3. Adjuvant chemotherapy

HER2 status was included (PREDICT version 1.1) and later KI67 was added to model (PRE-DICT version 1.2) to improve the estimates of breast cancer-specific mortality, especially in

While the overall fit of the model has been good in multiple independent case series, PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40, particularly those with ER+ disease. Another limitation of the model is the use of discrete categories for tumor size and node status which result in "step" changes in risk estimates on moving from one category to the next. For example, a woman with an 18 or 19 mm tumor will be predicted to have the same breast cancer specific mortality if all the other prognostic factors are the same whereas breast cancer-specific morality of women with a 19 or 20 mm tumor will differ. The PREDICT prognostic model was refitted using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumor size and node status. The fit of the model has been tested in three independent data sets that had also been used to validate the

KI67 positivity for the PREDICT model was defined as greater than 10% of tumor cells staining positive. Survival estimates, with and without adjuvant therapy, are presented in visual and text formats. Treatment benefits for hormone therapy and chemotherapy are calculated by applying relative risk reductions from the Oxford overview to the breast cancer specific mortality. Predicted mortality reductions are available for both second-generation (anthracyclinecontaining, >4 cycles or equivalent) and third-generation (taxane-containing) chemotherapy regimens. The survival estimates, presented both with and without adjuvant hormone therapy,

The Cambridge Breast Unit uses the absolute 10-year survival benefit from chemotherapy to guide decision-making for adjuvant chemotherapy as follows: <3% no chemotherapy; 3–5%

Online tools are valuable in guiding adjuvant treatment, especially in resource-constrained countries. However, in the era of personalized therapy, molecular profiling appears to be

The AJCC Prognostic Stage Group containing multigene panels has been globally used from January 1, 2018. It suggests that prognostic stage grouping should be used in countries where biomarker tests are routinely performed, indicating that multigene molecular profiling will become part of cancer stage evaluation and will need to be taken into consideration when

Oncotype DX and MammaPrint have the strongest evidence supporting their clinical utility and decision effectiveness in HR+ breast cancer [42]. The future of multigene panels is promising in personalizing treatment as more studies continue. However, many issues remain to be solved before multigene panels have a wider influence on breast cancer treatment. Importantly new issues, such as how to accurately predicate late recurrence in ER+ cancer and how to

chemotherapy discussed as a possible option; >5% chemotherapy recommended.

chemotherapy and trastuzumab, are provided for 5 and 10 years.

superior in predicting clinical outcome and guiding therapy.

provide more access to multigene panels, should be solved in the future.

HER2-positive patients [29, 39].

132 Breast Cancer and Surgery

original version of PREDICT [40].

making clinical decisions [41].

Several pathological factors including histological subtype, ER or PR expression, tumor grade, lymphovascular invasion, tumor stage, and clinical factors such as patient age, preferences and comorbidities should be taken into consideration during adjuvant chemotherapy indication is being decided. The genomic tests and benefit–risk calculators which were developed to be used in determining appropriate candidates for adjuvant chemotherapy in early stage HR+ breast cancer have been discussed in previous section.

Patients with HR+ breast cancer less than 5 mm and treated with only endocrine therapy have usually very good prognosis. Thus, they typically are not treated with adjuvant chemotherapy. However, patients with stage III HR+ breast cancer still require adjuvant chemotherapy since they carry high risk of recurrence without chemotherapy. Many patients with HR+ HER2 negative breast cancer fall in between these two categories, and they are called as intermediate risk group based on clinicopathological variables, genomic tests or online risk calculators.

Clinicians should inform the patients who required adjuvant chemotherapy about the risks and benefits of chemotherapy. Risks include acute or long-term toxicities such as emesis, alopecia, myelosuppression, neuropathy, cardiotoxicity, infertility and leukemias.

Breast cancer is the most frequent malignancy in women of reproductive age. Treatments for breast cancer may eliminate or diminish fertility. Additionally, even in patients who do not require chemotherapy, long duration of adjuvant endocrine therapy often leads natural decline in ovarian reserve during adjuvant treatment.

The chemotherapy-related risk of premature ovarian insufficiency is influenced by age, body mass index, the type and duration of therapy. After six cycles of CMF, the risk of amenorrhea is 33 and 81% in patients <40 and ≥ 40 years of age, respectively. Newer chemotherapy regimens including adriamycin & cyclophosphamide (AC), adriamycin & cyclophosphamide & taxane (ACT), fluorouracil & adriamycin & cyclophosphamide (FAC) and fluorouracil & adriamycin & cyclophosphamide & taxane (FACT) result in lower rates of persisting amenorrhea. The risk of amenorrhea is 10–20 and 13–68% in patients <30 years and in patients >30 years, respectively [43]. Hence, the rate of infertility risk with particular chemotherapy regimen at particular age should be discussed with patients prior to initiation of gonadotoxic therapies. Furthermore, premenopausal women who are willing to be pregnant in the future should be referred to a fertility specialist to be informed about various techniques of fertility preservation.

Although methods of fertility preservation in breast cancer should be a subject of a separate chapter, fertility preservation methods can be summarized as

• established methods: oocyte or embryo cryopreservation

• experimental methods: ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHa) and ovarian tissue cryopreservation [44].

When adjuvant chemotherapy is indicated in HR+ HER2-negative early breast cancer, taxane is mostly added to anthracycline-based regimen based on scientific data. However, patients who cannot receive taxane due to risks of allergic reactions or peripheral neuropathy, CMF can be

Adjuvant Systemic Treatment in Hormone Receptor Positive, HER2 Negative Breast Cancer

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Dose-dense chemotherapy plays a controversial role in the adjuvant treatment of breast cancer patients. Whereas meta-analyses persistently describe a significant superiority for dose-dense treatment, the results of large phase III trials remain contradictory [47]. Some of these trials showed important differences between the dose-dense and conventional groups regarding number of cycles, type of drug, and total dose. Other trials are accepted and interpreted as dose-dense but present a mixture of dose-dense and conventional

Goldvaser et al. performed a systemic review and meta-analysis of clinical trials in which patients with early stage breast cancer were treated with adjuvant dose-dense chemotherapy [48]. Dose-dense treatment significantly improved DFS (HR 0.85, P < 0.001) and OS (HR 0.86, P = 0.008). A significantly greater relative magnitude of benefit was observed in premenopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the

Although a direct head-to-head comparison is missing, intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddETC) or four cycles each of dose-dense epirubicin/cyclophosphamide followed by paclitaxel are the preferred adjuvant regimens for patients at risk.

However, in EBCTCG meta-analyses, information was lacking about tumor gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosen-

Estrogen receptor expression is the main indicator of potential responses to endocrine therapy (ET) which block estrogen-driven tumor growth through a variety of mechanisms. The use of hormonal therapy in breast cancer has improved the overall outcome for patients with earlystage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hor-

Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor

Patients with four positive lymph nodes should preferentially be treated with iddETC.

administered instead of anthracycline or taxane- based regimens.

inferiority of paclitaxel every 3 weeks as a control group.

modulators (SERMs) and down-regulators, and (iii) AIs.

schedules.

sitivity, or both.

mone therapy.

4. Adjuvant endocrine therapy
