San Antonio Breast Cancer Symposium is here, and this year, OFTIM (Oncology for the Inquisitive Mind) is bringing you the latest and greatest in all things breast cancer. With over 10000 attendees, the research and vibrant discussions did not disappoint, with updates, controversies and complexities. Taking centre stage were PIK3CA mutation treatments, updates on CDK4/6 inhibitors and the age-old question - does exercise improve outcomes for our patients?

Today, OFTIM celebrates its 80th episode and presents its ESMO23 plenary session, including two practice-changing, paradigm-shifting trials. The first investigates the EGFR mutation Non-Small Cell Lung Cancer world with new drugs (amivantamab and lazertinib) to treat patients hose who progressed on osimertinib. The second trial is the EV-302/KEYNOTE-A39, which explores whether enfortumab vedotin (ADC) and pembrolizumab (immunotherapy) can best-platinum-based chemotherapy. No prior trial has ever done this, so the stakes are high. As the little engine once said, "I think I can", and, we, too, continue to see seismic shifts in cancer treatment in our quest for better therapy. For now, the OFTIM team is signing out and taking a small break after daily reporting, but we hope you loved it and can't wait to return with more from the fascinating world of Medical Oncology.

As Oncology for the Inquisitive Mind's coverage of ESMO 2023 winds down, we bring some of the best presentations covering gynaecological cancer. An area of oncology that in many cases remains mired in the pre-immunotherapy and pre-targeted therapy ages, ESMO brought some much-needed positive trials in the areas of cervical cancer, as well as an interesting (albeit negative) study of the PARP-inhibitor olaparib that highlights some of the more practical challenges of running an international phase 3 study. As always, outcomes can improve, but progress in this critical area is always welcome.

Since the early development of immunotherapy, metastatic melanoma has been the golden child of medical oncology. In recent years, similar outcomes have been seen with immunotherapy in non-melanomatous skin cancers. Cemiplimab is now a standard of care for patients with locally advanced, unresectable or metastatic cSCC, and is particularly effective in patients with cancer driven by UV-induced DNA damage. However, oncologists and researchers are always looking for new and better ways to use established treatments. At ESMO 2023 two papers took this approach; one examined moving immunotherapy to the neoadjuvant space, while another added a venerable EGFR inhibitor to treatment of advanced cSCC. However, the undoubted star of this show is the long-term results of tebentafusp, the first efficacious treatment of a subtype of the notorious uveal melanoma. ESMO 2023 truly had something for everyone, and the melanoma and skin cancer areas were no exception.

Non-small cell lung cancer continues to show massive promise with new trials, better designs and exciting utilisation of existing therapies. Michael and Josh explore immunotherapy in a "sandwich setting" where nivolumab is given before and after surgery. Datopotamab deruxtecan, the new kid on the block, takes on the second-line champion docetaxel. Who will win, and will docetaxel finally be dethroned? And potentially the most promising and exciting addition to this lineup is AZD7789, a new bispecific antibody TIM-3 being added to existing immunotherapy to try and resensitise cancer to PD-1 inhibitors!

Metastatic colorectal cancer has an average overall survival of three years. With limited treatment options as standard of care or effective targetable mutations, ESMO23 shined, providing answers to unanswered questions and a potentially brighter future for this cancer. Concerningly, we are seeing higher rates of colorectal cancer in lower and middle-income countries and those under the age of 50. We explore sotorasib in KRASG12C mutated cancers with panitumumab, the use of aspirin to reduce the risk of cancer recurrence and whether triplet therapy is better than double in potentially resectable colorectal cancer.

Colorectal cancer remains the bread and butter of many an oncologist, but its commonality belies its complexity. In early and advanced disease alike, there remain many permutations, considerations and controversies regarding optimal treatment. What is the best way to treat potentially-resectable colorectal cancer with liver metastases (CRLM)? Is there a way to increase the responsiveness to immunotherapy in patients with proficient mismatch repair (pMMR)? And are we moving to a brighter future where patients with deficient MMR colorectal cancer could avoid surgical management through the miracle of immunotherapy? Ultimately, no one study is going to answer these questions, but with ESMO 2023, we may be starting to peel back the layers of this onion.

