozole). They have long-established superiority over tamoxifen in terms of disease-free survival (DFS) and overall survival. The optimal duration and sequence of use has not yet been determined, but trials are comparing 5 and 10 years of AI therapy and evaluating whether the sequence of hormone therapy (i.e. tamoxifen followed by AI therapy or vice versa) affects efficacy. Recent data from the MA. 17R study found that extending treatment with AIs to 10 years further reduced the risk of recurrence (95% DFS after 10 years of letrozole versus 91% with placebo, p=0.01) without any significant deterioration in overall quality of life. AIs have a favorable side-effect profile overall, with fewer gynecologic problems and vascular events, but an increase in the incidence of arthralgia and osteoporotic fractures. Interestingly, although the beneficial effect persists, the fracture risk is not higher after stopping treatment. Ovarian suppression. Estrogen depletion arrests breast cancer growth. Reversible ovarian suppression can be achieved medically using gonadotropin-releasing hormone (GnRH) analogs, which downregulate gonadotropin release from the pituitary gland through effects on the luteinizing hormone-releasing hormone (LHRH) receptor. The highly reversible effects of goserelin (the first GnRH analog) and similar drugs allow young women the opportunity to regain menses after completion of therapy. Goserelin was found to be equivalent to cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in patients with ER-positive breast cancer. However, CMF is not regarded as a modern standard chemotherapy regimen and, for most women, goserelin would not be regarded as a substitute. The Zoladex In Premenopausal Patients (ZIPP) trial indicated that ovarian suppression therapy (OST) may add to the benefit of chemotherapy and tamoxifen in younger premenopausal women (aged < 40 years), but not in older women. In the SOFT study, adding OST to tamoxifen did not improve disease-free survival at 5 years. A secondary analysis demonstrated that the combination of exemestane and OST improved rates compared with 5 years of tamoxifen, and in a (small) subset of patients under 35 years adding OST decreased the risk of relapse, particularly when combined with exemestane rather than tamoxifen. Given that combining GnRH analogs with AIs has now been shown to be effective, a GnRH analog may be recommended in women who decline chemotherapy and could be considered instead of tamoxifen in women who may wish to conceive later.




Chemotherapy


The benefit of adjuvant chemotherapy has been confirmed in many randomized controlled trials, and drugs that have been shown to be effective in metastatic breast cancer have been introduced into the treatment of early breast cancer. Different chemotherapy regimens vary considerably in their toxicity profiles, required level of supportive care, affordability and efficacy in different subgroup populations. All chemotherapy regimens have well-defined agent combinations, doses, sequencing and cycle frequency. However, the optimal drugs or drug combinations have not yet been established. Anthracyclines (e.g. doxorubicin and epirubicin) have been the mainstay of most modern adjuvant regimens for early breast cancer for decades. The multiple mechanisms by which anthracyclines inhibit cancer are still not completely clear but include inhibition of DNA and RNA synthesis, inhibition of topoisomerase 2, generation of free oxygen radicals, and inhibition of cell growth through antiangiogenic pathways. Analyses have confirmed the benefit of anthracycline- over nonanthracycline-based chemotherapy (e.g. CMF) in terms of both diseasefree and overall survival. The absolute difference in survival in favor of anthracyclines is approximately 3%. This has to be set against greater toxicity with a higher rate of alopecia, emesis, leukopenia and infection, mucositis and diarrhea with anthracycline regimens compared with CMF. Data are emerging to show that anthracyclines may be particularly important in patients who have over-expression of HER2 (see below) and topoisomerase 2α genes, which are both found on chromosome 17. Taxanes are among the most widely used chemotherapy agents in the treatment of early breast cancer. They stabilize microtubules, leading to cell cycle arrest and cell death. Two taxanes are in common use: paclitaxel and docetaxel. An overview analysis of taxane trials has confirmed the benefit of these drugs over anthracycline treatment alone, but debate continues as to whether this benefit is equal for the population as a whole or whether some women benefit more than others. At present, an anthracycline followed by or concurrent with a taxane is the optimal treatment for triple-negative breast cancer.
Guiding principles for chemotherapy selection are as follows.

  • The absolute benefits of chemotherapy are significantly greater in patients with ER-negative disease. In one study, 5-year disease-free survival increased by 22.8% in patients with ER-negative tumors if they received chemotherapy, compared with an increase of 7% for patients with ER-positive tumors receiving chemotherapy.
  • Retrospective analyses have demonstrated that the superiority of anthracycline-based adjuvant therapy over non-anthracycline-based therapy appears to be confined to patients with HER2-positive tumors. Hence, the decision to use anthracycline-based chemotherapy in HER2-negative patients, especially those with cardiac comorbidities, needs careful evaluation.
  • Quality of life must be taken into consideration. The NSABP (NRG) B-36 trial demonstrated worse quality of life at 6 months and a higher rate of amenorrhea after chemotherapy in women treated with a 5-fluorouracil–epirubicin–cyclophosphamide (FEC) regimen.
  • The role of carboplatin in addition to anthracyclines and taxanes in triple-negative patients is under investigation. The results of randomized trials have shown improvement in pathological complete response rates when carboplatin is added to anthracycline- and taxane-based chemotherapy in the neoadjuvant setting. However, its effect on long-term outcomes, such as overall or disease-free survival, are not yet known.
  • The addition of taxanes to anthracycline-based therapy has shown significant improvement in disease-free and overall survival. The absolute benefit was greater in the ER-negative population.
  • There are insufficient data to make specific chemotherapy regimen recommendations in patients over 70 years old. However, the general consensus is that the patient’s functional status and comorbidities should be taken into consideration when selecting chemotherapy, rather than using an arbitrary age cut-off. Elderly patients with good functional status receive the same benefits from chemotherapy as their younger counterparts.




