The PALLAS Clinical Trial

The PALLAS clinical trial has provided a wealth of material for future research into early-stage breast cancer.

The PALLAS trial studied the effects of adding a two-year course of palbociclib, a cell cycle inhibitor, to standard hormone-blocking treatment for patients with hormone-receptor-positive, HER2-negative early breast cancer.

PALLAS was an international clinical trial that recruited 5,795 patients worldwide, including more than 430 patients from Australia.

Researchers had hoped that palbociclib, currently used in patients with metastatic breast cancer to prolong the duration of cancer control and delay the need for chemotherapy, might reduce the risk of metastatic recurrence in patients with earlier stages of breast cancer.

“We were aiming to find patients who stood to gain the most from the study drug, based on their higher risk of recurrence,” says Dr Nicholas Zdenkowski, the Breast Cancer Trials Study Chair of the PALLAS clinical trial.

“All patients received standard hormone-blocking treatment and half received the additional palbociclib.

They had also received chemotherapy and radiotherapy if their treating doctor considered those treatments appropriate.”

However, interim results showed palbociclib wasn’t working in this setting, he says. “Over time, it was seen there was no difference between the groups, so the study drug was stopped in those who were still taking it as part of their planned two-year course.”

He’s not disheartened, though. “You read the headline, and you think it’s disappointing,” says Dr Zdenkowski. “But these large trials are always designed so we learn things, and we’ll continue to learn as we follow these patients up. We know recurrences can occur years down the track, and a difference may emerge over time between the two study groups.”

During the trial, researchers gathered a bio-bank of tissue samples from patients’ surgeries for analysis, along with blood samples over the course of their participation.

“That will provide some powerful information about the potential for some patients to benefit from palbociclib, about possible resistance mechanisms, and a range of other useful data,” says Dr Zdenkowski.

Data from ongoing patient questionnaires is also expected to provide insights into the patients’ perspectives on endocrine therapy and palbociclib, as well as their experience with breast cancer.

So, although this particular use of palbociclib has not been proven effective, its current use in patients with metastatic breast cancer will continue, and so will the research, says Dr Zdenkowski. “We’re not able to rest until all people have been cured of their cancer.” [ends]

Publication:

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

Mayer EL, Dueck AC, Martin M, Rubovsky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, PFeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Puyana Theall K, Ray Lu D, Huang Bartlett C, Koehler M, Fesl C, DeMichele A, Gnant M. Lancet Oncology. 2021; epub 15 January 2021; https://doi.org/10.1016/S1470-2045(20)30642-2.

IBIS II Clinical Trial Sub-Study

Doctors can now partly allay women’s concerns about bone density loss when taking breast cancer prevention drugs.

Women at high risk of developing breast cancer may benefit from the hormone therapy anastrozole, which has been shown by the International Breast Cancer Intervention Study (IBIS-II) to help prevent the disease.

However, one of anastrozole’s side effects is reduced bone density – which can have serious consequences.

“Bone density loss puts people at risk of breaking bones,” says Dr Nicholas Zdenkowski, Medical Advisor at Breast Cancer Trials, which co-led the study. “It might be 10 or 20 years’ time before they break their hip or have a compression fracture in their spine.” Such injuries can lead to chronic pain or kickstart a decline in health.

Because of this, the IBIS-II clinical trial included a sub-study on bone density in 1,410 postmenopausal women in Australia and New Zealand, who are more at risk of developing osteopenia and osteoporosis.

Patients were given anastrozole for five years, then the study tracked bone density between years five and seven. By year seven, bone density had improved by 1.25% in the lumbar spine.

This means when women stop taking anastrozole, bone density loss caused by the drug can be partially reversed. (It did not, however, improve at the hip.)

It’s a positive result, says Dr Zdenkowski. “This means we can reassure women that even if bone density does decline, it is expected to improve again after they stop anastrozole.”

Doctors now have more information to help patients weigh up the benefits and risks of taking anastrozole. As a safe medication that reduces the chance of breast cancer in high-risk women, it has some advantages over tamoxifen, as an alternative. But women can be reluctant to take it due to a potential reduction in bone density, particularly if they have low bone density, previous fractures or a family history of osteoporosis.

This research, says Dr Zdenkowski, “may mean there are more women willing to take anastrozole, because we now know their bone density does stabilise after they stop taking it.”

The study also showed risedronate, a bone-strengthening drug, can increase bone density after patients stop anastrozole.