Next up on the ESMO 2023 rollercoaster is an episode that is likely to be the shortest in our series: upper gastrointestinal and hepatobiliary oncology. As always, this remains a very challenging subarea of medical oncology, both in the clinical and trial spheres. However, our esteemed colleagues at ESMO remain undaunted by this challenge, and thus several studies of interest bear discussing. Will any of these studies lead to massive upheavals for clinicians and patients alike? For that answer, you'll have to listen on.

Genitourinary cancers come in all shapes and sizes, and this year, ESMO2023 takes the research up a notch. Prostate cancer is centre stage, and you might ask why, as it boasts extraordinary overall survival and progression-free survival. The issue lies in the sequencing of therapies and how to make treatment durable and better tolerated for all. Third, immunotherapy is not ready for primetime in this cohort of patients, and the reasons are unclear. Not to be outdone, bladder cancer continues to make strides in patient care with a phase 1 study that may be lost in no-man land or could harbour a shift in trial design with antibody-drug conjugates. Today, we discuss the following trials:

Welcome back to Oncology for the Inquisitive Mind's ongoing coverage of ESMO 2023. In the spirit of a worldwide oncology conference, here we present results from three very exciting trials in the early breast phase. Will immunotherapy begin to carve out a niche in early, high-risk, ER-positive breast cancer? Can atezolizumab demonstrate a benefit in early TNBC, and expand its own territory? Is abemaciclib pulling away from its rivals in the treatment of high-risk, ER-positive breast cancer? Will managing early breast cancer eventually have a similar success rate to the management of diabetes? And, most importantly, is Michelangelo a better Ninja Turtle than Donatello? The answers to all these questions, and more, lie within.

Every so often, an area of medical oncology has so many interesting presentations at a seminal conference that it becomes impossible to leave them out. At such times, Josh and Michael merely shrug their shoulders and say "why don't we do all of them." ESMO 2023 is one such instance. Despite their best efforts, our intrepid duo were unable to narrow down their presentation of early breast cancer highlights to one episode, so they are going to do two (for the price of one).

ESMO 2023 showcased several promising trials in the small-cell lung cancer space. A cancer that continues to send shivers down the spine of budding oncologists for decades. Today, we look at several different classes of drugs, the first being a novel immunotherapy agent, the second a well-known antibody-drug conjugate and the third a synthetic alkaloid analogue. Lurbinectedin and pembrolizumab, sacitizumab govitecan or toripalimab, while all difficult to say five times fast, may change the future of small cell lung cancer. Which is your drug of choice? Tune in to find out if you chose correctly!

Michael and Josh continue their examination of the crème-de-la-crème of the European Society of Medical Oncology conference of 2023. Today they focus on metastatic breast cancer, with a particular focus on antibody-drug conjugates (ADCs). T-Dxd, Dato-Dxd and trastuzumab duocarmazine are just three of the many novel agents in this space, and likely represent part of the future (and the present) of medical oncology. How effective are these treatments? Will the final results of the TULIP study blossom like its namesake? Will T-Dxd fulfil its DESTINY and become a treatment option for HER-2 low advanced breast cancer? Will Dato-Dxd assist in making cancer BEGON(IA)? For more excellent puns and the answers to these questions and more, listen on!

Another year, another international oncology conference in a beautiful European locale. In 2023, the world's oncology community has descended on the Spanish capital Madrid to discuss the latest and greatest scientific developments in Medical Oncology. And as always seems to be the case, Michael and Josh remain at home listening to this avalanche of information virtually. Despite a distinct lack of sun and Español, our intrepid duo will continue a grand tradition that dates back to 2022: bringing some of the best highlights from Madrid directly to your ears across a series of episodes to be released this week.

In the first episode of this series, Josh and Michael start in the most difficult of tumour streams: CNS oncology, an area where outcomes continue to be incredibly poor. ESMO 2023 brought some very interesting early-phase trials and no small amount of controversy, but that silver bullet unfortunately continues to elude oncology's brightest minds. Listen on to find out more.

