This series on Early Breast Cancer covers a multi-faceted approach involving experts from medical, surgical, and radiation oncology, and radiology, discussing the latest in treatment from their respective fields. In this part, Dr. Vishwanath reviews recent trials in EBC which have led to improvement in disease-free survival.

Personalised approach using several predictive and prognostic factors is the key in decision making. Widespread use of adjuvant chemotherapy, targeted therapy and endocrine therapy has reduced the mortality from breast cancer worldwide. The use of dose-dense chemotherapy has also been a recent development to improve outcome in EBC. Several trial results have been published in the last couple of years which are practice changing and have translated to improvement in outcome. The practice changing trials have been in all subsets (HR+, Her2+ and triple negative subset). Following are a few salient trials which are discussed.

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HR+/Her2 negative EBC: TAILORx study

The controversy of endocrine therapy vs. chemo-endocrine therapy in HR+ EBC was finally addressed in the TAILORx study. We know from the genomic recurrence score (21-gene breast cancer assay) that patients with high recurrence score benefit from chemotherapy followed by endocrine therapy and patients with low recurrence score may be managed with endocrine therapy alone. However, there has been a dilemma in patients with mid-range score. This was addressed in a large prospective trial involving over 10000 women with hormone-receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative early breast cancer. 6711 had midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemo-endocrine therapy or endocrine therapy alone. The trial looked at the noninferiority of endocrine therapy alone for invasive disease–free survival in this subset of patients.

Endocrine therapy was found to be noninferior to chemo-endocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemo-endocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26).

At 9 years, the invasive disease–free survival was 83.3% and 84.3% and overall survival 93.9% and 93.8% in the endocrine-therapy group and in the chemo-endocrine-therapy group respectively. However, the chemotherapy benefit was found in women 50 years of age or younger with a recurrence score of 16 to 25. So, these results are definitely practice changing in HR+, Her2- EBC and avoiding chemotherapy in patients with mid-range score does not lead to inferior outcome.

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GS3-03 and LEAD study

It is clear from various studies that the risk of late recurrences in HR+/Her2- EBC especially after 5 years is known. Two trials, GS3-03 and the LEAD study looked at the effect of extended aromatase inhibitors (AI) therapy. The GS3-03 trial looked at the effect of prolonging adjuvant AI beyond five years in HR+, Her2- EBC. This was an EBCTCG meta-analysis from ~25000 women with EBC, HR+, Her2-.

Findings: The authors concluded that extended therapy with AI benefited and the benefit was marked in those where AI was preceded by tamoxifen. The improvement in DFS was to the tune of 7.5% with 10 Vs. 5 years of AIs. This reinforces our stand on giving extended AIs to these subset of patients.

In the LEAD study, which was presented at the ASCO 2019, patients with HR+ EBC were evaluated to analyse the benefit of extended therapy with letrozole in women who received letrozole as part of their initial 5 yrs. of endocrine therapy. Post-menopausal women with ER+ and/or PgR+ stage I-III early BC (T1-3, N0-N+) received adjuvant tamoxifen for 2-3 years with an ECOG PS 0/1 were included. Patients with T4 or inflammatory BC, distant metastases, or disease recurrence were excluded. A total of 2056 patients was included in the study. Patients were randomised to receive 5 years of extended Letrozole up to 7-8 years of treatment or 2-3 years of Letrozole up to 5 years of treatment. The primary endpoint was iDFS and the secondary endpoints was OS and safety.

Findings: Following 2-3 years of tamoxifen treatment, extended adjuvant treatment with letrozole for 5 years vs 2-3 years led to a 19% reduction of invasive DFS events in patients with HR+ early breast cancer with a hazard ratio of 0.81; 95% CI: 0.65-1.00; P = .051. Moreover, extended letrozole in this setting did not result in significant improvement of OS (HR: 0.86; 0.63-1.18; P = .357). The authors concluded that 2-3 years of tamoxifen followed by 5-6 years of aromatase inhibitor therapy is a potential treatment strategy for patients with a history of breast cancer who are at risk of disease recurrence.

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Neoadjuvant CDK 4/6 inhibitors with AI in the neoadjuvant setting for EBC

The recent phase II NEOPAL trial which compared neoadjuvant chemotherapy to endocrine therapy plus palbociclib in 106 early-stage HER2-negative/luminal patients with EBC, showed that the response rates and breast conservation rates were comparable. Impressive results were also obtained in the NeoMonarch trial which evaluated abemaciclib as neoadjuvant treatment for early-stage HR-positive/HER2-negative BC.