The next step, says Dr Zdenkowski, is to study who is most likely to benefit from being on anastrozole in this setting. Anastrozole is not yet registered or covered by the PBS in Australia as a prevention medication. It is widely used for the treatment of early stage and metastatic breast cancer.

Publication:

Sestak I, Blake G, Patel R, Cuzick J, Howell A, Coleman R, Eastell R. Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial. British Journal of Cancer 2021; epub 22 January 2021. https://doi.org/10.1038/s41416-020-01228-2.

IBCSG VIII and IX Clinical Trial DNA Follow Up

Researchers are improving and refining breast cancer treatments by delving into the DNA of patients who have previously volunteered for breast cancer clinical trials.

“We already have the ability to distinguish between different levels of ‘severity’ of breast cancer, but we need to develop this further,” says Dr Nicholas Zdenkowski, Medical Advisor at Breast Cancer Trials.

While breast cancer treatments can already be targeted and personalised, Dr Zdenkowski says new and highly accurate tools could help determine which triple negative breast cancer patients can be cured with surgery alone. Triple negative breast cancer accounts for 15 per cent of all breast cancers.

“The standard approach is to offer women with the triple negative subtype of early stage breast cancer a fairly intensive treatment with chemotherapy, because there are no sufficiently accurate tests to determine which patients definitely don’t need any further treatment beyond surgery,” he says.

“Many patients worry that triple negative breast cancer has a worse prognosis than other breast cancer types, however, this is not always the case.”

Breast Cancer Trials provided data from previous trials called IBCSG VIII and IX, which had enrolled 228 and 330 patients respectively, towards the development of molecular tools to predict the recurrence of breast cancer after chemotherapy treatment.

The lab-based analysis looked at specific DNA methylation markers, or profiles, in the genes of breast cancers that had been surgically removed from patients. The study was centred around blood and tumour specimens held from clinical trials between 1985 and 2009.

The methylation markers helped categorise the early-stage triple negative patients into three groups: those who were cured with surgery to remove the cancer and so didn’t need further treatment; those who needed chemotherapy to prevent the cancer from returning after treatment; and those for whom chemotherapy was not effective, where the cancer came back elsewhere in their body despite that treatment.

However, Dr Zdenkowski says this test method needs further research before it can be considered for routine use in the clinic.

“As with any new test or treatment, the method requires rigorous evaluation to ensure it does what it promises to,” he says.

The use of well-collected and ‘clean’ clinical trial data in this way also illustrates the value in continuing to study and learn from patients who volunteered for previous trials.

“Ultimately, from this research, we hope to be able to reassure some patients that they can be cured with surgery alone,” Dr Zdenkowski says.

“We can also reassure others they will be cured with chemotherapy.”

“The third group, whose cancer will return even with surgery and chemotherapy, is the group in need of better treatments that we hope to find through ongoing research – so we can give them the best chance of being cured of cancer.”

Publication:

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.
Fackler MJ, Cho S, Cope L, Gabrielson E, Visvanathan K, Wilsbach K, Meir-Levi D, Lynch C.F., Marks J, Geradts J, Regan MM, Viale G, Wolff AC, Sukumar S, Umbricht CB. npj Breast Cancer 2020; 6Article No. 3;, https://doi.org/10.1038/s41523-020-0145-3.

Chemotherapy and BMI: BIG 2-98 Clinical Trial Follow-Up

The role of obesity as a risk factor is a common theme in breast cancer research. That’s not about to change anytime soon.

“In Western society there are more and more women who are overweight and, because being overweight increases your risk of getting breast cancer after menopause, we certainly see this in our clinic,” says Associate Professor Prue Francis, Chair of the Breast Cancer Trials Scientific Advisory Committee.

Some lipophilic, or fat-soluble, drugs are known to act differently in someone who has a high versus a low body mass index (BMI). What hasn’t been studied systematically is the relationship between the efficacy of anticancer drugs and BMI.

To learn more, researchers reanalysed data from the BIG 2-98 trial that included approximately 600 women enrolled by Breast Cancer Trials, some of whom were randomised to receive the lipophilic chemotherapy drug docetaxel as part of treatment.

They found that among the women who received docetaxel, those in the overweight or obese BMI categories had a lower chance of remaining disease-free or surviving compared to women with a lean BMI, despite receiving the same treatment.

“If you’re giving any drug that might have short-term but also longer-term side effects, the question is, are you getting the bang for your buck?” says Associate Professor Francis, who was one of the researchers in the study.

Docetaxel and other drugs of the same family (taxanes) can cause nerve damage, and occasionally permanent hair loss. The risk of experiencing such side effects must be balanced with the benefit an individual patient might receive.