Cisplatin is the mainstay for concurrent chemoradiotherapy in Locally Advanced Head and Neck Cancers. What happens to that significant group of patients who cannot have cisplatin? Michael and Josh focus on this challenging subgroup of patients. Can docetaxel be used as an alternative? This week, they debut a small but significant segment of our humble podcast called "Spotlight", where we dive deep into a single potentially practice-changing trial. Enjoy!

Gynaecological malignancies are a diverse group of terrible malignancies. From ovarian to endometrial to cervical, these cancers are notorious not just for their mortality burden, but the significant morbidity that they can inflict. To explore how to combat these challenging clinical entities, Michael and Josh interview Dr Vish Boolell, a clinical oncologist who brings his vast practical and trial experience to bear in exploring how to best treat patients and manage the myriad challenges gynaecological cancer can present. Today's episode is a must-listen for anyone who has been confronted by a malignant bowel obstruction, or wondered about the significance of dMMR in endometrial cancer, or who simply want some practical tips about how to best help their gynae onc patients.

It is frequently said that it takes a village to treat a patient with cancer. However, beyond the nuts and bolts of medical and allied health treatment, there exists a whole other world of advocacy and education. Charitable and not-for-profit foundations, both nationally and internationally, have done incredible work for many years in raising awareness and funding for cancer treatment and prevention, as well as providing both patient- and doctor-centred education. Oncology for the Inquisitive Mind is incredibly privileged to welcome the CEO of one such organisation, Meredith Cummins of Neuroendocrine Cancer Australia. Meredith brings decades of experience in oncology nursing, governance, fundraising and advocacy, and has done invaluable work in shining a light on the lesser-known challenges facing patients and doctors dealing with neuroendocrine cancers

"I have not failed, I've just found 10,000 ways that won't work!" so said Thomas Edison in describing his journey to the incandescent light bulb. This quote seemed appropriate as Michael and Josh conclude their journey in the neuroendocrine space and discuss neuroendocrine carcinomas (and poorly differentiated metastatic neuroendocrine tumours). Sometimes, when you are working in the oncological world, we all feel a bit like Thomas Edison, pouring sweat and tears into research that doesn't live up to expectations. But much like Thomas Edison, each step in this journey could revolutionise humanity or oncology, much like the CDK4/6 inhibitors, immunotherapy or tyrosine kinase inhibitors.

But we aren't there yet. This week, Michael discusses the immunotherapy agent (Spartalizumab) while Josh goes old-school and discusses the TOPIC-NEC Japanese trial comparing etoposide and cisplatin (EP) to irinotecan and cisplatin (IP). Michael and Josh smell small cell similarities coming aboard the neuroendocrine express!

Neuroendocrine Tumours could be described as an impassable obstacle, more complicated the more you research. That's where Michael and Josh come in, and this week, explore Grade 3 metastatic neuroendocrine tumours. Michael provides a brilliant overview of this well-differentiated cohort and the lack of efficacy platinum chemotherapies have, while Josh discusses CAPTEM (temozolomide and capecitabine) through a systematic review. Interestingly many of the current data is retrospectively collected, highlighting how challenging it is to collect enough patients to pursue meaningful research.

Note- there is a quote from Lance Armstrong, who was stripped of his titles due to illegal doping (which we do not endorse); he did start the Livestrong Foundation to support those affected by cancer.

"We go to the moon and other places not because they are easy, but because they are hard." So spoke US President John F. Kennedy, in a speech that galvanised the American public and fostered widespread support for the space race and the Apollo space program that would culminate in Neil Armstrong and Buzz Aldrin landing on the Moon on July 20, 1969. A similar approach must be taken to the treatment of neuroendocrine tumours, a rare and difficult-to-treat cancer type requiring inventiveness, preparation and lateral thinking (almost) on the level of the Apollo and Soyuz astronauts.

Last week, Michael and Josh discussed the front-line treatment of low-grade, well-differentiated neuroendocrine tumours. However, it always pays to be prepared. To that end, today our intrepid "onconauts" explore the lesser-known frontiers of later options, focussing on the competing everolimus and sunitinib. Will one option triumph over the other and reach the surface of the tumour first? Listen on to find out.