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Her2 positive EBC: HERA trial and PERSEPHONE study

Various trials like the HERA have shown that one year of adjuvant trastuzumab is the optimum. However, there has been a huge interest over the years to consider de-escalation of Her2 therapy from 1 year to 6 months. The PERSEPHONE study specifically looked at 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer.

This was an open-label, randomised phase 3 non-inferiority trial which randomly assigned patients with HER2-positive early breast cancer to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously given in combination with chemotherapy. The primary endpoint was disease-free survival, with a non-inferiority margin of 3% for 4-year disease-free survival. Between 2007 and 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment.

Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups and the 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer severe adverse events 19% vs 24%, p=0·0002 and fewer cardiotoxicity 3% Vs. 8%p<0·0001 leading to discontinuation. Patients who were ER+, those who received anthracyclines and who received trastuzumab sequentially benefited with the 6 months of trastuzumab. This trial showed that shorter course of trastuzumab was well tolerated and lead to similar outcome in select patients with Her2 + EBC.

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APHINITY trial

Recently, researchers have also looked at the efficacy of other Her2 targeted therapies like pertuzumab and TDM1 which have shown impressive results in the metastatic breast cancer setting. In the APHINITY trial, it was investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. Node-positive or high-risk node-negative HER2-positive, operable breast cancer were randomised to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and one-third had hormone-receptor–negative disease.

1. The estimates of the 3-year rates of invasive-disease–free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group.
2. In the node-positive subset, the 3-year rate of invasive-disease–free survival was 92.0% in the pertuzumab group and 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02).
3. In the node-negative subset, the 3-year rate of invasive-disease–free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64).
4. Cardiac toxicity were uncommon in both treatment groups. Diarrhoea of grade 3 or higher was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).

Pertuzumab significantly improved the rates of invasive-disease–free survival among patients with HER2-positive, EBC when it was added to trastuzumab and chemotherapy. Diarrhoea was more common with pertuzumab than with placebo.

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KATHERINE trial

The role of adjuvant TDM1 was defined in the KATHERINE TRIAL. It was a phase III study of trastuzumab emtansine Vs. trastuzumab as adjuvant therapy in patients with Her2 positive EBC with residual invasive disease after neo-adjuvant chemotherapy. Patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab were randomised to either adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease–free survival.

1. Out of the ~1500 randomised patients, the estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group.
2. Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (HR 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001).
3. Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group.
4. Though more adverse events were seen in the T-DM1 arm than the trastuzumab, it was well tolerated.
5. Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone.

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Prevention of cardiotoxicity in patients receiving adjuvant Trastuzumab

With the existing one year of trastuzumab adjuvant therapy, there is always the concern of cardiotoxicity. In this context, there was a randomised community based trial of lisinopril or carvedilol for the prevention of cardiotoxicity in patients with Her2+ EBC receiving adjuvant trastuzumab: This trial showed that prophylactic use of beta blockers or ACEi in these subset of patients receiving trastuzumab and anthracyclines reduced the cardiotoxicity and allowed safe delivery of trastuzumab and anthracycline based chemotherapy.

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Triple Negative Breast Cancer (TNBC): CREATE-X trial

Triple negative breast cancer has always been a challenge for clinicians even if diagnosed early. Moreover, post neoadjuvant chemotherapy, those with residual invasive disease in HER2–negative breast cancer portend to have a poor prognoses. The role of adjuvant chemotherapy in these patients has always been questionable. We also know from previous studies published in literature that those not achieving pathological complete response after neo adjuvant chemotherapy have a high risk of relapse.

Capecitabine is an oral chemotherapeutic drug which is used in several cancers with good benefit. In the CREATE-X trial, over 900 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy with anthracycline, taxane, or both), were randomised to post-surgical capecitabine very 3 weeks for six or eight cycles or without (control). 32.2% were triple negative. The primary end point was disease-free survival and secondary end points included overall survival.

1. The disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01).
2. Overall survival was also better in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01).
3. Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90).
4. Though adverse effects were more common in the capecitabine group, it was not severe and overall was well tolerated.

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This article is part of a early breast cancer management series. To read the other articles, click below.

Surgical options to consider for early breast cancer: Dr. Anil Kamath

Imaging modalities for Stage 0 and Stage 1 early breast cancer: Dr. Govindarajan MJ

'Radiotherapy in early breast cancer: How much is too much?'- Dr. Bindu Venugopal

The author, Dr. Vishwanath Sathyanarayanan is a Medical Oncologist at Apollo Hospital, Bengaluru.