Targeted treatment


Trastuzumab (Herceptin). Four large multicenter randomized trials of early breast cancer have found a survival benefit of using trastuzumab in combination with chemotherapy in HER2-positive tumors. The reduction in the relative risk of recurrence and death was over 50% and 26–40%, respectively. In absolute terms, the reduction in death was less than 10%. The incidence of cardiac toxicity was low with a cumulative incidence below 4% and no cardiac problems emerged after completion of trastuzumab therapy. Cardiac monitoring of left ventricular ejection fraction remains essential. Duration of treatment remains an important question. Several studies that have explored the efficacy of 9-week trastuzumab therapy have found similar survival outcomes to those seen with trastuzumab administered for 12 months. Trials investigating trastuzumab treatment for 6 months or less have suggested that the shorter duration have results that are not much worse than the longer duration with a potential to have fewer side effects. Treatment of early breast cancer. A meta-analysis of patients with HER2-positive tumors < 2 cm has shown that at 8 years’ follow-up, the addition of trastuzumab in both ER-positive and ER-negative cohorts improved recurrence rates and overall survival. Furthermore, the combination of paclitaxel and trastuzumab in HER2-positive tumors < 3 cm with no node involvement demonstrated 98.7% survival at 3 years. Given the limited data and short follow up, clinicians should still balance the efficacies and toxicities of treatment when prescribing adjuvant therapy for patients with small HER2-positive breast cancer.




Bisphosphonates


A number of trials have evaluated bisphosphonates in addition to standard adjuvant therapy to establish whether they reduce the incidence of bone and other metastases. However, they have also been found to improve survival. This is interesting, not only as it identifies another effective systemic therapy, but because biologically this is the first time that a drug that alters the internal milieu (rather than killing cancer cells) has been shown to improve outcome. A meta-analysis has confirmed the survival benefit of bisphosphonates (e.g. risidronate, 4 mg i.v. injection given 6 monthly for 5 years) in all postmenopausal women.




Making the choice of treatment


The decision to offer adjuvant therapy is complex and takes into account:

  • The best treatment according to the literature
  • Treatment interactions with comorbidity in an individual patient
  • Patient preference
  • Economic climate and national guidelines.
  • Some general rules of thumb, as starting points, are:
  • Hormone therapy reduces the proportionate risk of recurrence by approximately 40% in patients who are ER or PgR positive
  • Chemotherapy reduces the proportionate risk of recurrence by about 33% with CMF and up to 40–50% with newer chemotherapy regimens
  • The addition of chemotherapy and hormones (sequentially) provides an additional benefit of approximately 15%
  • Patients with HER2-positive breast cancer should receive HER2targeted therapy (trastuzumab) in addition to chemotherapy (± endocrine therapy)
  • Bisphosphonates should be recommended to all postmenopausal women.
Predicting individual response Adjuvant! Online (adjuvantonline.com) is arguably the first internet-based program that estimates the absolute benefit of adjuvant systemic treatment for an individual woman; it may, however, be too optimistic for patients with adverse prognostic factors and younger patients (≤ 30 years). Adjuvant! Online provides estimates of the benefit of trastuzumab for individual patients. However, it has been off-line for some time. NHS Predict - https://breast.predict.nhs.uk/ is the most commonly used web-based tool to assess the background risk and consequent benefit from systemic adjuvant therapy. Gene expression profiling. Analysis of the expression of multiple genes in an individual tumor would refine recurrence prediction and, in theory, treatment benefit prediction. Oncotype DX is a 21-gene assay that can be used to estimate the potential benefit of chemotherapy in cases where there is doubt about the benefits using conventional criteria. The EndoPredict clinical score, which combines the EndoPredict 11-gene assay with clinical factors, provides another approach to decision-making with respect to systemic chemotherapy. In general, these tests are expected to reduce the use of systemic chemotherapy by identifying those patients who may not derive substantial benefit from it. Although the tests can be expensive, the avoidance of chemotherapy in some patients could make them cost effective.




Side effects


Some of the side effects of cytotoxic drugs are generic and common to most chemotherapy drugs (e.g. emesis, leukopenia, alopecia, mucositis, gastrointestinal upset and fatigue). Others are more specific to individual drugs. For example, taxanes are associated with sensorimotor neuropathy and myalgia, as well as skin and nail changes, which are uncommon with the anthracyclines. Anthracylines can, however, be associated with cardiac toxicity leading to impaired left ventricular ejection fraction and, rarely, cardiomyopathy. There is a lifetime cumulative dose of anthracyclines, which should not be exceeded, and caution should be exercised in patients with cardiac risk factors, such as hypertension, obesity and diabetes. Hematopoietic growth factors may be used as primary or secondary prophylaxis to minimize the risks of infection associated with leukopenia. The American Society of Clinical Oncology (ASCO) recommends that primary prophylaxis should be considered for all patients in whom a drug is expected to have an incidence of neutropenia of 20% or more; in practice, this would include most patients receiving adjuvant taxanes. Cognitive impairment associated with adjuvant therapy is becoming increasingly recognized. Fertility may be a concern to younger women. The risk of infertility with adjuvant treatment depends on ovarian reserve, which is related to the age of the woman and the intensity of the adjuvant regimen. Women should be given an opportunity to consult with a fertility specialist, if possible, before starting treatment to discuss the pros and cons of fertility preservation. Currently, the only proven method is in vitro fertilization with embryo cryopreservation. GnRH analogs may enable the ovaries to ‘rest’ during chemotherapy and allow menses to resume but few data on this approach are available and there are uncertainties about safety, particularly in relation to ER-positive breast cancers.





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