Associate Professor Francis says that chemotherapy for obese patients should not change based on these results, but more research is needed. If the results of this study are confirmed in other studies, this could lead to a rethinking of treatment risks and benefits for these patients.

“If the taxane drugs were thought not to be working or distributed properly in the body of obese patients [we could consider] whether a modification of the dose would be appropriate or whether it’s just not worth adding those drugs,” she explains.

“If an obese patient may not be deriving so much benefit from that particular drug, maybe you could give a different drug, or stop it earlier if nerve damage symptoms are developing.”

Publication:

Differential benefit of adjuvant docetaxel-based chemotherapy in patients with early breast cancer according to baseline body mass index.
Desmedt C, Fornili M, Clatot F, Demicheli R, De Bortoli D, Di Leo A, Viale G, de Azambuja E, Crown J, Francis PA, Sotiriou C, Piccart M, Biganzoli E. Journal of Clinical Oncology. 2020; 38(25):2883-2891, epub 20/05/20 https://doi.org/10.1200/JCO.19.01771.

SOFT/TEXT Clinical Trial Follow-Up

Among premenopausal women with breast cancer, 80% have hormone-responsive breast cancer, where the hormone oestrogen can stimulate the growth of cancer cells.

To stop this from happening after the primary cancer has been removed, women may be treated with one or more drugs that either prevent the uptake of oestrogen by cells (oestrogen blockers like tamoxifen), switch off the production of oestrogen in the ovaries (ovarian function suppression), or block oestrogen production in body fat (aromatase inhibitors).

The SOFT and TEXT clinical trials investigated the effects of different treatment combinations in premenopausal women on survival and recurrence of cancer. Researchers also collected and analysed information about a common and distressing side effect of such treatments: sexual problems including low libido and difficulty becoming aroused.

The impact of treatment on sexual function can be so important for quality of life that it can affect adherence to treatment, says Associate Professor Prue Francis, Chair of the International Steering Committee responsible for the SOFT and TEXT clinical trials.

“Sometimes women just don’t want to take their treatment at all because they’re having problems and they just stop,” says Associate Professor Francis.

The researchers wanted to identify factors that, if present six months into the five-year treatment, predict whether a premenopausal woman will experience sexual difficulties later.

They found that women who reported vaginal dryness, sleep disturbance and bone or joint pain at the six-month mark were more likely to report sexual problems in the first two years.

Recognising these predictors in their patients may guide clinicians to ask about sexual problems, which patients may not otherwise bring up. These conversations might equip clinicians to take a more nuanced and individualised approach to treatment, she says.

Take, for example, a woman experiencing significant side effects from treatment with both aromatase inhibitor and ovarian suppression therapy. Clinicians might consider “the absolute benefit that they’re likely to obtain from having that more intense endocrine therapy,” says Associate Professor Francis.

“Should they really be encouraged to persevere because they have a very high-risk breast cancer and therefore they’re likely to derive more of a differential benefit from that maximal endocrine therapy? Or might their breast cancer not be at such high risk for recurrence, and perhaps it would be reasonable then to dial back to a less intense endocrine approach?”

Publication:

Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal women with early breast cancer receiving adjuvant endocrine therapy.

Ribi K, Luo W, Walley BA, Burstein HJ, Chirgwin J, Ansari RH, Salim M, van der Westhuizen A, Abdi E, Francis PA, Chia S, Harvey VJ, Giobbie-Hurder A, Fleming GF, Pagani O, Di Leo A, Colleoni M, Gelber RD, Goldhirsch A, Coates AS, Regan MM, Bernhard J. Breast Cancer Research and Treatment. 2020; 181(2):347-359, epub 09/04/20 doi.org/10.1007/s10549-020-05622-5.

The SEGMENT Study

Metastatic (stage 4) breast cancer is incurable, but a new study suggests that genomic profiling could lead to better treatment options for patients.

The SEGMENT study examined the feasibility of characterising genomic alterations using gene sequencing on tumour specimens from patients with breast cancer.

The study found that genomic sequencing for the management of metastatic breast cancer is both feasible and has implications for clinical practice, particularly for patients who are able to participate in clinical trials of newer treatments.

The project, which was spearheaded by Professor Sherene Loi at the Peter MacCallum Cancer Centre, received funding from Breast Cancer Trials.

“Patients with metastatic breast cancer are looking for anything that can give them hope,” says medical oncologist Dr Peter Savas, Dr Loi’s colleague at the Peter MacCallum Cancer Centre. “SEGMENT was about trying to use what was at the time quite a new technology, and bring it into the clinic to see if we could use that to give patients more options.”

The development of Herceptin – a drug that targets overactivity of the HER-2 gene in one of the more aggressive types of breast cancer – in the 1990s, opened the door to better-targeted therapies.

“Now, the prognosis of that cancer is significantly better,” Dr Savas says. “That’s a really good example of the proof of principle that tailoring treatments to specific features in the cancer can be very fruitful. The next logical question is, can we take that approach and make it more broadly applicable to patients with metastatic breast cancer?”

Meanwhile, sequencing technologies – relatively rare when SEGMENT began in 2013 – have become cheaper and more accurate, making profiling of metastatic breast cancer more available.

One barrier to that, Dr Savas says, is a lack of awareness among oncologists and patients. “But that’s improving over time, and the pairing of genomic findings with treatments will become more widespread.”

Launched in 2019, the drug alpelisib is one example of this. It specifically targets the PIK3CA mutation, which is common in many patients with hormone receptor positive breast cancer, Dr Savas says. “Following that, there’s a long tail of rarer alterations,” he adds.

“SEGMENT is a big study, but it doesn’t have enough patients to understand the importance of rarer alterations. But by putting it together with other datasets, we can get a better idea of the changes and their significance.”

Publication:

Clinical implications of prospective genomic profiling of metastatic breast cancer patients.
van Geelen CT, Savas P, Teo ZL, Luen SJ, Weng C-F, Ko Y-A, Kuykhoven KS, Caramia F, Salgado R, Francis PA, Dawson S-J, Fox SB, Fellowes A, Loi S. Breast Cancer Research. 2020; 22:91:https://doi.org/10.1186/s13058-020-01328-0.

Preventing The Side Effects Of Preventative Treatment

The saying ‘prevention is better than a cure’ is especially apparent when it comes to disease. But, while breast cancer prevention remains crucial, the side effects of individual treatment plans also need to be considered.

Anastrozole is a drug that is used to either prevent or control breast cancer. It’s a tablet that works by blocking the body’s production of oestrogen in postmenopausal women. It’s taken to prevent cancer recurrence, or control cancer that has spread to other parts of the body. It also reduces the chance of breast cancer in women with a higher risk of developing the disease by 50 per cent.

“So, why don’t we just give this drug to all women? Because of its potential side effects,” says Dr Nicholas Zdenkowski, Medical Advisor at Breast Cancer Trials.

He says a relatively common effect is one that would likely go unnoticed initially: bone density loss.

“This won’t be obvious until you end up with a bone fracture or see a decline in bone density on a scan,” he says.

Dr Zdenkowski was the Australian clinical lead on an international study to see if the drug risedronate could prevent anastrozole-induced bone loss.

The trial was co-led by Breast Cancer Trials and was a sub-study of the 4,000 post-menopausal high-risk patients already on the IBIS-II clinical trial that showed that anastrozole could prevent breast cancer.

This bone sub-study involved 258 of the 1,410 patients (229 from Australia and New Zealand) who enrolled in the bone study within IBIS-II. It found risedronate did indeed slow down anastrozole-induced bone loss – but couldn’t completely prevent it. While the drug stabilised loss in the lumbar spine, the hip still deteriorated.

“The options for breast cancer prevention include anastrozole, exemestane and tamoxifen, but they all come with their own set of potential side effects,” Dr Zdenkowski says.

“While bone density is something that naturally declines slowly over time, unfortunately anastrozole adds to that decline.”

He says more options are needed for patients on breast cancer prevention drugs.

Dr Zdenkowski suggests patients have their bone density monitored regularly so that osteoporotic changes are identified and treated accordingly, before the stage where they are at significantly higher risk of hip or spine fractures.

He said overall, the lessons learned from the risedronate trials tie into important decisions around preventative treatment plans. This includes, for patients with a high risk of breast cancer combined with a high risk of bone loss, whether to put them onto alternative treatments to counter the development of osteoporosis.

“There is obviously more work to be done on the prevention of breast cancer,” Dr Zdenkowski says. “The more we know, the more this helps with clinical decisions around the risk vs benefit of treatment recommendations.”

Publication:

Comparison of risedronate versus placebo in preventing anastrozole-induced bone loss in women at high risk of developing breast cancer with osteopenia. Sestak I, Blake GM, Patel R, Colemen RE, Cuzick J, Eastell R. Bone. 2019; 124:83-88, https://doi.org/10.1016/j.bone.2019.04.016.